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Background: Carbohydrate restriction shows promise for diabetes, but concerns regarding high saturated fat content of low-carbohydrate diets limit widespread adoption., Objectives: This preplanned ancillary study aimed to determine how diets varying widely in carbohydrate and saturated fat affect cardiovascular disease (CVD) risk factors during weight-loss maintenance., Methods: After 10-14% weight loss on a run-in diet, 164 participants (70% female; BMI = 32.4 ± 4.8 kg/m2) were randomly assigned to 3 weight-loss maintenance diets for 20 wk. The prepared diets contained 20% protein and differed 3-fold in carbohydrate (Carb) and saturated fat as a proportion of energy (Low-Carb: 20% carbohydrate, 21% saturated fat; Moderate-Carb: 40%, 14%; High-Carb: 60%, 7%). Fasting plasma samples were collected prerandomization and at 20 wk. Lipoprotein insulin resistance (LPIR) score was calculated from triglyceride-rich, high-density, and low-density lipoprotein particle (TRL-P, HDL-P, LDL-P) sizes and subfraction concentrations (large/very large TRL-P, large HDL-P, small LDL-P). Other outcomes included lipoprotein(a), triglycerides, HDL cholesterol, LDL cholesterol, adiponectin, and inflammatory markers. Repeated measures ANOVA was used for intention-to-treat analysis., Results: Retention was 90%. Mean change in LPIR (scale 0-100) differed by diet in a dose-dependent fashion: Low-Carb (-5.3; 95% CI: -9.2, -1.5), Moderate-Carb (-0.02; 95% CI: -4.1, 4.1), High-Carb (3.6; 95% CI: -0.6, 7.7), P = 0.009. Low-Carb also favorably affected lipoprotein(a) [-14.7% (95% CI: -19.5, -9.5), -2.1 (95% CI: -8.2, 4.3), and 0.2 (95% CI: -6.0, 6.8), respectively; P = 0.0005], triglycerides, HDL cholesterol, large/very large TRL-P, large HDL-P, and adiponectin. LDL cholesterol, LDL-P, and inflammatory markers did not differ by diet., Conclusions: A low-carbohydrate diet, high in saturated fat, improved insulin-resistant dyslipoproteinemia and lipoprotein(a), without adverse effect on LDL cholesterol. Carbohydrate restriction might lower CVD risk independently of body weight, a possibility that warrants study in major multicentered trials powered on hard outcomes. The registry is available through ClinicialTrials.gov: https://clinicaltrials.gov/ct2/show/NCT02068885., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Evidence is emerging that interdaily meal pattern variability potentially affects response such as thermic effect of food (TEF), macronutrient metabolism, and appetite., Objectives: To investigate the effect of irregular meal pattern on TEF, glucose, insulin, lipid profile, and appetite regulation in women who are overweight or with obesity and confirmed insulin resistance., Design: In a randomized crossover trial, 9 women [mean ± SD BMI (in kg/m2): 33.3 ± 3.1] with confirmed insulin resistance consumed a regular (14 d; 6 meals/d) and an irregular (14 d; 3-9 meals/d) meal pattern separated by a 14-d washout interval. Identical foods were provided during the interventions, and at the start and end of each meal pattern, participants attended the laboratory after an overnight fast. Energy expenditure, glucose, insulin, lipids, adiponectin, leptin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin were measured at baseline and for 3 h after consumption of a test drink, after which an ad libitum test meal was offered. Subjective appetite ratings were recorded before and after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 7 consecutive days during each intervention., Results: TEF (over 3 h) was significantly lower postirregular intervention compared with postregular (97.7 ± 19.2 kJ*3 h in postregular visit and 76.7 ± 35.2 kJ*3 h in postirregular visit, paired t test, P = 0.048). Differences in HOMA-IR between the 2 interventions (3.3 ± 1.7 and 3.6 ± 1.6 in postregular and postirregular meal pattern, respectively) were not significant. Net incremental AUC for GLP-1 concentrations (over 3 h) for the postregular meal pattern were higher (864.9 ± 456.1 pmol/L*3 h) than the postirregular meal pattern (487.6 ± 271.7 pmol/L*3 h, paired t test, P = 0.005)., Conclusions: Following a 14-d period of an irregular meal pattern, TEF was significantly less than following a regular meal pattern, potentially compromising weight management if sustained long term. This study was registered at www.clinicaltrials.gov as NCT02582606., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Altered meal-related gut hormone secretion seems important for weight loss and diabetes remission after Roux-en-Y gastric bypass (RYGB). Elucidating the responsible meal components and receptors could aid discovery of new treatments of obesity and diabetes. Enteroendocrine cells respond to digestion products of dietary triacylglycerol, especially long-chain fatty acids (LCFAs) and 2-oleoyl-glycerol (2-OG), but not medium-chain fatty acids (MCFAs)., Objective: We examined the impact of olive oil (20 mL) and its derivates, LCFAs and 2-OG, on enteroendocrine secretions [glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), peptide YY (PYY), and neurotensin (NT)] and on glucose, lipid, and bile acid metabolism in RYGB-operated and unoperated individuals., Methods: In an exploratory randomized crossover design, 10 RYGB-operated patients and 10 matched controls ingested 3 equimolar triacylglycerol formulations on separate days: olive oil (digested to 2-OG + LCFAs), C8-dietary oil (2-OG + MCFAs), and tricaprylin (MCFAs; negative control). Hormone responses were calculated as area under the curve (AUC)., Results: Independent of group status, olive oil had greater effects than C8-dietary oil on AUCs of plasma GLP-1 (+32%; 95% CI: 23%, 43%; P < 0.01), CCK (+53%, P < 0.01), and NT (+71%, P < 0.01), whereas the effect on GIP differed between groups (+90% in controls, P < 0.01; +24% in RYGB, P = 0.10). Independent of group status, C8-dietary oil had greater effects than tricaprylin on AUCs of plasma CCK (+40%, P < 0.01) and NT (+32%, P < 0.01), but not GLP-1 (+5%; 95% CI: -2.9%, 13%; P = 0.22), whereas the effect on GIP again differed between groups (+78% in controls, P < 0.01; +39% in RYGB, P = 0.01). Distal (GLP-1/PYY/NT), but not proximal (CCK/GIP), enteroendocrine responses were generally greater in RYGB patients than in controls., Conclusions: The combination of LCFAs plus 2-OG was substantially more effective than 2-OG plus MCFAs in stimulating enteroendocrine secretion in RYGB-operated and matched control individuals. Distal lipid-induced gut hormone release was greater after RYGB.This trial was registered at clinicaltrials.gov as NCT03223389., (Copyright © The Author(s) 2019.)

Background: Human milk oligosaccharides (HMOs) were recently found in serum of normal-weight pregnant women, with concentrations increasing from early to mid- and late pregnancy. Whether HMOs have effects on maternal metabolism is unknown., Objectives: We aimed to study the presence and changes in HMOs throughout pregnancy and assess associations with maternal glucose metabolism throughout pregnancy., Methods: The study was a prospective longitudinal cohort study including 87 overweight or obese women. Blood samples were taken at 15, 24, and 32 wk of pregnancy. In serum, 4 HMOs [2'-fucosyllactose (2'FL), lactodifucotetraose (LDFT), 3'-sialyllactose (3'SL), and 3'-sialyllactosamine (3'SLN)] were measured. In linear regression models, the associations between HMOs and (changes in) maternal metabolic parameters were assessed., Results: All 4 HMOs showed a significant increase from 15 to 32 weeks of gestation. 3'SL and 3'SLN, but not 2'FL or LDFT, at 15 wk were positively associated with (changes in) fasting glucose at 24 and 32 wk. LDFT was positively associated with (changes in) insulin and HOMA-index at 24 but not 32 wk. A model to predict the development of gestational diabetes mellitus (GDM) that included fasting glucose, prepregnancy BMI, gestational weight gain, age, parity, smoking, and history of macrosomia resulted in an area under the curve (AUC) of 0.81 (95% CI: 0.70, 0.92). Adding 3'SL to this model increased the AUC to 0.91 (95% CI: 0.84, 0.97)., Conclusions: The sialylated HMOs 3'SL and 3'SLN were associated with fasting glucose; LDFT was associated with fasting insulin and HOMA-index. Furthermore, 3'SL was more predictive of future GDM diagnoses than was fasting glucose in early pregnancy. Causal relations are unclear and need further investigation., (Copyright © American Society for Nutrition 2019.)

Background: Diet-induced weight loss (WL) is usually accompanied by increased appetite, a response that seems to be absent when ketogenic diets are used. It remains unknown if sex modulates the appetite suppressant effect of ketosis., Objective: The aim of this study was to examine if sex modulates the impact of WL-induced changes in appetite and if ketosis alters these responses., Methods: Ninety-five individuals (55 females) with obesity (BMI [kg/m 2]: 37  ± 4) underwent 8 wk of a very-low-energy diet, followed by 4 wk of refeeding and weight stabilization. Body composition, plasma concentration of β-hydroxybutyrate (β-HB) and appetite-related hormones (active ghrelin, active glucagon-like peptide 1 [GLP-1], total peptide YY [PYY], cholecystokinin and insulin), and subjective feelings of appetite were measured at baseline, week 9 in ketosis, and week 13 out of ketosis., Results: The mean WL at week 9 was 17% for males and 15% for females, which was maintained at week 13. Weight, fat, and fat-free mass loss were greater in males (P < 0.001 for all) and the increase in β-HB at week 9 higher in females (1.174 ± 0.096 compared with 0.783 ± 0.112 mmol/L, P = 0.029). Basal and postprandial GLP-1 and postprandial PYY (all P < 0.05) were significantly different for males and females. There were no significant sex × time interactions for any other appetite-related hormones or subjective feelings of appetite. At week 9, basal GLP-1 was decreased only in males (P < 0.001), whereas postprandial GLP-1 was increased only in females (P < 0.001). No significant changes in postprandial PYY were observed over time for either sex., Conclusions: Ketosis appears to have a greater beneficial impact on GLP-1 in females. However, sex does not seem to modulate the changes in the secretion of other appetite-related hormones, or subjective feelings of appetite, seen with WL, regardless of the ketotic state. This trial was registered at clinicaltrials.gov as NCT01834859., (Copyright © American Society for Nutrition 2019.)

Background: Obesity is closely associated with bone health. Although diet and weight loss produce many metabolic benefits, studies of weight loss diets on bone health are conflicting. Genetic variations, such as vitamin D levels, may partly account for these conflicting observations by regulating bone metabolism., Objective: We investigated whether the genetic variation associated with vitamin D concentration affected changes in bone mineral density (BMD) in response to a weight-loss diet intervention., Design: In the 2-y Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, BMD was measured for 424 participants who were randomly assigned to 1 of 4 diets varying in macronutrient intakes. A genetic risk score (GRS) was calculated based on 3 genetic variants [i.e., 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657 and group-specific component globulin (GC) rs2282679] related to circulating vitamin D levels. A dual-energy X-ray absorptiometry scan was performed to assess changes in whole-body BMD over 2 y. The final analysis included 370 participants at baseline., Results: We found a significant interaction between dietary fat intake and vitamin D GRS on 2-y changes in whole-body BMD (P-interaction = 0.02). In the high-fat diet group, participants with higher GRS showed significantly less reduction in whole-body BMD than those with lower GRS, whereas the genetic associations were not significant in the low-fat diet group. We also found a significant interaction between dietary fat intake and the GRS on 6-mo change in femur neck BMD (P-interaction = 0.02); however, the interaction became nonsignificant at 2 y., Conclusion: Our data indicate that dietary fat intake may modify the effect of vitamin D-related genetic variation on changes in BMD. Overweight or obese patients predisposed to sufficient vitamin D may benefit more in maintaining BMD along with weight loss by eating a low-fat diet. This trial was registered at clinicaltrials.gov as NCT03258203.

Background: The 2010 Dietary Guidelines for Americans (DGA) recommend nutrient needs be met by increasing fruit, vegetable, and whole-grain intake with the use of low-fat or fat-free dairy products and by reducing sodium, solid fats, and added sugars. However, the DGA, as a dietary pattern, have not been tested in an intervention trial., Objective: The aim of this study was to evaluate the impact of a DGA-based diet compared with a representative typical American diet (TAD) on glucose homeostasis and fasting lipids in individuals at risk of cardiometabolic disease., Design: A randomized, double-blind, controlled 8-wk intervention was conducted in overweight and obese women selected according to indexes of insulin resistance or dyslipidemia. Women were randomly assigned to the DGA or TAD group (n = 28 DGA and 24 TAD). The TAD diet was based on average adult intake from the NHANES 2009-2010. The DGA and TAD diets had respective Healthy Eating Index scores of 98 and 62. All foods and beverages were provided during the intervention. Oral-glucose tolerance and fasting lipids were evaluated at 0, 2, and 8 wk of the intervention. Insulin resistance and sensitivity were estimated with the use of surrogates (e.g., homeostasis model assessment of insulin resistance)., Results: By design, volunteers maintained their weight during the intervention. Fasting insulin, glucose, triglycerides, oral-glucose tolerance, and indexes of insulin resistance were not affected by either of the diets. Systolic blood pressure decreased in the DGA group (∼-9 mm Hg; P < 0.05). Total and HDL cholesterol also decreased in both groups (P < 0.05). Exploratory analysis comparing volunteers entering the study with insulin resistance and dyslipidemia with those with only dyslipidemia did not show an effect of pre-existing conditions on glucose tolerance or fasting lipid outcomes., Conclusions: The consumption of a DGA dietary pattern for 8 wk without weight loss reduced systolic blood pressure. There were no differences between the DGA and TAD diets in fasting insulin, glucose, indexes of insulin resistance, or fasting lipids. This trial was registered at www.clinicaltrials.gov as NCT02298725.

Background: Some country guidelines recommend that people with type 2 diabetes (T2D) limit their consumption of eggs and cholesterol. Our previously published 3-mo weight-maintenance study showed that a high-egg (≥12 eggs/wk) diet compared with a low-egg diet (<2 eggs/wk) did not have adverse effects on cardiometabolic risk factors in adults with T2D., Objective: The current study follows the previously published 3-mo weight-maintenance study and assessed the effects of the high-egg compared with the low-egg diets as part of a 3-mo weight-loss period, followed by a 6-mo follow-up period for a total duration of 12 mo., Design: Participants with prediabetes or T2D (n = 128) were prescribed a 3-mo daily energy restriction of 2.1 MJ and a macronutrient-matched diet and instructed on specific types and quantities of foods to be consumed, with an emphasis on replacing saturated fats with monounsaturated and polyunsaturated fats. Participants were followed up at the 9- and 12-mo visits., Results: From 3 to 12 mo, the weight loss was similar (high-egg compared with low-egg diets: -3.1 ± 6.3 compared with -3.1 ± 5.2 kg; P = 0.48). There were no differences between groups in glycemia (plasma glucose, glycated hemoglobin, 1,5-anhydroglucitol), traditional serum lipids, markers of inflammation (high-sensitivity C-reactive protein, interleukin 6, soluble E-selectin), oxidative stress (F2-isoprostanes), or adiponectin from 3 to 12 mo or from 0 to 12 mo., Conclusions: People with prediabetes or T2D who consumed a 3-mo high-egg weight-loss diet with a 6-mo follow-up exhibited no adverse changes in cardiometabolic markers compared with those who consumed a low-egg weight-loss diet. A healthy diet based on population guidelines and including more eggs than currently recommended by some countries may be safely consumed. This trial is registered at http://www.anzctr.org.au/ as ACTRN12612001266853.

Background: In view of evidence linking pericardial fat accumulation with increased cardiovascular disease risk, strategies to reduce its burden are needed. Data comparing the effects of specific long-term dietary interventions on pericardial fat tissue mobilization are sparse. Objective: We sought to evaluate intrapericardial-fat (IPF) and extrapericardial-fat (EPF) changes during weight-loss interventions by different dietary regimens. Design: During 18 mo of a randomized controlled trial, we compared a Mediterranean/low-carbohydrate (MED/LC) diet plus 28 g walnuts/d with a calorically equal low-fat (LF) diet among randomly assigned participants with moderate abdominal obesity. We performed whole-body MRI and volumetrically quantified IPF and EPF among 80 participants to follow the 18-mo changes. Results: The participants [mean age: 48.6 y; mean body mass index (BMI; in kg/m 2 ); 31.7; 90% men] had baseline IPF and EPF (mean ± SD) volumes of 172.4 ± 53.3 mL and 194.9 ± 71.5 mL, respectively. The 18-mo moderate weight loss of 3.7 kg was similar in both groups, but the reduction in waist circumference was higher in the MED/LC group (-6.9 ± 6.6 cm) than in the LF diet group (-2.3 ± 6.5 cm; P = 0.01). After 18 mo, the IPF volume had reduced twice as much in the MED/LC group compared with the LF group [-37 ± 26.2 mL (-22% ± 15%) compared with -15.5 ± 26.2 mL (-8% ± 15%), respectively; P < 0.05, after adjustment for changes in weight or visceral adipose tissue]. The EPF volume had reduced similarly in both groups [-41.6 ± 30.2 mL (-23% ± 16%) in the MED/LC group compared with -37.9 ± 28.3 mL (-19% ± 14%) in the LF group; P > 0.1]. After controlling for weight loss, IPF and EPF volume reduction paralleled changes in lipid profile but not with improved glycemic profile variables: the IPF relative reduction was associated with a decrease in triglycerides (TGs) (β = 0.090; 95% CI: 0.026, 0.154; P = 0.007) and the ratio of TGs to high-density lipoprotein (HDL) cholesterol (β = 2.689; 95% CI: 0.373, 5.003; P = 0.024), and the EPF relative reduction was associated with an increase in HDL cholesterol (β = -0.452; 95% CI: -0.880, -0.023; P = 0.039) and a decrease in total cholesterol and HDL cholesterol (β = 3.766; 95% CI: 1.092, 6.440; P = 0.007). Conclusions: Moderate but persistent dietary-induced weight loss substantially decreased both IPF and EPF volumes. Reduction of pericardial adipose tissues is independently associated with an improved lipid profile. The Mediterranean diet, rich in unsaturated fats and restricted carbohydrates, is superior to an LF diet in terms of the IPF burden reduction. This trial was registered at clinicaltrials.gov as NCT01530724., (© 2017 American Society for Nutrition.)

Background: Circulating branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) have been shown to be associated with insulin resistance and diabetes risk. The common rs1440581 T allele in the protein phosphatase Mg2+/Mn2+ dependent 1K ( PPM1K ) gene has been related to elevated BCAA concentrations and risk of type 2 diabetes. Objective: In the present study, we tested whether dietary fat and carbohydrate intakes influenced the association between the rs1440581 PPM1K genetic variant and glucose-metabolism traits during weight loss. Design: The rs1440581 PPM1K genetic variant was genotyped in a total of 757 nondiabetic individuals who were randomly assigned to 1 of 2 energy-restricted diets that differed in macronutrient composition (low-fat diet: 20-25% fat, 15% protein, and 60-65% carbohydrate; high-fat diet: 40-45% fat, 15% protein, and 40-45% carbohydrate). The changes in fasting glucose, fasting insulin, insulin resistance (homeostasis model assessment of insulin resistance) and homeostasis model assessment of β cell function (HOMA-B) were measured after a mean ± SD weight loss of 6.8 ± 3.4 kg over 10 wk and analyzed according to the presence of the T allele of rs1440581. Results: The rs1440581 T allele was associated with a smaller improvement in glucose concentrations after the 10-wk dietary intervention (β ± SE: 0.05 ± 0.02 mg/dL; P = 0.03). In addition, significant gene-diet interactions were shown for the rs1440581 PPM1K genetic variant in relation to changes in insulin and HOMA-B ( P -interaction = 0.006 and 0.002, respectively). In response to the high-fat diet, the T allele was associated with a higher reduction of insulin (β ± SE: -0.77 ± 0.40 μU/mL; P = 0.04) and HOMA-B (β ± SE: -13.2 ± 3.81; P = 0.003). An opposite effect was observed in the low-fat diet group, although in this group the T allele was marginally ( P = 0.10) and not significantly ( P = 0.24) associated with insulin and HOMA-B, respectively. Conclusion: PPM1K rs1440581 may affect changes in glucose metabolism during weight loss, and this effect is dependent on dietary fat and carbohydrate intakes. This trial was registered at controlled-trials.com as ISRCTN25867281., (© 2017 American Society for Nutrition.)

Background: Which diet is optimal for weight loss and maintenance remains controversial and implies that no diet fits all patients. Objective: We studied concentrations of fasting plasma glucose (FPG) and fasting insulin (FI) as prognostic markers for successful weight loss and maintenance through diets with different glycemic loads or different fiber and whole-grain content, assessed in 3 randomized trials of overweight participants. Design: After an 8-wk weight loss, participants in the DiOGenes (Diet, Obesity, and Genes) trial consumed ad libitum for 26 wk a diet with either a high or a low glycemic load. Participants in the Optimal well-being, development and health for Danish children through a healthy New Nordic Diet (OPUS) Supermarket intervention (SHOPUS) trial consumed ad libitum for 26 wk the New Nordic Diet, which is high in fiber and whole grains, or a control diet. Participants in the NUGENOB (Nutrient-Gene Interactions in Human Obesity) trial consumed a hypocaloric low-fat and high-carbohydrate or a high-fat and low-carbohydrate diet for 10 wk. On the basis of FPG before treatment, participants were categorized as normoglycemic (FPG <5.6 mmol/L), prediabetic (FPG 5.6-6.9 mmol/L), or diabetic (FPG ≥7.0 mmol/L). Modifications of the dietary effects of FPG and FI before treatment were examined with linear mixed models. Results: In the DiOGenes trial, prediabetic individuals regained a mean of 5.83 kg (95% CI: 3.34, 8.32 kg; P < 0.001) more on the high- than on the low-glycemic load diet, whereas normoglycemic individuals regained a mean of 1.44 kg (95% CI: 0.48, 2.41 kg; P = 0.003) more [mean group difference: 4.39 kg (95% CI: 1.76, 7.02 kg); P = 0.001]. In SHOPUS, prediabetic individuals lost a mean of 6.04 kg (95% CI: 4.05, 8.02 kg; P < 0.001) more on the New Nordic Diet than on the control diet, whereas normoglycemic individuals lost a mean of 2.20 kg (95% CI: 1.21, 3.18 kg; P < 0.001) more [mean group difference: 3.84 kg (95% CI: 1.62, 6.06 kg); P = 0.001]. In NUGENOB, diabetic individuals lost a mean of 2.04 kg (95% CI: -0.20, 4.28 kg; P = 0.07) more on the high-fat and low-carbohydrate diet than on the low-fat and high-carbohydrate diet, whereas normoglycemic individuals lost a mean of 0.43 kg (95% CI: 0.03, 0.83 kg; P = 0.03) more on the low-fat and high-carbohydrate diet [mean group difference: 2.47 kg (95% CI: 0.20, 4.75 kg); P = 0.03]. The addition of FI strengthened these associations. Conclusion: Elevated FPG before treatment indicates success with dietary weight loss and maintenance among overweight patients consuming diets with a low glycemic load or with large amounts of fiber and whole grains. These trials were registered at clinicaltrials.gov as NCT00390637 (DiOGenes) and NCT01195610 (SHOPUS), and at ISRNCT.com as ISRCTN25867281 (NUGENOB)., (© 2017 American Society for Nutrition.)

Background: Cholecystokinin (CCK) is an important satiety factor, acting at type 1 receptors (CCK1Rs) on vagal afferent neurons; however, CCK agonists have failed clinical trials for obesity. We postulated that CCK1R function might be defective in such patients due to abnormal membrane composition, such as that observed in cholesterol gallstone disease. Objective: Due to the challenges in directly studying CCK1Rs relevant to appetite control, our goal was to develop and apply a method to determine the impact of a patient's own cellular environment on CCK stimulus-activity coupling and to determine whether CCK sensitivity correlated with the metabolic phenotype of a high-risk population. Design: Wild-type CCK1Rs were expressed on leukocytes from 112 Hispanic patients by using adenoviral transduction and 24-h culture, with quantitation of cholesterol composition and intracellular calcium responses to CCK. Results were correlated with clinical, biochemical, and morphometric characteristics. Results: Broad ranges of cellular cholesterol and CCK responsiveness were observed, with elevated cholesterol correlated with reduced CCK sensitivity. This was prominent with increasing degrees of obesity and the presence of diabetes, particularly when poorly controlled. No single standard clinical metric correlated directly with CCK responsiveness. Reduced CCK sensitivity best correlated with elevated serum triglycerides in normal-weight participants and with low HDL concentrations and elevated glycated hemoglobin in obese and diabetic patients. Conclusions: CCK responsiveness varies widely across the population, with reduced signaling in patients with obesity and diabetes. This could explain the failure of CCK agonists in previous clinical trials and supports the rationale to develop corrective modulators to reverse this defective servomechanism for appetite control. This trial was registered at www.clinicaltrials.gov as NCT03121755., (© 2017 American Society for Nutrition.)

Background: Dietary intake of phytonutrients present in fruits and vegetables, such as carotenoids, is associated with a lower risk of obesity and related traits, but the impact of genetic variation on these associations is poorly understood, especially in children. Objective: We estimated common genetic influences on serum carotenoid concentrations and obesity-related traits in Mexican American (MA) children. Design: Obesity-related data were obtained from 670 nondiabetic MA children, aged 6-17 y. Serum α- and β-carotenoid concentrations were measured in ∼570 (α-carotene in 565 and β-carotene in 572) of these children with the use of an ultraperformance liquid chromatography-photodiode array. We determined heritabilities for both carotenoids and examined their genetic relation with 10 obesity-related traits [body mass index (BMI), waist circumference (WC), high-density lipoprotein (HDL) cholesterol, triglycerides, fat mass (FM), systolic and diastolic blood pressure, fasting insulin and glucose, and homeostasis model assessment of insulin resistance] by using family data and a variance components approach. For these analyses, carotenoid values were inverse normalized, and all traits were adjusted for significant covariate effects of age and sex. Results: Carotenoid concentrations were highly heritable and significant [α-carotene: heritability ( h 2 ) = 0.81, P = 6.7 × 10 -11 ; β-carotene: h 2 = 0.90, P = 3.5 × 10 -15 ]. After adjusting for multiple comparisons, we found significant ( P ≤ 0.05) negative phenotypic correlations between carotenoid concentrations and the following traits: BMI, WC, FM, and triglycerides (range: α-carotene = -0.19 to -0.12; β-carotene = -0.24 to -0.13) and positive correlations with HDL cholesterol (α-carotene = 0.17; β-carotene = 0.24). However, when the phenotypic correlations were partitioned into genetic and environmental correlations, we found marginally significant ( P = 0.051) genetic correlations only between β-carotene and BMI (-0.27), WC (-0.30), and HDL cholesterol (0.31) after accounting for multiple comparisons. None of the environmental correlations were significant. Conclusions: The findings from this study suggest that the serum carotenoid concentrations were under strong additive genetic influences based on variance components analyses, and that the common genetic factors may influence β-carotene and obesity and lipid traits in MA children., (© 2017 American Society for Nutrition.)

Background: Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes. Existing clinical trials have been limited by short duration, low doses of vitamin D, variability in participants' vitamin D-deficiency status, and the use of surrogate measures of body composition, insulin sensitivity, and insulin secretion. Objective: To address existing knowledge gaps, we conducted a double-blind, randomized, placebo-controlled trial to investigate whether vitamin D supplementation that is provided in a sufficient dose and duration to vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of gold-standard methods. We hypothesized that vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo. Design: Sixty-five overweight or obese, vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] concentration ≤50 nmol/L) adults were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk. Before and after the intervention, participants received gold-standard assessments of body composition (via dual X-ray absorptiometry), insulin sensitivity (via hyperinsulinemic-euglycemic clamps), and insulin secretion [via intravenous-glucose-tolerance tests (IVGTTs)]. Results: Fifty-four participants completed the study [35 men and 19 women; mean ± SD age: 31.9 ± 8.5 y; body mass index (in kg/m 2 ): 30.9 ± 4.4]. 25(OH)D increased with vitamin D supplementation compared with placebo (57.0 ± 21.3 compared with 1.9 ± 15.1 nmol/L, respectively; P = 0.02). Vitamin D and placebo groups did not differ in change in insulin sensitivity (0.02 ± 2.0 compared with -0.03 ± 2.8 mg · kg -1 · min -1 , respectively; P = 0.9) or first-phase insulin secretion (-21 ± 212 compared with 24 ± 184 mU/L, respectively; P = 0.9). Results remained nonsignificant after adjustment for age, sex, percentage of body fat, sun exposure, physical activity, and dietary vitamin D intake ( P > 0.1). Conclusions: Vitamin D supplementation does not improve insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults, despite using high-dose vitamin D supplementation and robust endpoint measures. Therefore, it is unlikely that vitamin D supplementation would be an effective strategy for reducing diabetes risk even in vitamin D-deficient populations. This trial was registered at clinicaltrials.gov as NCT02112721., (© 2017 American Society for Nutrition.)

Background: Studies have demonstrated associations between polyunsaturated fatty acids (PUFAs) and adiposity. It is unclear whether PUFAs in pregnancy have an effect on maternal weight retention after childbirth, which can contribute to long-term obesity. Objective: We examined the association of maternal plasma PUFAs in pregnancy with 18-mo postpartum weight retention (PPWR) in a multiethnic Asian cohort. Design: We studied pregnant women ( n = 653) recruited between June 2009 and September 2010 from a prospective cohort. At 26-28 wk of gestation, plasma phosphatidylcholine PUFA concentrations were measured and determined as percentages of total fatty acids (FAs). PPWR was calculated based on the difference between measured weight at the first antenatal clinic visit and at 18 mo postpartum. Results: The median retained weight of women was 0.90 kg (IQR: -1.40, 3.25) at 18 mo postpartum. Of 653 women, 544 women (83.3%) had PPWR of <5 kg and 109 (16.7%) had PPWR of ≥5 kg. In adjusted linear regression models, higher plasma eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and total ω-3 (n-3) PUFA concentrations were associated with lower PPWR [EPA: β = -0.62 kg/1% increase of total FAs (95% CI: -1.18, -0.05); DHA: β = -0.24 kg/1% increase (95% CI: -0.45, -0.02); total ω-3 PUFAs: β = -0.20 kg/1% increase (95% CI: -0.36, -0.03)], whereas a higher ratio of plasma ω-6-to-ω-3 PUFAs was associated with a higher PPWR [β = 0.21 kg/unit increase (95% CI: 0.05, 0.36)]. Conclusions: Higher plasma percentages of ω-3 PUFAs and a lower ratio of ω-6-to-ω-3 PUFAs in the late-second trimester of pregnancy are associated with less weight retention at 18 mo postpartum. This may offer an alternative strategy to assist postpartum weight reduction by increasing EPA and DHA status together with a decreased ratio of ω-6-to-ω-3 PUFA through diet or fish-oil supplementation during pregnancy. This study was registered at clinicaltrials.gov as NCT01174875., (© 2017 American Society for Nutrition.)

Background: Postprandial dysmetabolism-an exaggerated spike in triglycerides, glucose, and insulin-increases cardiovascular disease risk by inducing oxidative stress, inflammation, and endothelial dysfunction. Polyphenol-rich foods may blunt these effects when they are incorporated into a high-fat, calorie-dense meal. Strawberries are a rich source of polyphenols, but there is little research on their postprandial effects., Objective: This study was designed to investigate the effect of adding 40 g freeze-dried strawberry powder (∼1 lb. or 0.45 kg fresh strawberries) to a high-fat (50 g total fat) meal on postprandial vascular function, as well as triglyceride, glucose, and insulin responses., Design: Healthy, overweight or obese [mean ± SEM body mass index (in kg/m 2 ): 31 ± 0.5] adults (mean ± SEM age: 28 ± 2 y; 17 men and 13 women) consumed a control meal and a strawberry meal in a randomized crossover design. Testing sessions were separated by ≥1 wk for men and ∼1 mo for women to control for hormonal variations. Blood samples were obtained before the meal and 0.5, 1, 2, and 4 h after the meal. Central blood pressure and arterial stiffness indexes were measured at baseline and 2 and 4 h postmeal with the use of pulse waveform analysis., Results: There were no significant differences between the strawberry and control meals for any outcomes. Consumption of either meal significantly decreased the augmentation index at 2 and 4 h (P < 0.002) and significantly increased triglycerides, insulin, and glucose at all time points (P < 0.001) relative to baseline., Conclusions: The strawberry intervention did not alter vascular function or attenuate postprandial metabolic derangements in triglycerides, glucose, or insulin relative to the control meal. Additional research is needed to clarify whether strawberries or other polyphenol-rich interventions improve postprandial responses, and future studies should take into account the acute meal-induced improvements in measures of vascular function. This trial was registered at clinicaltrials.gov as NCT01989637., (© 2017 American Society for Nutrition.)

Background: Obesity and associated metabolic disorders are related to impairments of the intestinal barrier., Objective: We examined lactulose:mannitol (Lac:Man) permeability in obese individuals with and without liver steatosis undergoing a weight-reduction program to test whether an effective weight-loss program improves gut barrier function and whether obese patients with or without liver steatosis differ in this function., Design: Twenty-seven adult, nondiabetic individuals [mean ± SD body mass index (BMI; in kg/m 2 ): 43.7 ± 5.2; 78% with moderate or severe liver steatosis] were included in the follow-up intervention study (n = 13 by month 12). All patients reduced their weight to a mean ± SD BMI of 36.4 ± 5.1 within 12 mo. We assessed barrier functions by the oral Lac:Man and the fecal zonulin tests. Insulin resistance was assessed by the homeostatic model assessment index (HOMA), and liver steatosis by sonography and the fatty liver index (FLI)., Results: The Lac:Man ratio and circulating interleukin (IL) 6 concentration decreased during intervention from 0.080 (95% CI: 0.073, 0.093) to 0.027 (95% CI: 0.024, 0.034; P < 0.001) and from 4.2 ± 1.4 to 2.8 ± 1.6 pg/mL (P < 0.01), respectively. At study start, the Lac:Man ratio was higher in patients with moderate or severe steatosis than in those without any steatosis (P < 0.001). The Lac:Man ratio tended to correlate with HOMA (ρ = 0.55, P = 0.052), which correlated with FLI (ρ = 0.75, P < 0.01). A multiple-regression analysis led to a final model explaining FLI best through BMI, waist circumference, and the Lac:Man ratio., Conclusions: Intestinal permeability is increased in obese patients with steatosis compared with obese patients without. The increased permeability fell to within the previously reported normal range after weight reduction. The data suggest that a leaky gut barrier is linked with liver steatosis and could be a new target for future steatosis therapies. This trial was registered at clinicaltrials.gov as NCT01344525., (© 2017 American Society for Nutrition.)

Background: Endothelial dysfunction (ED) is involved in the development of atherosclerosis. Hesperidin, a citrus flavonoid with antioxidant and other biological properties, potentially exerts beneficial effects on endothelial function (EF)., Objective: We investigated the effect of hesperidin 2S supplementation on EF in overweight individuals., Design: This was a randomized, double-blind, placebo-controlled study in which 68 individuals were randomly assigned to receive hesperidin 2S (450 mg/d) or a placebo for 6 wk. At baseline and after 6 wk of intervention, flow-mediated dilation (FMD), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), soluble P-selectin (sP-selectin), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were assessed. Acute, reversible ED was induced by intake of a high-fat meal (HFM). A second FMD scan was performed 2 h postprandially, and adhesion molecules were assessed 2 and 4 h postprandially. An additional exploratory analysis was performed in subjects with baseline FMD ≥3%., Results: No significant change in fasting or postprandial FMD was observed after 6 wk of hesperidin intake compared with placebo intake. However, there was a trend for a reduction of sVCAM-1, sICAM-1, sP-selectin, SBP, and DBP after 6 wk of hesperidin treatment. In the FMD ≥3% group, hesperidin protected individuals from postprandial ED (P = 0.050) and significantly downregulated sVCAM-1 and sICAM-1 (all P ≤ 0.030). The results reported in the current article were not adjusted for multiplicity., Conclusions: Six weeks of consumption of hesperidin 2S did not improve basal or postprandial FMD in our total study population. There was a tendency toward a reduction of adhesion molecules and a decrease in SBP and DBP. Further exploratory analyses revealed that, in subjects with baseline FMD ≥3%, hesperidin 2S improved ED after an HFM and reduced adhesion molecules. These results indicate the cardiovascular health benefits of hesperidin 2S in overweight and obese individuals with a relatively healthy endothelium. This trial was registered at clinicaltrials.gov as NCT02228291., (© 2016 American Society for Nutrition.)

Background: Green tea has been suggested to improve cardiovascular disease risk factors, including circulating lipid variables. However, current evidence is predominantly based on small, short-term randomized controlled trials conducted in diverse populations., Objective: The aim of this study was to examine the efficacy and impact of green tea extract (GTE) supplementation high in epigallocatechin gallate (EGCG) on blood lipids in healthy postmenopausal women., Design: This was an ancillary study of a double-blind, randomized, placebo-controlled, parallel-arm trial investigating the effects of a GTE supplement containing 1315 mg catechins (843 mg EGCG) on biomarkers of breast cancer risk. Participants were randomly assigned to receive GTE (n = 538) or placebo (n = 537) and were stratified by catechol-O-methyltransferase (COMT) genotype activity (high COMT compared with low or intermediate COMT genotype activity). They consumed either 4 GTE or identical placebo capsules daily for 12 mo. A total of 936 women completed this substudy. Circulating lipid panels including total cholesterol (TC), HDL cholesterol, and triglycerides were measured at baseline and at months 6 and 12., Results: Compared with placebo, 1-y supplementation with GTE capsules resulted in a significant reduction in circulating TC (-2.1% compared with 0.7%; P = 0.0004), LDL cholesterol (-4.1% compared with 0.9%; P < 0.0001) and non-HDL cholesterol (-3.1% compared with 0.4%; P = 0.0032). There was no change in HDL-cholesterol concentration, but triglyceride concentrations increased by 3.6% in the GTE group, whereas they decreased by 2.5% in the placebo group (P = 0.046). A significant reduction in TC was observed only among women with high (i.e., ≥200 mg/dL) baseline TC concentrations (P-interaction = 0.01) who consumed GTE capsules. The effect of GTE on the increase in triglycerides was mainly observed among obese women and statin users (P-interaction = 0.06)., Conclusion: Supplementation with GTE significantly reduced circulating TC and LDL-cholesterol concentrations, especially in those with elevated baseline TC concentrations. This trial was registered at clinicaltrials.gov as NCT00917735., (© 2016 American Society for Nutrition.)

Background: Obesity is associated with lower concentrations of serum 25-hydroxyvitamin D; however, uncertainty exists as to the direction of causation. To date, meta-analyses of randomized controlled vitamin D-supplementation trials have shown no effect of raising circulating vitamin D on body weight, although several weight-loss-intervention trials have reported an increase in circulating vitamin D after weight reduction., Objective: We undertook a systematic review and meta-analysis of randomized and nonrandomized controlled trials to determine whether weight loss compared with weight maintenance leads to an increase in serum 25-hydroxyvitamin D., Design: A systematic search for controlled weight-loss-intervention studies published up to 31 March 2016 was performed. Studies that included participants of any age with changes in adiposity and serum 25-hydroxyvitamin D as primary or secondary outcomes were considered eligible., Results: We identified 4 randomized controlled trials (n = 2554) and 11 nonrandomized controlled trials (n = 917) for inclusion in the meta-analysis. Random assignment to weight loss compared with weight maintenance resulted in a greater increase in serum 25-hydroxyvitamin D with a mean difference of 3.11 nmol/L (95% CI: 1.38, 4.84 nmol/L) between groups, whereas a mean difference of 4.85 nmol/L (95% CI: 2.59, 7.12 nmol/L) was observed in nonrandomized trials. No evidence for a dose-response effect of weight loss on the change in serum 25-hydroxyvitamin D was shown overall., Conclusions: Our results indicate that vitamin D status may be marginally improved with weight loss in comparison with weight maintenance under similar conditions of supplemental vitamin D intake. Although additional studies in unsupplemented individuals are needed to confirm these findings, our results support the view that the association between obesity and lower serum 25-hydroxyvitamin D may be due to reversed causation with increased adiposity leading to suboptimal concentrations of circulating vitamin D. This trial was registered at www.crd.york.ac.uk/PROSPERO/ as CRD42015023836., (© 2016 American Society for Nutrition.)

Background: Iron deficiency is common in obese subjects. This may be due to an increase in serum hepcidin and a decrease in iron absorption from adiposity-related inflammation., Objective: We evaluated whether weight and fat loss in obese subjects would decrease inflammation and serum hepcidin and thereby improve iron absorption., Design: We performed a 6-mo prospective study in obese [body mass index (in kg/m 2 ) ≥35 and <45] adults who had recently undergone laparoscopic sleeve gastrectomy. At 2 and 8 mo postsurgery, subjects consumed a test drink with 6 mg 57 Fe as ferrous sulfate and were intravenously infused with 100 μg 58 Fe as iron citrate. We then compared erythrocyte incorporation of iron isotopic labels, changes in body composition, iron status, hepcidin, and inflammation at each time point., Results: Forty-three subjects were studied at baseline, and 38 completed the protocol (32 women and 6 men). After 6 mo, total body fat, interleukin IL-6, and hepcidin were significantly lower (all P < 0.005). In iron-deficient subjects (n = 17), geometric mean (95% CI) iron absorption increased by 28% [from 9.7% (6.5%, 14.6%) to 12.4% (7.7%, 20.1%); P = 0.03], whereas in iron-sufficient subjects (n = 21), absorption did not change [5.9% (4.0%, 8.6%) and 5.6% (3.9%, 8.2%); P = 0.81]., Conclusion: Adiposity-related inflammation is associated with a reduction in the normal upregulation of iron absorption in iron-deficient obese subjects, and this adverse effect may be ameliorated by fat loss. This protocol was approved by the ethics committees of Wageningen University, ETH Zurich, the University of Monterrey, and the Federal Commission for the Protection against Sanitary Risks, and registered at clinicaltrials.gov as NCT01347905., (© 2016 American Society for Nutrition.)

Background: Plasma lysophospholipids have emerged as signaling molecules with important effects on inflammation, insulin resistance, and fatty liver disease, each of which is linked closely to obesity. Dietary n-3 (ω-3) polyunsaturated fatty acids (PUFAs) may be able to improve these conditions., Objective: The objective of this study was to assess the response of plasma lysophospholipids to obesity, n-3 PUFA consumption, and a high-fat meal challenge to better understand the role of lysophospholipid metabolism in the progression of obesity-related disorders., Design: We determined the concentrations of 8 lysophosphatidylcholines, 11 lysophosphatidylethanolamines, and 7 lysophosphatidylinositols in the plasma of 34 normal-weight and 38 obese subjects randomly assigned to consume corn oil (control) or n-3 PUFA-rich fish oil (3 g/d; n = 15-19/group) for 90 d. Blood samples were collected on the last day of the study under fasting conditions and 6 h after a high-fat meal (1135 kcal, 86 g fat) challenge. The profile of secreted lysophospholipids was studied in HepG2 cells under palmitate-induced steatosis., Results: Obese and normal-weight subjects had different profiles of plasma lysophospholipids. A multivariate combination of the 26 lysophospholipids could discriminate between normal-weight and obese subjects with an accuracy of 98%. The high-fat meal challenge altered the concentration of plasma lysophosphatidylcholines in an oil treatment-dependent manner in normal-weight but not obese subjects, suggesting that obesity impairs the sensitivity of lysophospholipid metabolism to n-3 PUFAs. Noncytotoxic steatosis in HepG2 cells affected the secretion pattern of lysophospholipids, partially resembling the changes observed in the plasma of obese subjects., Conclusions: Obesity has a substantial impact on lysophospholipid metabolism, altering the plasma lysophospholipid profile and abolishing its sensitivity to dietary n-3 PUFAs. These effects could contribute to the onset or progression of alterations associated with obesity, such as inflammation, insulin resistance, and fatty liver disease. This trial was registered at www.controlled-trials.com as ISRCTN96712688., (© 2016 American Society for Nutrition.)

Background: It is unclear whether and at what dose vitamin D supplementation affects insulin resistance (IR)., Objective: We sought to investigate whether vitamin D at doses higher than currently recommended decreases indexes of IR in an ambulatory population of overweight elderly subjects., Design: This double-blind, randomized, controlled multicenter trial enrolled 257 elderly overweight individuals aged ≥65 y with baseline 25-hydroxyvitamin D [25(OH)D] concentrations between 10 and 30 ng/mL. All subjects received 1000 mg calcium citrate/d, with vitamin D administered weekly at an equivalent dose of 600 or 3750 IU/d. The homeostasis model assessment (HOMA) of IR index at 1 y was the primary outcome. We also assessed the McAuley index., Results: In total, 222 subjects (55% women) with a mean ± SD age and body mass index (BMI; in kg/m(2)) of 71 ± 4 y and 30 ± 4, respectively, completed the study. Subjects' baseline characteristics, including IR indexes, were similar across groups: 69% had prediabetes, 54% had hypertension (47% were taking antihypertensive medications), and 60% had hyperlipidemia, nearly half of whom were receiving lipid-lowering drugs. At 1 y, mean ± SD serum 25(OH)D increased from 20 ± 7 to 26 ± 7 ng/mL in the low-dose arm (P < 0.0001) and from 21 ± 8 to 36 ± 10 ng/mL in the high-dose arm (P < 0.001). Median HOMA-IR indexes did not change compared with baseline concentrations and were similar in the high- [2.2 (IQR: 1.5, 2.9)] and low-dose [2.3 (IQR: 1.6, 3.3] treatment groups. Adjusted analyses showed that HOMA-IR was predicted by the baseline HOMA index and BMI but not by vitamin D dose, baseline serum 25(OH)D, or change in 25(OH)D., Conclusion: Vitamin D3 at 3750 IU/d did not improve HOMA-IR compared with the Institute of Medicine Recommended Dietary Allowance of 600 IU/d in elderly overweight individuals. This trial was registered at clinicaltrials.gov as NCT01315366., (© 2016 American Society for Nutrition.)

Background: The extent to which dietary sodium intake may confer alterations in the inflammatory status is unclear. GlycA is a novel proton nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation, which is associated with the development of cardiovascular disease and diabetes., Objective: We determined associations of the inflammatory markers GlycA and high-sensitivity C-reactive protein (hsCRP) with 24-h sodium excretion., Design: A cross-sectional, population-based study was performed in 3935 subjects who were not using an antihypertensive medication, lipid-lowering drugs, or a glucose-lowering treatment. Urinary sodium excretion was calculated as the mean of two 24-h urine excretions. Linear regression models were used, with 24-h sodium excretion as an independent variable and GlycA or ln hsCRP as a dependent variable., Results: The mean ± SD sodium excretion was 143.0 ± 53.4 mmol/24 h. The GlycA concentration was 343.6 ± 58.7 μmol/L, and the geometric mean of the hsCRP concentration was 1.20 mg/L (95% CI: 1.16, 1.25 mg/L). In age- and sex-adjusted analyses, GlycA and ln hsCRP were not significantly associated with 24-h sodium excretion [B: 1.23 (95% CI: -0.67, 3.13; P = 0.21) and 0.03 (95% CI: -0.004, 0.07; P = 0.08), respectively, per 1-SD increase]. After additional adjustment for body mass index (BMI), both GlycA (B: -2.76; 95% CI: -4.65, -0.86; P = 0.004) and ln hsCRP (B: -0.07; 95% CI: -0.11, -0.04; P < 0.001) were inversely associated with 24-h sodium excretion. These associations were similar if adjustment was performed for waist circumference instead of BMI or if additional adjustment was performed for relevant clinical and laboratory variables and were particularly present in men., Conclusions: The proinflammatory biomarkers GlycA and hsCRP are inversely related to higher 24-h sodium excretion when taking into account the variation in adiposity. These inverse relations remain present after taking into account other covariates., (© 2016 American Society for Nutrition.)

Background: The mechanism and clinical significance of low circulating 25-hydroxyvitamin D [25(OH)D] in obese people are unknown. Low total 25(OH)D may be due to low vitamin D-binding proteins (DBPs) or faster metabolic clearance. However, obese people have a higher bone mineral density (BMD), which suggests that low 25(OH)D may not be associated with adverse consequences for bone., Objective: We sought to determine whether 1) vitamin D metabolism and 2) its association with bone health differ by body weight., Design: We conducted a cross-sectional observational study of 223 normal-weight, overweight, and obese men and women aged 25-75 y in South Yorkshire, United Kingdom, in the fall and spring. A subgroup of 106 subjects was also assessed in the winter. We used novel techniques, including an immunoassay for free 25(OH)D, a stable isotope for the 25(OH)D3 half-life, and high-resolution quantitative tomography, to make a detailed assessment of vitamin D physiology and bone health., Results: Serum total 25(OH)D was lower in obese and overweight subjects than in normal-weight subjects in the fall and spring (geometric means: 45.0 and 40.8 compared with 58.6 nmol/L, respectively; P < 0.001) but not in the winter. Serum 25(OH)D was inversely correlated with body mass index (BMI) in the fall and spring and in the winter. Free 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were lower in obese subjects. DBP, the DBP genotype, and the 25(OH)D3 half-life did not differ between BMI groups. Bone turnover was lower, and bone density was higher, in obese people., Conclusions: Total and free 25(OH)D and 1,25(OH)2D are lower at higher BMI, which cannot be explained by lower DBP or the shorter half-life of 25(OH)D3 We speculate that low 25(OH)D in obesity is due to a greater pool of distribution. Lower 25(OH)D may not reflect at-risk skeletal health in obese people, and BMI should be considered when interpreting serum 25(OH)D as a marker of vitamin D status., (© 2016 American Society for Nutrition.)

Background: Increased maternal body mass index (BMI) is a robust risk factor for later pediatric obesity. Accumulating evidence suggests that human milk (HM) may attenuate the transfer of obesity from mother to offspring, potentially through its effects on early development of the infant microbiome., Objectives: Our objective was to identify early differences in intestinal microbiota in a cohort of breastfeeding infants born to obese compared with normal-weight (NW) mothers. We also investigated relations between HM hormones (leptin and insulin) and both the taxonomic and functional potentials of the infant microbiome., Design: Clinical data and infant stool and fasting HM samples were collected from 18 NW [prepregnancy BMI (in kg/m(2)) <24.0] and 12 obese (prepregnancy BMI >30.0) mothers and their exclusively breastfed infants at 2 wk postpartum. Infant body composition at 2 wk was determined by air-displacement plethysmography. Infant gastrointestinal microbes were estimated by using 16S amplicon and whole-genome sequencing. HM insulin and leptin were determined by ELISA; short-chain fatty acids (SCFAs) were measured in stool samples by using gas chromatography. Power was set at 80%., Results: Infants born to obese mothers were exposed to 2-fold higher HM insulin and leptin concentrations (P < 0.01) and showed a significant reduction in the early pioneering bacteria Gammaproteobacteria (P = 0.03) and exhibited a trend for elevated total SCFA content (P < 0.06). Independent of maternal prepregnancy BMI, HM insulin was positively associated with both microbial taxonomic diversity (P = 0.03) and Gammaproteobacteria (e.g., Enterobacteriaceae; P = 0.04) and was negatively associated with Lactobacillales (e.g., Streptococcaceae; P = 0.05). Metagenomic analysis showed that HM leptin and insulin were associated with decreased bacterial proteases, which are implicated in intestinal permeability, and reduced concentrations of pyruvate kinase, a biomarker of pediatric gastrointestinal inflammation., Conclusion: Our results indicate that, although maternal obesity may adversely affect the early infant intestinal microbiome, HM insulin and leptin are independently associated with beneficial microbial metabolic pathways predicted to increase intestinal barrier function and reduce intestinal inflammation. This trial was registered at clinicaltrials.gov as NCT01693406., (© 2016 American Society for Nutrition.)

Background: A subset of obese individuals does not exhibit metabolically unfavorable features; this group is referred to as metabolically healthy obese (MHO). Serum concentrations of polychlorinated biphenyls (PCBs), which are chemicals with endocrine-disrupting properties, have been shown to be lower in MHO than in metabolically unhealthy obese (MUO)., Objective: We studied PCB serum concentrations during and after weight loss and their relation with metabolic health., Design: We determined metabolic health features (weight, blood pressure, lipids, inflammation, and glucose metabolism) and serum PCB concentrations of 27 PCBs in a cohort of 184 overweight and obese subjects. Metabolic health was evaluated with the use of the criteria of the metabolic syndrome (MetS) [metabolic syndrome according to Adult Treatment Panel III criteria present (MetS+) or metabolic syndrome according to Adult Treatment Panel III criteria absent (MetS−)] or with extended criteria with inflammation and insulin resistance taken into account (MUO compared with MHO). Participants were treated with lifestyle counseling or bariatric surgery. A metabolic and toxicological re-evaluation was performed after 6 and 12 mo., Results: At baseline, serum ΣPCB concentrations were significantly higher in MUO than in MHO (ΣPCBs: 138 ±105 compared with 365 ± 481 ng/g lipid weight; P = 0.01) but not in MetS+ compared with MetS− subjects. No difference was detected in the percentage increase in PCB serum concentrations in MetS+ compared with MetS− subjects (median: 58% compared with 43% and 31% compared with 69% at 6 and 12 mo, respectively). The comparison of persistent with resolved MetS and MUO did not reveal any difference in ΣPCB concentration increments (median: 49% compared with 58% at 12 mo for MUO; P > 0.05). In a regression model with age, smoking, and body mass index corrected for, PCB serum concentrations at baseline were not predictive of the persistence or resolution of a metabolically unfavorable state., Conclusion: Our study indicates that the increment in serum concentrations of PCBs does not differ according to metabolic health and does not seem to influence the beneficial metabolic health effects of weight loss. This study was registered at clinicaltrials.gov at NCT01778868.

Background: Circulating amino acids, such as branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), have been associated with diabetes risk; however, little is known about how a long-term dietary intervention for weight loss affects circulating amino acids., Objectives: We examined the effects of weight-loss diets on long-term changes in plasma amino acids and the associations of these changes with weight loss and the improvement of insulin resistance., Design: We repeatedly measured plasma amino acid profiles over 2 y in overweight or obese participants from 2 randomized, dietary intervention, weight-loss trials [774 subjects from the POUNDS LOST (Preventing Overweight Using Novel Dietary Strategies Trial) and 318 subjects from the DIRECT (Dietary Intervention Randomized Controlled Trial)]., Results: Intervention diets consistently lowered most of the amino acid concentrations, including BCAAs and AAAs, in both trials. In the POUNDS LOST, average-protein diets (15% of daily energy) showed stronger effects than did high-protein diets (25% of daily energy) on reducing concentrations of the diabetes-associated BCAA valine at 6 mo independent of the weight change. In both trials, weight loss was directly related to the concurrent reduction of the BCAAs leucine and isoleucine, the AAAs tyrosine and phenylalanine, and 4 other amino acids. For example, per kilogram of weight loss, there was a 0.04-SD decrease in log tyrosine (∼0.6 μmol/L) in both trials. In addition, we showed that reductions in alanine and the AAA tyrosine were significantly related to improved insulin resistance (measured with the use of the homeostasis model assessment of insulin resistance), independent of weight loss, in both trials (both P < 0.05). For example, per 1-SD decrease in log tyrosine (∼17 μmol/L), there was a 0.04-SD (∼3%) improvement in insulin resistance in the POUNDS LOST and a 0.13-SD (∼8%) improvement in insulin resistance in the DIRECT., Conclusion: Our findings underscore the potential importance of dietary interventions in improving amino acid profiles (i.e., reducing diabetes risk-enhancing amino acid concentrations) along with and beyond weight loss. The POUNDS LOST and the DIRECT were registered at clinicaltrials.gov as NCT00072995 and NCT00160108, respectively., (© 2016 American Society for Nutrition.)

Background: In contrast with some epidemiologic evidence, our previous research showed that a 4-wk diet that was high in low-fat dairy reduced insulin sensitivity compared with the effect of a diet that was high in red meat., Objective: We investigated whether a dairy meal would produce a greater insulin response than a carbohydrate-matched red meat meal would, which might account for the change in insulin sensitivity., Design: One meal contained lean red meat, bread, and orange juice, and the other meal contained skim milk, low-fat yogurt, cheese, and bread. Meals were isoenergetic, equal in macronutrient profile, and consumed 1 wk apart. Glucose, insulin, and triglycerides were measured before and 30, 60, 90, 120, 150, and 180 min after meal consumption. Differences between meals were tested with the use of a repeated-measures ANOVA and paired sample t tests., Results: Nineteen men and 24 women [mean ± SD age: 50.8 ± 16.0 y; body mass index (in kg/m(2)): 30.0 ± 3.5] completed the study. Twenty-two participants had normal glucose tolerance, and 21 participants had impaired fasting glucose or impaired glucose tolerance. The red meat meal resulted in a higher glucose response at 30 min after consumption (P < 0.001); however, the glucose total AUC was not different between meals (P = NS). The mean ± SEM incremental AUC (iAUC) for glucose was significantly higher after the dairy meal than after the red meat meal (2.23 ± 0.49 compared with 0.88 ± 0.57 mmol/L · 3 h, respectively; P = 0.004). The insulin total AUC and iAUC were not different between meals (iAUC: 159.65 ± 20.0 mU/L · 3 h for red meat compared with 167.49 ± 24.1 mU/L · 3 h for dairy; P = NS)., Conclusions: Lean red meat and low-fat dairy produced a similar glycemic response. The higher glucose response 30 min after consumption of the red meat meal was likely attributable to differences in the glycemic load between orange juice and milk and yogurt. An insulinotropic effect of dairy was not observed. This trial was registered at www.anzctr.org.au as ACTRN12615000164594., (© 2016 American Society for Nutrition.)

Background: Iron deficiency is common in overweight and obese individuals. This deficiency may be due to adiposity-related inflammation that increases serum hepcidin and decreases dietary iron absorption. Because hepcidin reduces iron efflux from the basolateral enterocyte, it is uncertain whether luminal enhancers of dietary iron absorption such as ascorbic acid can be effective in overweight and obese individuals., Objective: In this study, we compared iron absorption from a meal with ascorbic acid (+AA) and a meal without ascorbic acid (-AA) in women in a normal-weight group (NW) with those in overweight and obese groups combined (OW/OB)., Design: Healthy, nonanemic women [n = 62; BMI (in kg/m(2)): 18.5-39.9] consumed a stable-isotope-labeled wheat-based test meal -AA and a wheat-based test meal +AA (31.4 mg ascorbic acid). We measured iron absorption and body composition with the use of dual-energy X-ray absorptiometry, blood volume with the use of a carbon monoxide (CO)-rebreathing method, iron status, inflammation, and serum hepcidin., Results: Inflammatory biomarkers (all P < 0.05) and hepcidin (P = 0.08) were lower in the NW than in the OW/OB. Geometric mean (95% CI) iron absorptions in the NW and OW/OB were 19.0% (15.2%, 23.5%) and 12.9% (9.7%, 16.9%) (P = 0.049), respectively, from -AA meals and 29.5% (23.3%, 38.2%) and 16.6% (12.8%, 21.7%) (P = 0.004), respectively, from +AA meals. Median percentage increases in iron absorption for -AA to +AA meals were 56% in the NW (P < 0.001) and 28% in OW/OB (P = 0.006). Serum ferritin [R(2) = 0.22; β = -0.17 (95% CI: -0.25, -0.09)], transferrin receptor [R(2) = 0.23; β = 2.79 (95% CI: 1.47, 4.11)], and hepcidin [R(2) = 0.13; β = -0.85 (95% CI: -1.41, -0.28)] were significant predictors of iron absorption., Conclusions: In overweight and obese women, iron absorption is two-thirds that in normal-weight women, and the enhancing effect of ascorbic acid on iron absorption is one-half of that in normal-weight women. Recommending higher intakes of ascorbic acid (or other luminal enhancers of iron absorption) in obese individuals to improve iron status may have a limited effect. This trial was registered at clinicaltrials.gov as NCT01884506., (© 2015 American Society for Nutrition.)

Background: In lean individuals, intraduodenal protein and lipid modulate gastrointestinal motor and hormone functions and reduce energy intake in a load-dependent manner; protein also stimulates insulin, with modest effects on reducing blood glucose. The effect of intraduodenal lipid on gastrointestinal motor and hormone responses is diminished in obesity; whether the effects of protein are also attenuated remains unclear., Objectives: The objectives of this study were to characterize the load-dependent effects of intraduodenal whey protein hydrolysate on antropyloroduodenal pressures, gut hormones, glycemia, appetite, and energy intake in obese subjects and to compare the responses to the higher protein load with those in lean subjects., Design: We measured antropyloroduodenal pressures, plasma cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, insulin, blood glucose, appetite, and energy intake in 12 nondiabetic obese men on 3 separate occasions, in a double-blind, randomized order, during 60-min intraduodenal infusions of hydrolyzed whey protein at either 0 (saline control), 1.5, or 3 kcal/min. Twelve age-matched lean individuals received a 3-kcal/min infusion only. Immediately after the infusions, energy intake from a buffet lunch was quantified., Results: In obese subjects, protein suppressed antral and duodenal pressures; stimulated plasma CCK, GLP-1, GIP, insulin, and glucagon (all r > 0.57, P < 0.01); and tended to reduce energy intake (r = -10.38, P = 0.057) in a dose-dependent manner. In response to the 3-kcal/min protein load, antropyloroduodenal pressures, CCK, GLP-1, and glucagon did not differ between lean and obese subjects. Insulin release was greater, and GIP release less, in obese than in lean subjects (both P < 0.05), whereas the reduction in glucose was comparable. Energy intake tended to be higher in obese subjects (P = 0.08)., Conclusions: The gastrointestinal effects of hydrolyzed whey protein remain relatively intact in obesity; however, the observed changes in insulin and GIP suggest early disturbances in the insulin-incretin axis. This study was registered at www.anzctr.org.au as ACTRN 12612000203853., (© 2015 American Society for Nutrition.)

Background: Obesity is related to hormonal disorders that affect the reproductive system. Low-glycemic index (LGI) diets seem to exert a positive effect on weight loss and on metabolic changes that result from obesity., Objective: We investigated the effects of a hypocaloric diet with an LGI and low glycemic load on anthropometric and metabolic variables, ghrelin and leptin concentrations, and the pregnancy rate in overweight and obese infertile women who were undergoing in vitro fertilization (IVF)., Design: The study was a randomized block-design controlled trial in which we analyzed 26 overweight or obese infertile women. Patients were assigned to a hypocaloric LGI-diet group or a control group and followed the protocol for 12 wk. Body weight, body mass index (BMI), percentage of body fat, glucose, insulin, homeostasis model assessment of insulin resistance, serum lipids, reproductive hormones, leptin, acylated ghrelin, number of oocytes retrieved in the IVF cycle, and pregnancy rate were determined., Results: There were greater reductions in body mass, BMI, percentage of body fat, waist:hip ratio, and leptin in the LGI-diet group than in the control group (P < 0.05). Despite a change of 18% in mean values, there was no significant increase in acylated ghrelin concentrations in the LGI group compared with the control group (P = 0.215). The LGI-diet group had 85.4% more oocytes retrieved than did the control group (7.75 ± 1.44 and 4.18 ± 0.87, respectively; P = 0.039) in the IVF cycle. Three patients (21.4%) in the LGI group experienced a spontaneous pregnancy during the follow-up, which generated 3 live births., Conclusions: The hypocaloric LGI diet promoted a decrease in BMI, percentage of body fat, and leptin concentrations, which improved oocyte development and pregnancy rate. These results support the clinical recommendation to advise overweight and obese women to lose weight through a balanced diet before being submitted for treatment with assisted reproduction technologies. A hypocaloric diet combined with LGI foods seems to be beneficial for these patients, but additional studies are required before this treatment is recommended. This trial was registered at clinicaltrials.gov as NCT02416960., (© 2015 American Society for Nutrition.)

Background: Obesity is associated with multiple diseases. Bariatric surgery is the most effective therapy for severe obesity that can reduce body weight and obesity-associated morbidity. The metabolic alterations associated with obesity and respective changes after bariatric surgery are incompletely understood., Objective: We comprehensively assessed metabolic alterations associated with severe obesity and distinct bariatric procedures., Design: In our longitudinal observational study, we applied a (1)H-nuclear magnetic resonance-based global, untargeted metabolomics strategy on human serum samples that were collected before and repeatedly ≤1 y after distinct bariatric procedures [i.e., a sleeve gastrectomy, proximal Roux-en Y gastric bypass (RYGB), and distal RYGB]. For comparison, we also analyzed serum samples from normal-weight and less-obese subjects who were matched for 1-y postoperative body mass index (BMI) values of the surgical groups., Results: We identified a metabolomic fingerprint in obese subjects that was clearly discriminated from that of normal-weight subjects. Furthermore, we showed that bariatric surgery (sleeve gastrectomy and proximal and distal RYGB) dynamically affected this fingerprint in a procedure-dependent manner, thereby establishing new fingerprints that could be discriminated from those of BMI-matched and normal-weight control subjects. Metabolites that largely contributed to the metabolomic fingerprints of severe obesity were aromatic and branched-chain amino acids (elevated), metabolites related to energy metabolism (pyruvate and citrate; elevated), and metabolites suggested to be derived from gut microbiota (formate, methanol, and isopropanol; all elevated)., Conclusion: Our data indicate that bariatric surgery, irrespective of the specific kind of procedure used, reverses most of the metabolic alterations associated with obesity and suggest profound changes in gut microbiome-host interactions after the surgery. This trial was registered at clinicaltrials.gov as NCT02480322., (© 2015 American Society for Nutrition.)

Background: Impaired energy metabolism is a possible mechanism that contributes to insulin resistance and ectopic fat storage., Objective: We examined whether meal ingestion differently affects hepatic phosphorus metabolites in insulin-sensitive and insulin-resistant humans., Design: Young, lean, insulin-sensitive humans (CONs) [mean ± SD body mass index (BMI; in kg/m(2)): 23.2 ± 1.5]; insulin-resistant, glucose-tolerant, obese humans (OBEs) (BMI: 34.3 ± 1.7); and type 2 diabetes patients (T2Ds) (BMI: 32.0 ± 2.4) were studied (n = 10/group). T2Ds (61 ± 7 y old) were older (P < 0.001) than were OBEs (31 ± 7 y old) and CONs (28 ± 3 y old). We quantified hepatic γATP, inorganic phosphate (Pi), and the fat content [hepatocellular lipids (HCLs)] with the use of (31)P/(1)H magnetic resonance spectroscopy before and at 160 and 240 min after a high-caloric mixed meal. In a subset of volunteers, we measured the skeletal muscle oxidative capacity with the use of high-resolution respirometry. Whole-body insulin sensitivity (M value) was assessed with the use of hyperinsulinemic-euglycemic clamps., Results: OBEs and T2Ds were similarly insulin resistant (M value: 3.5 ± 1.4 and 1.9 ± 2.5 mg · kg(-1) · min(-1), respectively; P = 0.9) and had 12-fold (P = 0.01) and 17-fold (P = 0.002) higher HCLs, respectively, than those of lean persons. Despite comparable fasting hepatic γATP concentrations, the maximum postprandial increase of γATP was 6-fold higher in OBEs (0.7 ± 0.2 mmol/L; P = 0.03) but only tended to be higher in T2Ds (0.6 ± 0.2 mmol/L; P = 0.09) than in CONs (0.1 ± 0.1 mmol/L). However, in the fasted state, muscle complex I activity was 53% lower (P = 0.01) in T2Ds but not in OBEs (P = 0.15) than in CONs., Conclusions: Young, obese, nondiabetic humans exhibit augmented postprandial hepatic energy metabolism, whereas elderly T2Ds have impaired fasting muscle energy metabolism. These findings support the concept of a differential and tissue-specific regulation of energy metabolism, which can occur independently of insulin resistance. This trial was registered at clinicaltrials.gov as NCT01229059., (© 2015 American Society for Nutrition.)

Background: Maternal obesity and hyperglycemia increase risk of obesity and diabetes in offspring later in life., Objective: We examined the relation between gestational glycemia and prepregnancy body mass index (ppBMI) with offspring growth in an Asian mother-offspring cohort., Design: Pregnant mothers undertook a 75-g 2-h oral-glucose-tolerance test at 26-28 wk of gestation. In 937 singleton offspring, ≤9 serial measurements of weight and length were obtained from birth until 36 mo of age., Results: Gestational fasting plasma glucose (FPG) was positively associated with birth weight (B: 0.17; 95% CI: 0.10, 0.24; P < 0.001) and birth BMI (B: 0.15; 95% CI: 0.06, 0.40; P = 0.001) but not at ≥3 mo of age. In contrast, maternal ppBMI was positively associated with birth variables and conditional growth in weight and BMI in the first 36 mo of life. However, gestational FPG and prepregnancy obesity status interacted significantly for the association with offspring growth and overweight status in the first 36 mo of life (P-interaction < 0.01). In nonobese mothers, each unit increase in gestational FPG was associated with increased offspring weight (B: 0.08; 95% CI: 0.008, 0.16; P = 0.03) and BMI (B: 0.08; 95% CI: 0.003, 0.15; P = 0.04) as well as increased risk of overweight in the first 36 mo of life (OR: 1.36; 95% CI: 1.10, 1.68). However, in obese mothers, each unit increase in gestational FPG was associated with decreased offspring weight (B: -0.01; 95% CI: -0.02, -0.003) and BMI (B: -0.008; 95% CI: -0.01, -0.002) velocity (P < 0.01 for both) and decreased risk of overweight (OR: 0.59; 95% CI: 0.41, 0.86) in the first 36 mo of life., Conclusions: Prepregnancy adiposity was associated with offspring growth in early childhood. Although pooled analyses showed no demonstrable difference by 3 mo of age, there were contrasting and opposite associations of gestational glycemia with weight and BMI in the first 36 mo of life in offspring of nonobese and obese mothers separately. This study was registered at clinicaltrials.gov as NCT01174875., (© 2015 American Society for Nutrition.)

Background: Disease risk is lower in metabolically healthy obese adults than in their unhealthy obese counterparts. Studies considering physical activity as a modifiable determinant of healthy obesity have relied on self-reported measures, which are prone to inaccuracies and do not capture all movements that contribute to health., Objective: We aimed to examine differences in total and moderate-to-vigorous physical activity between healthy and unhealthy obese groups by using both self-report and wrist-worn accelerometer assessments., Design: Cross-sectional analyses were based on 3457 adults aged 60-82 y (77% male) participating in the British Whitehall II cohort study in 2012-2013. Normal-weight, overweight, and obese adults were considered "healthy" if they had <2 of the following risk factors: low HDL cholesterol, hypertension, high blood glucose, high triacylglycerol, and insulin resistance. Differences across groups in total physical activity, based on questionnaire and wrist-worn triaxial accelerometer assessments (GENEActiv), were examined by using linear regression. The likelihood of meeting 2010 World Health Organization recommendations for moderate-to-vigorous activity (≥2.5 h/wk) was compared by using prevalence ratios., Results: Of 3457 adults, 616 were obese [body mass index (in kg/m²) ≥30]; 161 (26%) of those were healthy obese. Obese adults were less physically active than were normal-weight adults, regardless of metabolic health status or method of physical activity assessment. Healthy obese adults had higher total physical activity than did unhealthy obese adults only when assessed by accelerometer (P = 0.002). Healthy obese adults were less likely to meet recommendations for moderate-to-vigorous physical activity than were healthy normal-weight adults based on accelerometer assessment (prevalence ratio: 0.59; 95% CI: 0.43, 0.79) but were not more likely to meet these recommendations than were unhealthy obese adults (prevalence ratio: 1.26; 95% CI: 0.89, 1.80)., Conclusions: Higher total physical activity in healthy than in unhealthy obese adults is evident only when measured objectively, which suggests that physical activity has a greater role in promoting health among obese populations than previously thought.

Background: Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children., Objective: The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study., Design: We conducted a genomewide association study with 1.1 million genetic markers in 815 children., Results: We found serum uric acid to be significantly heritable [h(2) ± SD = 0.45 ± 0.08, P = 5.8 × 10(-11)] and associated with SLC2A9 variants (P values between 10(-16) and 10(-7)). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (ρG = 0.45, P = 0.002), percentage of body fat (ρG = 0.28, P = 0.04), fat mass (ρG = 0.34, P = 0.02), waist circumference (ρG = 0.42, P = 0.003), and waist-to-height ratio (ρG = 0.46, P = 0.001)., Conclusions: Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children., (© 2015 American Society for Nutrition.)

Background: Previously published research that examined the effects of high egg consumption in people with type 2 diabetes (T2D) produced conflicting results leading to recommendations to limit egg intake. However, people with T2D may benefit from egg consumption because eggs are a nutritious and convenient way of improving protein and micronutrient contents of the diet, which have importance for satiety and weight management., Objective: In this randomized controlled study, we aimed to determine whether a high-egg diet (2 eggs/d for 6 d/wk) compared with a low-egg diet (<2 eggs/wk) affected circulating lipid profiles, in particular high-density lipoprotein (HDL) cholesterol, in overweight or obese people with prediabetes or T2D., Design: A total of 140 participants were randomly assigned to one of the 2 diets as part of a 3-mo weight maintenance study. Participants attended the clinic monthly and were instructed on the specific types of foods and quantities to be consumed., Results: There was no significant difference in the change in HDL cholesterol from screening to 3 mo between groups; the mean difference (95% CI) between high- and low-egg groups was +0.02 mmol/L (-0.03, 0.08 mmol/L; P = 0.38). No between-group differences were shown for total cholesterol, low-density lipoprotein cholesterol, triglycerides, or glycemic control. Both groups were matched for protein intake, but the high-egg group reported less hunger and greater satiety postbreakfast. Polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid (MUFA) intakes significantly increased from baseline in both groups., Conclusions: High egg consumption did not have an adverse effect on the lipid profile of people with T2D in the context of increased MUFA and PUFA consumption. This study suggests that a high-egg diet can be included safely as part of the dietary management of T2D, and it may provide greater satiety. This trial was registered at the Australia New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) as ACTRN12612001266853., (© 2015 American Society for Nutrition.)

Background: Inverse associations between dairy intake and the risk of type 2 diabetes have been shown, but more studies are needed, especially from low- and middle-income countries., Objective: The objective was to describe the association between dairy products and direct measures of glycemic status in adults without known diabetes., Design: The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) includes 15,105 adults, aged 35-74 y, enrolled from universities and research institutions in 6 Brazilian capital cities. We excluded participants with a known diabetes diagnosis, cardiovascular diseases, and cancer. Dairy consumption was assessed by a food-frequency questionnaire, and we computed servings per day for total and subgroups of dairy. Associations with fasting blood glucose (FG) and fasting insulin, 2-h postload glucose (PG), 2-h postload insulin (PI), glycated hemoglobin (Hb A1c), and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed through multivariable linear regression analysis with adjustment for demographic characteristics, behavioral risk factors, other dietary factors, and anthropometric measurements., Results: The sample size after exclusions was 10,010. The intake of total dairy was inversely associated with FG (linear β for dairy servings/d = -0.46 ± 0.2 mg/dL), PG (-1.25 ± 0.5 mg/dL), PI (-1.52 ± 0.6 mg/dL), Hb A1c (-0.02 ± 0.0%), and HOMA-IR (-0.04 ± 0.0) after adjustment for all covariates (P < 0.05 for all). The findings were consistent across categories of sex, race, obesity status, and dairy fat amount (reduced-fat vs. full-fat dairy). Fermented dairy products showed particularly strong inverse associations with the outcomes, with adjusted differences for a 1-serving/d increment of -0.24 (95% CI: -0.46, -0.02) mg/dL for FG, -0.86 (-1.42, -0.30) mg/dL for PG, and -0.01% (-0.02%, 0.00%) for Hb A1c. Myristic acid was the only nutrient that appeared to mediate the association between dairy intake and glycemia., Conclusion: Dairy intake, especially fermented dairy, was inversely associated with measures of glycemia and insulinemia in Brazilian adults without diagnosed diabetes. This trial was registered at clinicaltrials.com as NCT02320461., (© 2015 American Society for Nutrition.)

Background: There is limited evidence with regard to the effect of different sources of protein on appetite during weight loss. Vegetarian and meat-based high-protein diets may have contrasting effects on appetite and biomarkers of protein-induced satiety., Objective: The aim was to assess appetite response to meat or vegetarian high-protein weight-loss (HPWL) diets in obese men to monitor plasma amino acid profile and gut peptide response as potential satiety biomarkers., Design: Twenty obese [body mass index (in kg/m²): 34.8] men participated in a dietary intervention study. After 3 d of a maintenance diet, they were provided in a crossover design with either a vegetarian HPWL (Soy-HPWL) or a meat-based HPWL (Meat-HPWL) diet for 2 wk. Both diets comprised 30% protein, 30% fat, and 40% carbohydrate, provided to measured resting metabolic rate. Body weight and the motivation to eat were measured daily. Plasma satiety biomarkers were collected during a test-meal challenge (5 h) at the end of each diet period., Results: Over the 2 wk, subjects lost, on average, 2.41 and 2.27 kg with consumption of the Soy- and Meat-HPWL diets, respectively [P = 0.352; SE of the difference (SED): 0.1]. ANOVA confirmed that subjectively rated hunger (P = 0.569; SED: 3.8), fullness (P = 0.404; SED: 4.1), desire to eat (P = 0.356; SED: 3.7), preservation of lean body mass (P = 0.334; SED: 0.2), and loss of percentage fat mass (P = 0.179; SED: 0.2) did not differ between the 2 HPWL diets. There were differences in absolute concentrations of ghrelin and peptide YY between the 2 HPWL diets, although the response as net area under the curve was not different., Conclusions: Appetite control and weight loss were similar for both HPWL diets. Gut hormone profile was similar between the diets, which suggests that vegetarian diets can be as effective as meat-based diets for appetite control during weight loss., (© 2014 American Society for Nutrition.)

Background: Higher whole-grain (WG) intake is associated with a lower prevalence of metabolic syndrome (MetS); however, there is inconsistent clinical evidence with regard to the benefit of WGs compared with refined grains (RGs) on MetS., Objective: We hypothesized that consuming WGs in the place of RGs would improve MetS criteria in individuals with or at risk of MetS., Design: A randomized, controlled, open-label parallel study was conducted in 50 overweight and obese individuals with increased waist circumference and one or more other MetS criteria. Participants consumed a controlled weight-loss diet containing either WG or RG (control) products for 12 wk. Body composition, MetS criteria and related markers, and plasma alkylresorcinols (compliance marker of WG intake) were measured at baseline and at 6 and 12 wk. A subgroup (n = 28) underwent magnetic resonance imaging to quantify subcutaneous and visceral adipose tissue (AT)., Results: Baseline variables were not significantly different between groups; however, the RG group tended to have higher triglycerides and lower high-density lipoprotein (HDL) cholesterol (P = 0.06). Alkylresorcinols increased with consumption of the WG diet and did not change with consumption of the RG diet (time × treatment, P < 0.0001), which showed dietary compliance. There were no differences in anthropometric changes between groups; however, weight, body mass index, and percentage of body AT decreased at both 6 and 12 wk (P < 0.05), and reductions in percentage of abdominal AT occurred by 6 wk and did not change between 6 and 12 wk (P = 0.09). Both glucose (P = 0.02) and HDL cholesterol (P = 0.04) were lower with the consumption of the WG compared with the RG diet. However, when noncompliant individuals (n = 3) were removed, the glucose effect was stronger (P = 0.01) and the HDL-cholesterol effect was no longer significant (P = 0.14)., Conclusions: Replacing RGs with WGs within a weight-loss diet does not beneficially affect abdominal AT loss and has modest effects on markers of MetS. WGs appear to be effective at normalizing blood glucose concentrations, especially in those individuals with prediabetes., (© 2014 American Society for Nutrition.)

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance, the metabolic syndrome, and type 2 diabetes. Because many non-Western immigrants in the Netherlands are vitamin D deficient, obese, and at high risk of diabetes, vitamin D supplementation may contribute to prevent diabetes and insulin resistance., Objective: We examined the effect of vitamin D supplementation on insulin sensitivity and β cell function in overweight, vitamin D-deficient, non-Western immigrants at high risk of diabetes., Design: The study was a 16-wk, randomized, placebo-controlled trial. A total of 130 non-Western immigrants with prediabetes (fasting glucose concentration >5.5 mmol/L or random glucose concentration from 7.8 to 11.1 mmol/L) and vitamin D deficiency (serum 25[OH]D concentration <50 nmol/L) were randomly assigned after stratification by sex to receive either cholecalciferol (1200 IU/d) or a placebo for 16 wk. All participants received 500 mg Ca/d as calcium carbonate. The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment. Secondary outcomes were insulin-sensitivity variables, β cell-function variables, and metabolic syndrome., Results: Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups. After 4 mo of therapy, the mean between-group difference was 38 nmol/L (95% CI: 32.1, 43.9 nmol/L; P < 0.001). There was no significant effect on insulin sensitivity and β cell function. In a post hoc analysis, when patients with diabetes at baseline were excluded, a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L (P = 0.040)., Conclusions: Vitamin D supplementation in non-Western vitamin D-deficient immigrants with prediabetes did not improve insulin sensitivity or β cell function or change the incidence of metabolic syndrome. However, after the exclusion of diabetic subjects, an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. This trial was registered at trialregister.nl as NTR1827., (© 2014 American Society for Nutrition.)

Background: Obesity and other noncommunicable disease (NCD) risk factors are increasing in low- and middle-income countries. There are few data on the association between increased added sugar intake and NCD risk in these countries., Objective: We assessed the relation between added sugar intake and NCD risk factors in an African cohort study. Added sugars were defined as all monosaccharides and disaccharides added to foods and beverages during processing, cooking, and at the table., Design: We conducted a 5-y follow-up of a cohort of 2010 urban and rural men and women aged 30-70 y of age at recruitment in 2005 from the North West Province in South Africa., Results: Added sugar intake, particularly in rural areas, has increased rapidly in the past 5 y. In rural areas, the proportion of adults who consumed sucrose-sweetened beverages approximately doubled (for men, from 25% to 56%; for women, from 33% to 63%) in the past 5 y. After adjustment, subjects who consumed more added sugars (≥10% energy from added sugars) compared with those who consumed less added sugars had a higher waist circumference [mean difference (95% CI): 1.07 cm (0.35, 1.79 cm)] and body mass index (in kg/m²) [0.43 (0.12, 0.74)] and lower HDL cholesterol [-0.08 mmol/L (-0.14, 0.002 mmol/L)]., Conclusions: This cohort showed dramatic increases in added sugars and sucrose-sweetened beverage consumption in both urban and rural areas. Increased consumption was associated with increased NCD risk factors. In addition, the study showed that the nutrition transition has reached a remote rural area in South Africa. Urgent action is needed to address these trends., (© 2014 American Society for Nutrition.)

Background: Recent studies have reported beneficial effects of probiotics on maternal glycemia in healthy pregnant women. Obesity significantly increases risk of impaired glucose tolerance in pregnancy, but glycemic effects of probiotics in this specific obstetric group require additional investigation., Objective: The aim of the Probiotics in Pregnancy Study was to investigate the effect of a probiotic capsule on maternal fasting glucose in obese pregnant women., Design: In this placebo-controlled, double-blind, randomized trial, 175 pregnant women with an early pregnancy body mass index (BMI; in kg/m²) from 30.0 to 39.9 were recruited from antenatal clinics at the National Maternity Hospital, Dublin, Ireland. Exclusion criteria were BMI <30.0 or >39.9, prepregnancy or gestational diabetes, age <18 y, multiple pregnancy, and fetal anomaly. Women were randomly assigned to receive either a daily probiotic or a placebo capsule from 24 to 28 wk of gestation in addition to routine antenatal care. The primary outcome was the change in fasting glucose between groups from preintervention to postintervention. Secondary outcomes were the incidence of gestational diabetes and neonatal anthropometric measures., Results: In 138 women who completed the study (63 women in the probiotic group; 75 women in the placebo group), mean (±SD) early pregnancy BMI was 33.6 ± 2.6, which differed significantly between probiotic (32.9 ± 2.4) and placebo (34.1 ± 2.7) groups. With adjustment for BMI, the change in maternal fasting glucose did not differ significantly between treated and control groups [-0.09 ± 0.27 compared with -0.07 ± 0.39 mmol/L; P = 0.391; B = -0.05 (95% CI: -0.17, 0.07)]. There were also no differences in the incidence of impaired glycemia (16% in the probiotic group compared with 15% in the placebo group; P = 0.561), birth weight (3.70 kg in the probiotic group compared with 3.68 kg in the placebo group; P = 0.723), or other metabolic variables or pregnancy outcomes. A secondary analysis of 110 women, excluding antibiotic users and poor compliers, also revealed no differences in maternal glucose or other outcomes between groups., Conclusion: Probiotic treatment of 4 wk during pregnancy did not influence maternal fasting glucose, the metabolic profile, or pregnancy outcomes in obese women., (© 2014 American Society for Nutrition.)

Background: Vitamin D deficiency is associated with obesity; whether repletion supports weight loss and changes obesity-related biomarkers is unknown., Objective: We compared 12 mo of vitamin D3 supplementation with placebo on weight, body composition, insulin, and C-reactive protein (CRP) in postmenopausal women in a weight-loss intervention., Design: A total of 218 overweight/obese women (50-75 y of age) with serum 25-hydroxyvitamin D [25(OH)D] ≥10 ng/mL but <32 ng/mL were randomly assigned to weight loss + 2000 IU oral vitamin D3/d or weight loss + daily placebo. The weight-loss intervention included a reduced-calorie diet (10% weight loss goal) and 225 min/wk of moderate-to-vigorous aerobic activity. Mean 12-mo changes in weight, body composition, serum insulin, CRP, and 25(OH)D were compared between groups (intent-to-treat) by using generalized estimating equations., Results: A total of 86% of participants completed the 12-mo measurements. The mean (95% CI) change in 25(OH)D was 13.6 (11.6, 15.4) ng/mL in the vitamin D3 arm compared with -1.3 (-2.6, -0.3) ng/mL in the placebo arm (P < 0.0001). Changes in weight [-7.1 (-8.7, -5.7) compared with -7.4 (-8.1, -5.4) kg], body mass index (in kg/m(2): both -2.8), waist circumference [-4.9 (-6.7, -2.9) compared with -4.5 (-5.6, -2.6) cm], percentage body fat [-4.1 (-4.9, -2.9) compared with -3.5 (-4.5, -2.5)], trunk fat [-4.1 (-4.7, -3.0) compared with -3.7 (-4.3, -2.9) kg], insulin [-2.5 (-3.4, -1.7) compared with -2.4 (-3.3, -1.4) μU/mL], and CRP [-0.9 (-1.2, -0.6) compared with -0.79 (-0.9, -0.4) mg/L] [corrected] were similar between groups (all P > 0.05). Compared with women who achieved 25(OH)D <32 ng/mL, women randomly assigned to vitamin D who became replete (ie, 25(OH)D ≥32 ng/mL) lost more weight [-8.8 (-11.1, -6.9) compared with -5.6 (-7.2, -5.0) kg; P = 0.05], waist circumference [-6.6 (-9.3, -4.3) compared with -2.5 (-4.6, -2.0) cm; P = 0.02], and percentage body fat [-4.7 (-6.1, -3.5) compared with -2.6 (-3.9, -2.2); P = 0.04]. Among women with complete pill counts (97% adherence), the mean decrease in CRP was 1.18 mg/mL (46%) in the vitamin D arm compared with 0.46 mg/mL (25%) in the placebo arm (P = 0.03)., Conclusions: Vitamin D3 supplementation during weight loss did not increase weight loss or associated factors compared with placebo; however, women who became replete experienced greater improvements. This trial was registered at clinicaltrials.gov as NCT01240213.

Background: Lower vitamin D status during gestation may be associated with cardiovascular disease risk later in life. No studies have assessed this hypothesis with a follow-up time reaching beyond childhood., Objective: The objective was to assess the link between season of birth, neonatal 25-hydroxyvitamin D₃ [25(OH)D₃] status, and adult cardiovascular disease risk., Design: Markers of cardiovascular and metabolic disease risk were measured in 284 subjects aged 35 y, born either at the end of the winter or at the end of the summer of 1975. In 275 of these 284 subjects, concentrations of neonatal 25(OH)D₃ were measured in dried blood samples by using a highly sensitive liquid chromatography-tandem mass spectroscopy method., Results: Subjects born after the winter had lower neonatal 25(OH)D₃ concentrations than did those born after the summer (31.5 compared with 48.5 nmol/L; P < 0.001). In regression analyses adjusted for sex, season of birth, postnatal age at neonatal sample collection, preterm birth, maternal age, education, smoking, fish consumption per week, exercise per week, and current 25-hydroxyvitamin D, higher neonatal 25(OH)D₃ (per 50 nmol/L) was associated with 25.8% (95% CI: 1.0%, 58.4%) higher fasting insulin in adult life, 29.6% (5.1%, 58.4%) higher triglycerides, and 4.64 (95% CI: 1.93, 7.36) mmol/L higher serum cholesterol in women. Neonatal 25(OH)D₃ (per 1 nmol/L) was directly associated with risk of adult overweight (OR: 1.03; 95% CI: 1.01, 1.05) and with adult obesity in women (OR: 1.09; 95% CI: 1.02, 1.17). Neonatal 25(OH)D₃ was not associated with adult aortic pulse wave velocity, blood pressure, fasting glucose, HDL, LDL, or C-reactive protein. Season of birth was not associated with any of the adult outcomes., Conclusions: Higher neonatal 25(OH)D₃ was associated with higher fasting insulin, triglyceride, and cholesterol (in women) concentrations and with a higher risk of overweight at 35 y of age but not with other adult cardiovascular disease risk factors.

Background: Reports have suggested that the consumption of dairy foods may reduce risk of type 2 diabetes on the basis of evidence of raised circulating ruminant fatty acids., Objective: We determined whether certain phospholipid species and fatty acids that are associated with full-fat dairy consumption may also be linked to diminished insulin resistance., Design: Four variables of insulin resistance and sensitivity were defined from oral-glucose-tolerance tests in 86 overweight and obese subjects with metabolic syndrome. Plasma phospholipids, sphingolipids, and fatty acids were determined by using a lipidomic analysis and gas chromatography-mass spectrometry to provide objective markers of dairy consumption. Food records provided information on dairy products. Associations were determined by using linear regression analyses adjusted for potential confounders age, sex, systolic blood pressure, waist:hip ratio, or body mass index (BMI) and corrected for multiple comparisons., Results: Lysophosphatidylcholine, lyso-platelet-activating factor, and several phospholipid fatty acids correlated directly with the number of servings of full-fat dairy foods. Lysophosphatidylcholine and lyso-platelet-activating factor were also associated directly with insulin sensitivity when accounting for the waist:hip ratio (Matsuda index unadjusted, P < 0.001 for both; adjusted for multiple comparisons, P < 0.02 for both) and inversely with insulin resistance (fasting insulin unadjusted, P < 0.001 for both; adjusted, P = 0.04 and P < 0.05, respectively; homeostasis model assessment of insulin resistance adjusted, P = 0.04 for both; post-glucose insulin area under the plasma insulin curve during the 120 min of the test adjusted, P < 0.01 for both). The substitution of BMI for the waist:hip ratio attenuated associations modestly. Phospholipid fatty acid 17:0 also tended to be associated directly with insulin sensitivity and inversely with resistance., Conclusion: Variables of insulin resistance were lower at higher concentrations of specific plasma phospholipids that were also indicators of full-fat dairy consumption. This trial was registered at clinicaltrials.gov as NCT00163943.

Background: Medium-chain triglyceride (MCT) supplements are used by clinicians to treat patients with severe hypertriglyceridemia who are at risk of pancreatitis. However, the potential mechanisms underlying the effects of MCT on triglyceride-rich lipoprotein (TRL) metabolism have not yet been thoroughly examined in humans., Objective: This double-blind randomized crossover study compared the impact of 4 wk of supplementation with 20 g MCT oil/d or 20 g corn oil/d on the kinetics of apolipoprotein (apo) B-48-containing TRLs and apo B-100-containing very-low-density lipoprotein (VLDL), as well as on the expression of key intestinal genes involved in lipid metabolism in 28 obese, insulin-resistant men., Design: The in vivo kinetics of TRL apo B-48 and VLDL apo B-100 were assessed by using a primed-constant infusion of l-[5,5,5-d3]leucine for 12 h in the fed state. Real-time polymerase chain reaction quantification was performed on duodenal biopsy samples taken at the end of each phase of supplementation., Results: Compared with corn oil, MCT supplements had no significant effect on plasma lipoprotein profile or TRL apo B-48 and VLDL apo B-100 kinetics. Positive correlations were observed between the intestinal expression of several key genes involved in lipoprotein metabolism in a subgroup of participants (n = 16) after MCT supplementation. However, there was no difference between MCT and the corn oil control supplement in the intestinal messenger RNA expression levels of these key genes., Conclusion: These data indicate that short-term supplementation with MCT has a neutral effect on TRL apo B-48 and VLDL apo B-100 kinetics and on the intestinal expression of genes involved in lipid and fatty acid metabolism in men with insulin resistance. This trial was registered at www.clinicaltrials.gov as NCT01806142.