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This study examined associations between BMI and dietary sugar intake with sucrose-induced fibroblast growth factor 21 (FGF21) and whether circulating FGF21 is associated with brain signaling following sucrose ingestion in humans.A total of 68 adults (29 male; mean [SD), age 23.2 [3.8] years; BMI 27.1 [4.9] kg/mHigher circulating FGF21 levels were associated with reduced blood flow in the striatum in response to sucrose (β = -7.63, p = 0.03). This association was greatest among persons with healthy weight (β = -15.70, p = 0.007) and was attenuated in people with overweight (β = -4.00, p = 0.63) and obesity (β = -12.45, p = 0.13). BMI was positively associated with FGF21 levels in response to sucrose (β = 0.53, p = 0.02). High versus low dietary sugar intake was associated with greater FGF21 responses to acute sucrose ingestion in individuals with healthy weight (β = 8.51, p = 0.04) but not in individuals with overweight or obesity (p0.05).These correlative findings support evidence in animals showing that FGF21 acts on the brain to regulate sugar consumption through a negative feedback loop.

OBJECTIVE This study investigated whether brain regions involved in the regulation of food intake respond differently to glucose ingestion in children and adults and the relationship between brain responses and weight status. METHODS Data included 87 children (ages 7-11 years) and 94 adults (ages 18-35 years) from two cohorts. Healthy weight, overweight, and obesity were defined by Centers for Disease Control and Prevention criteria. Brain responses to glucose were determined by measuring cerebral blood flow using arterial spin labeling magnetic resonance imaging in brain regions involved in the regulation of eating behavior. RESULTS Children showed significantly larger increases in brain responses to glucose than adults in the dorsal striatum (p < 0.01), insula (p < 0.01), hippocampus (p < 0.01), and dorsal-lateral prefrontal cortex (p < 0.01). Responses to glucose in the dorsal striatum (odds ratio [OR] = 1.52, 95% CI 1.05-2.20; p = 0.03), hippocampus (OR = 1.51, 95% CI: 1.02-2.22; p = 0.04), insula (OR = 1.64, 95% CI: 1.11-2.42; p = 0.01), and orbitofrontal cortex (OR = 1.63 95% CI: 1.12-2.39; p = 0.01) were positively associated with overweight or obesity, independent of age group. CONCLUSIONS Children have greater brain responses to glucose ingestion than adults in regions involved in eating behavior, and these responses are associated with weight status.

Context Growing evidence suggests an important role for sleep for the metabolic health of children. Objective We aimed to determine how sleep is related to insulin sensitivity, insulin secretion, beta-cell function, and adiposity (BMI z-scores, body fat %, waist to height ratio) using objectively measured sleep and oral glucose tolerance test (OGTT)-derived measures. Methods Sixty-two children aged 7-11 years, born at Kaiser Permanente Southern California, wore wrist accelerometers for 7 days to objectively measure sleep, completed an OGTT, and had anthropometric measures (height [cm], weight [kg], waist [cm], body fat [%]) collected. Using linear regression, associations between Matsuda insulin sensitivity index (ISI), insulinogenic index (IGI), disposition index (DI), BMI z-score, waist to height ratio, and body fat % with sleep parameters [total sleep time (TST; min), sleep efficiency (SE; %), time in bed (TIB; min), wake after sleep onset (WASO; min), and sleep latency (SL; min)] were assessed. Body fat % was tested as a mediator of the relationship between TST and ISI. Results Longer TST was associated with better insulin sensitivity (P = 0.02), but not after adjusting for body fat %. Sleep parameters were not associated with IGI or DI. Longer TST was associated with lower % body fat (P = 0.01) and lower waist-to-height-ratios (P = 0.05). Body fat % explained 62% (P = 0.01) of the relationship between TST and ISI. Longer TIB was associated with lower adiposity measures (P Conclusion Objectively measured sleep duration was associated with lower adiposity, and the relationship between sleep duration and ISI appeared partly through adiposity levels in preadolescent children. Longer sleep duration may be important for metabolic health.

Intrauterine exposure to metabolic dysfunction leads to offspring metabolic dysfunction in human and rodent models, but underlying mechanisms are unclear. The mediobasal hypothalamus (MBH) is involved in energy homeostasis and weight regulation, and MBH gliosis associates with obesity and insulin resistance. We tested the hypothesis that offspring exposed to gestational diabetes mellitus (GDM) in utero vs those unexposed would demonstrate evidence of MBH gliosis. Participants in the BrainChild Study (age 7-11 years, with confirmed GDM exposure or no GDM exposure) underwent brain magnetic resonance imaging to acquire T2 weighted images. By using the amygdala (AMY) and white matter (WM) as reference regions, MBH:AMY and MBH:WM T2 signal ratios were calculated as a radiologic measure of MBH gliosis. Linear regressions examined associations between GDM exposure (GDM overall, and by timing of GDM exposure (£26 weeks or >26 weeks) and MBH gliosis. Secondary analyses examined associations between pre-pregnancy BMI and child MBH gliosis. There were no differences in T2 signal ratios in children exposed vs unexposed to GDM overall, but children exposed to early GDM (<26 weeks gestation) had higher MBH:WM ratios compared to unexposed (β=0.147, SE 0.06; p=0.03), adjusting for child’s age, sex, BMI z-score and maternal pre-pregnancy BMI; whereas no associations were seen for the control ratio. Pre-pregnancy BMI was not associated with evidence of MBH gliosis. Early exposure to GDM was associated with radiologic evidence of MBH gliosis in children. These data provide mechanistic insight into brain pathways by which exposure to GDM may increase risk for metabolic dysfunction.

Children of overweight and obese parents have an increased risk of obesity. Little is known the neural mechanisms underlying this relationship, specifically the brain systems implicated in self-regulation of food intake. The primary goal here is to examine relationships between maternal body mass index (BMI) and brain responses to food cues in children. Seventy-six children (8.62 ± 1.02 years; 28 M,48F) were included in this study. Height and weight were assessed for children and their biological parents. Maternal height and weight before pregnancy were extracted from the Electronic Medical Records (EMR). BMI (kg/m(2)) or BMIz (age- and sex-specific BMI) were calculated. Children underwent a magnetic resonance imaging session where they viewed food and non-food images before and after glucose ingestion. The dorsolateral prefrontal cortex (dlPFC) and anterior cingulate cortex (ACC) food cue reactivity was the measurement of interest for region-of-interest (ROI) analyses. Whole-brain exploratory analysis was performed as well. Non-parametric methods were used for data analysis. ROI and whole brain analyses showed that maternal current BMI was inversely associated with child’s ACC and dlPFC food cue reactivity after glucose ingestion, adjusting for age and sex. No significant relationships were found between paternal BMI and child’s food cue reactivity. Child BMIz was negatively associated with the ACC food cue reactivity after glucose ingestion. Our results supported the role of maternal adiposity on child’s responses to appetitive food cues in brain self-regulation circuitry, which may influence eating behavior and obesity risk in children.

Key Points Question Are adiposity and sex associated with neural, metabolic, and behavioral responses to consumption of nonnutritive sweeteners (NNSs) vs nutritive sugar? Findings In this randomized crossover trial, both obesity and female sex were associated with differential neural food cue responsivity in reward processing areas following ingestion of sucralose (an NNS) compared with sucrose (nutritive sugar). Meaning These findings suggest that female individuals and those with obesity have greater neural reward responses to NNS vs nutritive sugar consumption, highlighting the need to consider individual biological factors that might influence the efficacy of NNS., This randomized crossover trial examines neural reactivity to different types of high-calorie food cues, metabolic responses, and eating behavior following sucralose vs sucrose consumption among healthy young adults., Importance Nonnutritive sweeteners (NNSs) are used as an alternative to nutritive sweeteners to quench desire for sweets while reducing caloric intake. However, studies have shown mixed results concerning the effects of NNSs on appetite, and the associations between sex and obesity with reward and appetitive responses to NNS compared with nutritive sugar are unknown. Objective To examine neural reactivity to different types of high-calorie food cues (ie, sweet and savory), metabolic responses, and eating behavior following consumption of sucralose (NNS) vs sucrose (nutritive sugar) among healthy young adults. Design, Setting, and Participants In a randomized, within-participant, crossover trial including 3 separate visits, participants underwent a functional magnetic resonance imaging task measuring blood oxygen level–dependent signal in response to visual cues. For each study visit, participants arrived at the Dornsife Cognitive Neuroimaging Center of University of Southern California at approximately 8:00 am after a 12-hour overnight fast. Blood was sampled at baseline and 10, 35, and 120 minutes after participants received a drink containing sucrose, sucralose, or water to measure plasma glucose, insulin, glucagon-like peptide(7-36), acyl-ghrelin, total peptide YY, and leptin. Participants were then presented with an ad libitum meal. Participants were right-handed, nonsmokers, weight-stable for at least 3 months before the study visits, nondieters, not taking medication, and with no history of eating disorders, illicit drug use, or medical diagnoses. Data analysis was performed from March 2020 to March 2021. Interventions Participants ingested 300-mL drinks containing either sucrose (75 g), sucralose (individually sweetness matched), or water (as a control). Main Outcomes and Measures Primary outcomes of interest were the effects of body mass index (BMI) status and sex on blood oxygen level–dependent signal to high-calorie food cues, endocrine, and feeding responses following sucralose vs sucrose consumption. Secondary outcomes included neural, endocrine, and feeding responses following sucrose vs water and sucralose vs water (control) consumption, and cue-induced appetite ratings following sucralose vs sucrose (and vs water). Results A total of 76 participants were randomized, but 2 dropped out, leaving 74 adults (43 women [58%]; mean [SD] age, 23.40 [3.96] years; BMI range, 19.18-40.27) who completed the study. In this crossover design, 73 participants each received water (drink 1) and sucrose (drink 2), and 72 participants received water (drink 1), sucrose (drink 2), and sucralose (drink 3). Sucrose vs sucralose was associated with greater production of circulating glucose, insulin, and glucagon-like peptide–1 and suppression of acyl-ghrelin, but no differences were found for peptide YY or leptin. BMI status by drink interactions were observed in the medial frontal cortex (MFC; P for interaction < .001) and orbitofrontal cortex (OFC; P for interaction = .002). Individuals with obesity (MFC, β, 0.60; 95% CI, 0.38 to 0.83; P

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that regulates energy homeostasis. In humans, few studies have investigated whether FGF21 may act to suppress sugar intake and influence eating behavior, and the effects of adiposity on post-ingestive FGF21 regulation of appetite are unknown. Here, we demonstrate among two cohorts of healthy, young adults that acute oral fructose and sucrose compared to glucose lead to greater circulating FGF21. Moreover, high compared to low dietary added sugar intake is associated with greater sucrose-stimulated FGF21 among participants with healthy weight but attenuated in people with overweight and obesity. In addition, our study is the first to demonstrate associations between circulating FGF21 and neural signaling following an acute sucrose load among humans with healthy weight. Collectively, our results suggest that these potential compensatory relationships between sucrose-stimulated circulating FGF21, habitual sugar intake, and post-ingestive brain responses may be altered among adults with overweight and obesity.Significance StatementAnimal models have established FGF21 as an autoregulator of sweet consumption, but few studies have examined post-ingestive FGF21 effects in humans. In this report, we demonstrate a compensatory relationship between sucrose-stimulated FGF21 and high dietary added sugar intake through a potential liver-to-brain negative-feedback cycle among healthy, young adults. Notably, our findings also suggest that humans with overweight and obesity may have altered FGF21 neuroendocrine signaling.

OBJECTIVE Children exposed to gestational diabetes mellitus (GDM) or maternal obesity in utero have an increased propensity to develop obesity. Little is known about the mechanisms underlying this phenomenon. We aimed to examine relationships between exposure to GDM or maternal obesity and daily energy intake (EI), brain responses to food cues within reward regions, and adiposity in children. RESEARCH DESIGN AND METHODS Participants were 159 children ages 7–11 years. Repeated 24-h recalls were conducted to assess mean daily EI. A subset of children (n = 102) completed a food cue task in the MRI scanner. A priori regions of interest included the orbital frontal cortex (OFC), insula, amygdala, ventral striatum, and dorsal striatum. Adiposity measurements, BMI z-scores, percent body fat, waist-to-height ratio (WtHR), and waist-to-hip ratio (WHR) were assessed. RESULTS Exposure to GDM was associated with greater daily EI, and children exposed to GDM diagnosed before 26 weeks gestation had greater OFC food cue reactivity. Children exposed to GDM also had larger WHR. Results remained significant after adjusting for child’s age and sex, maternal education and race/ethnicity, maternal prepregnancy BMI, and child’s physical activity levels. Furthermore, children who consumed more daily calories had greater WHR, and the relationship between GDM exposure and WHR was attenuated after adjustment for daily EI. Prepregnancy BMI was not significantly related to daily EI or food cue reactivity in reward regions. However, prepregnancy BMI was significantly related to all adiposity measurements; results remained significant for BMI z-scores, WtHR, and WHR after controlling for child’s age and sex, maternal education and race/ethnicity, maternal GDM exposure, and child’s physical activity levels. CONCLUSIONS Exposure to GDM in utero, in particular before 26 weeks gestation, is associated with increased EI, enhanced OFC food cue reactivity, and increased WHR. Future study with longitudinal follow-up is merited to assess potential pathways of daily EI and food cue reactivity in reward regions on the associations between GDM exposure and childhood adiposity.

Background/Objectives: With rising obesity rates among pregnant women, more children are exposed in utero to maternal obesity. In prior epidemiological studies, exposure to maternal obesity was associated with lower intelligence quotient (IQ) scores and worse cognitive abilities in offspring. Further studies have shown that offspring exposed to maternal obesity, exhibit differences in the white matter microstructure properties, fractional anisotropy (FA) and mean diffusivity (MD). In contrast, physical activity was shown to improve cognition and white matter microstructure during childhood. We examined if child physical activity levels modify the relationship between prenatal exposure to maternal obesity with IQ and white matter microstructure in offspring. Subjects/Methods: One hundred children (59% girls) age 7–11 years underwent brain magnetic resonance imaging and IQ testing. Maternal pre-pregnancy BMI was abstracted from electronic medical records. White matter was assessed using diffusion tensor imaging with the measures, global FA, MD. The 3-day physical activity recall was used to measure moderate-to-vigorous physical activity and vigorous physical activity (VPA). Linear regression was used to test for interactions between prenatal exposure to maternal overweight/obesity and child PA levels on child IQ and global FA/MD. Results: The relationship between prenatal exposure to maternal overweight/obesity and child IQ and global FA varied by child VPA levels. Children exposed to mothers with overweight/obesity who engaged in more VPA had higher IQ scores and global FA compared to exposed children who engaged in less VPA. Associations were independent of child age, sex, BMI Z-score and socioeconomic status. Children born to normal-weight mothers did not differ in either IQ or global FA by time in VPA. Conclusions: Our findings support findings in rodent models and suggest that VPA during childhood modifies the relationship between prenatal exposure to maternal obesity and child IQ and white matter microstructure.

Prenatal exposure to maternal obesity is linked to neurocognitive deficits in offspring. In contrast, engaging in physical activity (PA) is beneficial for cognition and brain development. We aimed to determine if greater PA is associated with higher intelligence quotient (IQ) scores and greater brain white matter integrity in children born to mothers with a range of pre-pregnancy BMI. Ninety-nine children (59 girls) ages 7-13 years completed the study. Maternal pre-pregnancy BMI was obtained from electronic medical records. Wechsler Abbreviated Scale of Intelligence was used to measure IQ. Diffusion tensor imaging was used to measure mean global fractional anisotropy (FA), a marker of white matter integrity. Time spent in moderate-to-vigorous PA (MVPA) and vigorous PA (VPA) was assessed using 3-day PA recalls. Linear regressions were used to assess whether maternal pre-pregnancy BMI or child MVPA and VPA were associated with child IQ scores and global FA. Maternal pre-pregnancy BMI ranged from 19.0-54.0 kg/m2 (43% obese). Mean±SD child IQ was 106.4±14.0, MVPA was 132.8±95.4 min/day, and VPA was 19.0±27.1 min/day. Maternal pre-pregnancy BMI was negatively associated with child IQ scores (β=-0.31; p=0.10); this marginal association remained after adjusting for child age, sex, puberty, BMI z-score, and socioeconomic status (β=-0.42; p=0.095). MVPA was not associated with child IQ (β=2.63; p=0.16). However, children who spent more time in VPA had higher IQ scores before (β=7.05; p=0.003) and after adjusting for the same co-variates (β=5.65; p=0.024) and further adjusting for maternal pre-pregnancy BMI (β=5.01; p=0.049). Children who spent more time in VPA also had greater mean global FA (unadjusted: β=0.01; p=0.017; adjusted: β=0.01; p=0.005). These findings suggest that engaging in VPA is beneficial for cognition and white matter microstructure in children, independent of maternal pre-pregnancy BMI. Disclosure J. Alves: None. B.C. Angelo: None. S.H. Luo: None. T. Chow: None. A.G. Yunker: None. A. Xiang: None. K.A. Page: None. J. Zink: None. B.R. Belcher: None. K. Clark: None. Funding American Diabetes Association (1-14-ACE-36 to K.A.P.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116858); National Institute of Mental Health (F31MH115640)

Children exposed to gestational diabetes mellitus (GDM) in utero have an increased propensity of developing obesity. Little is known about the mechanisms underlying this propensity. Here we examine the relationship between GDM exposure and its timing on energy intake (EI) and brain reward responses to food cues in children. Participants were 142 children (39% boys; 56% GDM-exposed) aged from 7 to 11 years old. GDM status was extracted from EMR. Adiposity measurements were collected. Repeated 24-hour recalls were conducted to assess mean daily EI (kcal/day). A subset (n=89) of children completed an MRI session where they viewed food and non-food cues. %signal change in the orbital frontal cortex (OFC), insula and amygdala for food vs. non-food contrast was measure of interest. GDM exposure was modeled by: 1) yes vs. no at any time in pregnancy and 2) GDM diagnosed at 26 weeks (late exposed) and unexposed. GDM exposure (vs. unexposed) was associated with greater EI (mean difference ±SE: 169 ±65, P=0.01) and OFC food cue reactivity (0.19±0.09, P=0.04). Results were strengthened after adjusting for age, sex, physical activity, SES and pre-pregnancy BMI (EI: P=0.008; OFC: P=0.024). In the adjusted models, both subgroups (early exposed(N=27): 178 ± 92, P=0.055; late exposed (N=53): 173±72, P=0.018) had greater EI than controls. Early exposed group had greater OFC food cue reactivity than controls (0.30±0.15, P=0.048) and the difference between late exposed and controls was marginally significant (0.20±0.11, P=0.07). Children exposed to GDM (vs. unexposed) had larger WHR (0.02±0.01, P=0.03), and this was driven by the difference between early exposed vs. controls (0.04±0.01, P=0.006). Exposure to GDM in utero, in particular before 26 weeks gestation, is associated with increased energy intake, enhanced OFC food cue reactivity and increased WHR. Whether these changes predict development of obesity remains to be determined. Disclosure S.H. Luo: None. B.C. Angelo: None. T. Chow: None. J. Alves: None. T.A. Buchanan: None. A. Xiang: None. K.A. Page: None. Funding National Institutes of Health (K01DK11563)

The hypothalamus has an abundant expression of sweet taste receptors that play a role in glucose sensing and energy homeostasis. Evidence suggests that liking “sweets” can be associated with weight gain, but the influence of sweet taste preference (STP) on hypothalamic regulation of appetite is unknown. We tested the hypothesis that STP is associated with increased hypothalamic activation in response to glucose (a potential marker of obesity risk), and that greater STP and glucose-linked hypothalamic activation would predict greater weight gain. Forty-six (24 female) adults age 18-35 years completed the study. Height and weight were measured at baseline and 6-12 months later in a subset of 38. STP was assessed via the Monell 2-series, forced-choice tracking procedure. Arterial spin labeling magnetic resonance imaging was performed before and ∼35 min after 75g glucose ingestion, and hypothalamic response to glucose was measured by calculating hypothalamic blood flow (BF) after minus before glucose ingestion. Linear regression was used to examine relationships between STP and the hypothalamic response to glucose and changes in BMI before and after adjusting for age, sex, BMI, mean cerebral BF, and baseline BMI. Baseline BMI was 27.61±5.13 kg/m2. STP scores ranged from 3% to 29.39% w/v. The hypothalamic response to glucose ranged from -14.64 to 15.63 ml/100g/min. Change in BMI ranged from -2.93 to 6.00 kg/m2. STP was positively associated with hypothalamic response to glucose (unadjusted: β=0.65, p Disclosure A.G. Yunker: None. J. Alves: None. B.C. Angelo: None. A.W. DeFendis: None. S.H. Luo: None. K.A. Page: None. Funding National Institutes of Health (R01DK102794)

In Table 1 of the above-cited article, data for GDM-exposed and unexposed children for characteristics daily energy intake (EI), moderate to vigorous physical activity (MVPA), and …

In rodent literature, there is evidence that excessive fructose consumption during development has a detrimental impact on hippocampal structure and function. In this study of 103 children ages 7&ndash, 11 years old, we investigated whether dietary fructose intake was related to alterations in hippocampal volume and connectivity in humans. To examine if these associations were specific to fructose or were related to dietary sugars intake in general, we explored relationships between dietary intake of added sugars and the monosaccharide, glucose, on the same brain measures. We found that increased dietary intake of fructose, measured as a percentage of total calories, was associated with both an increase in the volume of the CA2/3 subfield of the right hippocampus and increased axial, radial, and mean diffusivity in the prefrontal connections of the right cingulum. These findings are consistent with the idea that increased fructose consumption during childhood may be associated with an inflammatory process, and/or decreases or delays in myelination and/or pruning. Increased habitual consumption of glucose or added sugar in general were associated with an increased volume of right CA2/3, but not with any changes in the connectivity of the hippocampus. These findings support animal data suggesting that higher dietary intake of added sugars, particularly fructose, are associated with alterations in hippocampal structure and connectivity during childhood.