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Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

ObjectivesChronic pancreatitis (CP) is an inflammatory disease that affects the absorption of nutrients like fats. Molecular signaling in pancreatic cells can be influenced by fatty acids (FAs) and changes in FA abundance could impact CP-associated complications. Here, we investigated FA abundance in CP compared to controls and explored how CP-associated complications and risk factors affect FA abundance.MethodsBlood and clinical parameters were collected from subjects with (n=47) and without CP (n=22). Plasma was analyzed for relative FA abundance using gas chromatography and compared between controls and CP. Changes in FA abundance due to clinical parameters were also assessed in both groups.ResultsDecreased relative abundance of polyunsaturated fatty acids (PUFAs) and increased monounsaturated fatty acids (MUFAs) were observed in subjects with CP in a sex-dependent manner. The relative abundance of linoleic acid increased, and oleic acid decreased in CP subjects with exocrine pancreatic dysfunction and a history of substance abuse.ConclusionsPlasma FAs like linoleic acid are dysregulated in CP in a sex-dependent manner. Additionally, risk factors and metabolic dysfunction further dysregulate FA abundance in CP. These results enhance our understanding of CP and highlight potential novel targets and metabolism-related pathways for treating CP.

Cardiolipin (CL) is a phospholipid unique to the inner mitochondrial membrane that supports respiratory chain structure and function and is demonstrated to be influenced by types of dietary fats. However, the influence of dietary fat on CL species and how this best supports mitochondrial function in brown adipose tissue (BAT), which exhibits an alternative method of energy utilization through the uncoupling of the mitochondrial proton gradient to generate heat, is not well understood. Therefore, the aim of our study was to evaluate metabolic parameters, interscapular BAT CL quantity, species, and mitochondrial function in mice consuming isocaloric moderate-fat diets with either lard (LD; similar fatty acid profile to western dietary patterns) or safflower oil high in linoleic acid (SO), shown to be metabolically favorable in large clinical meta-analyses. Mice fed the SO diet exhibited decreased adiposity, improved insulin sensitivity, and enrichment of LA-containing CL species in BAT CL. Furthermore, mice fed the SO diet exhibit higher levels of OXPHOS complex proteins and increased oxygen consumption in BAT. Our findings demonstrate that dietary consumption of LA-rich oil improves metabolic parameters, increases LA-containing CL species, and improves BAT function when compared to the consumption of lard in mice during diet-induced weight gain.

Background Sarcopenia may hasten the risk of mortality in women with breast cancer. Long-chain omega-3 (n-3) polyunsaturated fatty acids (LCn-3PUFAs) may favor muscle mass which, in turn, could enhance resilience of cancer patients toward cancer treatment. Objectives The objective of this study was to measure the relation of erythrocyte LCn-3PUFA concentrations with lean mass, grip strength, and postprandial energy metabolism in women with newly diagnosed breast cancer. Methods This cross-sectional analysis evaluated women (n = 150) ages 65 y and younger who were recently diagnosed with breast cancer (stages I-III). Erythrocyte LCn-3PUFA composition was measured using GC. Body composition was measured by DXA. Grip strength was assessed at the same visit. Postprandial energy metabolism was measured for 7.5 h after the consumption of a high-calorie, high-saturated-fat test meal using indirect calorimetry. Associations of fatty acids with outcomes were analyzed using multiple linear regression models and linear mixed-effects models. Results The ω-3 index, a measurement of LCn-3PUFA status, was positively associated with appendicular lean mass (ALM)/BMI (β = 0.015, P = 0.01) and grip strength (β = 0.757, P = 0.04) after adjusting data for age and cancer stage. However, when cardiorespiratory fitness was also included in the analyses, these relations were no longer significant (P > 0.08). After a test meal, a higher ω-3 index was associated with a less steep rise in fat oxidation (P = 0.02) and a steeper decline in glucose (P = 0.01) when adjusting for age, BMI, cancer stage, and cardiorespiratory fitness. Conclusions The ω-3 index was positively associated with ALM/BMI and grip strength in women newly diagnosed with breast cancer and was associated with altered postprandial substrate metabolism. These findings warrant further studies to determine whether enriching the diet with LCn-3PUFAs during and after cancer treatments is causally linked with better muscle health and metabolic outcomes in breast cancer survivors.

Many commonly used chemotherapies induce mitochondrial dysfunction in cardiac muscle, which leads to cardiotoxicity and heart failure later in life. Dietary long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have demonstrated cardioprotective function in non-chemotherapy models of heart failure, potentially through the formation of LC n-3 PUFA-derived bioactive lipid metabolites. However, it is unknown whether dietary supplementation with LC n-3 PUFA can protect against chemotherapy-induced cardiotoxicity. To test this, 36 female ovariectomized C57BL/6J mice were randomized in a two-by-two factorial design to either a low (0 g/kg EPA + DHA) or high (12.2 g/kg EPA + DHA) LC n-3 PUFA diet, and received either two vehicle or two chemotherapy (9 mg/kg anthracycline + 90 mg/kg cyclophosphamide) tail vein injections separated by two weeks. Body weight and food intake were measured as well as heart gene expression and fatty acid composition. Heart mitochondria were isolated using differential centrifugation. Mitochondrial isolate oxylipin and N-acylethanolamide levels were measured by mass spectrometry after alkaline hydrolysis. LC n-3 PUFA supplementation attenuated some chemotherapy-induced differences (Myh7, Col3a1) in heart gene expression, and significantly altered various lipid species in cardiac mitochondrial preparations including several epoxy fatty acids [17(18)-EpETE] and N-acylethanolamines (arachidonoylethanolamine, AEA), suggesting a possible functional link between heart lipids and cardiotoxicity.

Higher circulating linoleic acid (LA) and muscle-derived tetralinoleoyl-cardiolipin (LAIn this randomized controlled trial, adults are instructed to consume one cookie per day delivering 10 g grapeseed (LA-cookie, N = 42) or high oleate (OA) safflower (OA-cookie, N = 42) oil. In the LA-cookie group, LA increases in plasma, erythrocyte, and PBMC by 6%, 7%, and 10% respectively. PBMC and erythrocyte OA increase by 7% and 4% in the OA-cookie group but is unchanged in the plasma. PBMC LALA-rich oil fortification increases while OA-oil has no effect on LA

Short-term (3-day) consumption of a high fat diet (HFD) rich in saturated fats is associated with a neuroinflammatory response and subsequent cognitive impairment in aged, but not young adult, male rats. This exaggerated effect in aged rats could be due to a “primed” microglial phenotype observed in the normal aging process in rodents in which aged microglia display a potentiated response to immune challenge. Here, we investigated the impact of HFD on microglial priming and lipid composition in the hippocampus and amygdala of young and aged rats. Furthermore, we investigated the microglial response to palmitate, the main saturated fatty acid (SFA) found in HFD that is proinflammatory. Our results indicate that HFD increased gene expression of microglial markers of activation indicative of microglial priming, including CD11b, MHCII, CX3CR1, and NLRP3, as well as the pro-inflammatory marker IL-1β in both hippocampus and amygdala-derived microglia. Furthermore, HFD increased the concentration of SFAs and decreased the concentration of polyunsaturated fatty acids (PUFAs) in the hippocampus. We also observed a specific decrease in the anti-inflammatory PUFA docosahexaenoic acid (DHA) in the hippocampus and amygdala of aged rats. In a separate cohort of young and aged animals, isolated microglia from the hippocampus and amygdala exposed to palmitate in vitro induced an inflammatory gene expression profile mimicking the effects of HFD in vivo. These data suggest that palmitate may be a critical nutritional signal from the HFD that is directly involved in hippocampal and amygdalar inflammation. Interestingly, microglial activation markers were increased in response to HFD or palmitate in an age-independent manner, suggesting that HFD sensitivity of microglia, under these experimental conditions, is not the sole mediator of the exaggerated inflammatory response observed in whole tissue extracts from aged HFD-fed rats.

Cachexia occurs in up to 80% of pancreatic ductal adenocarcinoma (PDAC) patients and is characterized by unintentional weight loss and tissue wasting. To understand the metabolic changes that occur in PDAC-associated cachexia, we compared the abundance of plasma fatty acids (FAs), measured by gas chromatography, of subjects with treatment-naïve metastatic PDAC with or without cachexia, defined as a loss of > 2% weight and evidence of sarcopenia (n = 43). The abundance of saturated, monounsaturated, and polyunsaturated FAs was not different between subjects with cachexia and those without. Oleic acid was significantly higher in subjects with cachexia (p = 0.0007) and diabetes (p = 0.015). Lauric (r = 0.592, p = 0.0096) and eicosapentaenoic (r = 0.564, p = 0.015) acids were positively correlated with age in cachexia patients. Subjects with diabetes (p = 0.021) or both diabetes and cachexia (p = 0.092) had low palmitic:oleic acid ratios. Linoleic acid was lower in subjects with diabetes (p = 0.018) and correlated with hemoglobin (r = 0.519, p = 0.033) and albumin (r = 0.577, p = 0.015) in subjects with cachexia. Oleic or linoleic acid may be useful treatment targets or biomarkers of cachexia in patients with metastatic PDAC, particularly those with diabetes.

Scope Cancer cachexia is characterized by the loss of skeletal muscle resulting in functional impairment, reduced quality of life and mortlity. Naringenin, a flavonoid found in citrus fruits, improves insulin sensitivity and reduces inflammation and tumor growth in preclinical models. Therefore, we hypothesized that dietary supplementation of naringenin would improve insulin sensitivity, decrease inflammation, slow body weight loss and delay tumor growth in a mouse model of cancer cachexia. Methods & results Mice were fed 2 wt% dietary naringenin before and during initiation of cancer cachexia using inoculated adenocarcinoma-26 cells (C-26). Food intake, body weight, body composition, muscle function, insulin tolerance, and inflammatory status were assessed. Although naringenin-fed tumor-bearing mice exhibited reductions in body weight and food intake earlier than control diet-fed tumor-bearing mice, dietary naringenin was protective against loss of muscle strength, and attenuated the onset of insulin resistance and markers of inflammation. Conclusions Dietary supplementation of naringenin improved multiple aspects of metabolic disturbance and inflammation during cancer cachexia progression in [C-26 tumor-bearing] mice. However, the acceleration of anorexia and weight loss was also observed. These findings emphasize the link between inflammation and insulin resistance as a basis for understanding their roles in the pathogenesis of cancer cachexia. This article is protected by copyright. All rights reserved.

While there is considerable evidence supporting health benefits of consuming diets high in omega-3 (n-3) fatty acids, there is no quick and effective tool to measure n-3 intake. The objective of this study was to evaluate the accuracy of a rapid assessment questionnaire (the Omega-3 Checklist) used to quantify intake of n-3 fatty acids. This was done by comparing n-3 intakes to blood biomarkers of n-3 exposure in a population of healthy men and women. In addition, a separate analysis was run including covariates age, sex, and weight, which have been shown to affect n-3 biomarker levels. Reported intake of eicosapentaenoic acid (EPA), docoshexaenoic acid (DHA), and EPA + DHA was correlated with erythrocyte EPA (Spearman's rank correlation rs = 0.51, p

Cachexia is responsible for nearly 20% of all cancer‑related deaths, yet effective therapies to prevent or treat the disease are lacking. Clinical studies have shown that male patients lose weight at a faster rate than females. Additionally, an 'obesity paradox' may exist where excess adiposity may confer survival to patients with cancer cachexia. To further explore these phenomena, the aim of this study was to evaluate the role of changes of adipose tissue mass, sex status, and tumor mass on outcomes of male, female and ovariectomized (OVX) mice with C‑26 adenocarcinoma‑induced cachexia. We used EchoMRI to assess body composition and grip strength to measure muscle function. Body weights and food intake were measured daily. Mice were euthanized 19 days post‑-inoculation. Post‑necropsy, muscle fiber cross‑sectional areas were quantified and real‑time PCR was performed for genes relating to proteolysis. Survival curve, correlation and multiple linear regression analyses were performed to identify predictors of cachexia. Female and OVX tumor mice developed cachexia similarly to males, as evidenced by loss of skeletal and adipose masses, decreased grip strength, and increased proteolytic gene expression. Notably, female and OVX tumor mice had earlier onset of cachexia (≥5% weight loss) than male tumor mice. Larger tumor mass and lower adipose mass were the strongest predicting factors for increased severity of cachexia, regardless of sex or ovariectomy status. These results indicated that the impact of sex status may be subtle in comparison to the predictive effect of tumor and adipose mass in mice with C‑26‑induced cachexia.

Polyunsaturated fats are energy substrates and precursors to the biosynthesis of lipid mediators of cellular processes. Adipose tissue not only provides energy storage, but influences whole-body energy metabolism through endocrine functions. How diet influences adipose–lipid mediator balance may have broad impacts on energy metabolism. To determine how dietary lipid sources modulate brown and white adipose tissue and plasma lipid mediators, mice were fed low-fat (15% kcal fat) isocaloric diets, containing either palm oil (POLF) or linoleate-rich safflower oil (SOLF). Baseline and post body weight, adiposity, and 2-week and post fasting blood glucose were measured and lipid mediators were profiled in plasma, and inguinal white and interscapular brown adipose tissues. We identified over 30 species of altered lipid mediators between diets and found that these changes were unique to each tissue. We identified changes to lipid mediators with known functional roles in the regulation of adipose tissue expansion and function, and found that there was a relationship between the average fold difference in lipid mediators between brown adipose tissue and plasma in mice consuming the SOLF diet. Our findings emphasize that even with a low-fat diet, dietary fat quality has a profound effect on lipid mediator profiles in adipose tissues and plasma.

OBJECTIVES: Anthracyclines damage the heart by binding to the inner mitochondrial membrane phospholipid cardiolipin and promoting mitochondrial dysfunction. Our goal is to characterize how anthracylcines change the fatty acid profile of cardiolipin, and the genes controlling cardiolipin synthesis and remodeling in order to develop dietary strategies to target cardiolipin within damaged hearts. METHODS: Male C57BL/6J mice were randomized to receive seven IP, anthracycline injections (one week apart) or saline control injections. Six hours after the final injection, mice were euthanized under isoflurane and hearts were collected for mRNA and cardiolipin species analysis. Cardiolipin was measured using liquid chromatography coupled to electrospray ionization mass spectrometry in an API 4000 mass spectrometer (Sciex, Framingham, MA). A student's t-test was used to determine significance between the groups. RESULTS: While the amount of tetralinolylcardiolipin (the major cardiolipin species in the heart) was not altered with anthracycline treatment, several other cardiolipin species were significantly increased, including cardiolipin species that contain arachidonic acid and docosahexaenoic acid. In addition we observed a significant decrease in the proportion of monolysocardiolipin species in the heart and a trend towards increased oxidized cardiolipin species given anthracycline treatment. CONCLUSIONS: Previous studies have shown the fatty acid composition of cardiolipin effects mitochondrial structure and function. Administration of anthracyclines alters cardiolipin species in the heart. Knowing that anthracyclines influences the fatty acid composition of cardiolipin, we can explore dietary interventions that favorably change cardiolipin fatty acid composition, with the goal of preventing anthracycline-induced heart damage by improving mitochondrial function. FUNDING SOURCES: Funding was provided by NIH R21CA185140, Ohio Agriculture Research and Development Center, the Carol S. Kennedy Professorship, and the Ohio State University Education and Human Ecology Dissertation Research Fellowship.

OBJECTIVES: Dietary fat quality alters the fatty acid composition of phospholipids in cell membranes. The fatty acid composition of the inner mitochondrial membrane phospholipid cardiolipin (CL) impacts mitochondria function where linoleic acid (LA) -rich cardiolipin, e.g., tetralinoleoyl-cardiolipin (L4CL). This study compared the effects of a LA-rich diet and a saturated fat (SF)-rich diet on L4CL in the liver of mice. METHODS: Male C57BL6/J mice (9 weeks, N = 24) randomized by body weight to a high fat diet (24% fat w/w) containing LA-rich safflower oil (SO) or SF-rich oil (LD) for 18 weeks. Food intake and body weight were measured every two days. Fasting blood glucose and body composition (Echo/MRI) were measured in the washout period and again 11 weeks later. Insulin tolerance test (ITT) measured insulin sensitivity on day 85, and mice were euthanized starting after day 100. Liver cardiolipin speciation was measured using HPLC/MS. A two-sample t-test at a 5% significance level was used to determine differences between diet groups. RESULTS: Body weight, cumulative food intake, adipose and lean tissues were not significantly different between diet groups at Day 130. Fasting glucose between diets was not significantly different at any timepoints throughout the study. Blood glucose during the ITT was significantly different between LA-rich and SF-rich diets for the last two time points, 90 minute and 120 minute. The SO diet increased hepatic L4CL (% of total CL) compared to the LD diet (P-value

OBJECTIVES: Linoleic acid (LA) is the major fatty acid in cardiolipin (CL), a phospholipid important for mitochondria function. Increasing dietary LA elevates tetralinoleoyl CL (LA(4) CL) in cardiac muscle of animals; however, it is not clear if dietary LA increases LA(4) CL in humans. The aim of this study was to determine if daily consumption of a cookie made with a LA-rich oil for two weeks could alter LA(4) CL in peripheral blood mononuclear cells (PBMC) in healthy adults. METHODS: In a double-masked placebo-controlled study, 84 healthy adults were randomly assigned to consume one cookie made with LA-rich grapeseed oil (LA-cookie) or one cookie made with oleic acid-rich (OA) safflower oil (OA-cookie), every day for two weeks. Fasting blood samples were collected for analysis of PBMC cardiolipin species. RESULTS: Daily consumption of the LA-cookie for 2 weeks increased LA(4) CL in PBMC, while consuming the OA-cookie did not alter LA(4) CL (group x week interaction p

Background The onset of menopause increases the risk of metabolic syndrome (MetS). Adiponectin is an adipokine associated with insulin sensitivity that is lower in people with MetS. Supplementing diets with linoleic acid (LA)-rich oil increased adiponectin concentrations and improved glucose control in women with type 2 diabetes. The effect of LA on adipokines, especially total and the bioactive form of adiponectin, high-molecular-weight (HMW) adiponectin, in women with MetS is unknown. Objectives The aim of this study was to explore the effect of supplementation of the diet with an oil rich in LA on adipokines in women with MetS. The effect of the LA-rich oil (LA-oil) on oxylipins, key metabolites that may influence inflammation and metabolism, was also explored. Methods In this open-label single-arm pilot study, 18 postmenopausal nondiabetic women with MetS enrolled in a 2-phase study were instructed to consume LA-rich vegetable oil (10 mL/d) as part of their habitual diets. Women consumed an oleic acid–rich oil (OA-oil) for 4 wk followed by an LA-oil for 16 wk. Fasting concentrations of adipokines, fatty acids, oxylipins, and markers of glycemia and inflammation were measured. Results After 4 wk of OA-oil consumption, fasting glucose and total adiponectin concentrations decreased whereas fasting C-reactive protein increased. After 16 wk of LA-oil supplementation total and HMW adiponectin and plasma oxylipins increased. Markers of inflammation and glycemia were unchanged after LA-oil consumption. Conclusions Supplementation with LA-oil increased total and HMW adiponectin concentrations and altered plasma oxylipin profiles. Larger studies are needed to elucidate the links between these changes and MetS. This trial was registered at clinicaltrials.gov as NCT02063165., The essential fatty acid, linoleate, affects glucose homeostasis. This article evaluates the addition of a small amount of linoleate-rich oil to increase the insulin-sensitizing adipokine, adiponectin.

Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n − 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n − 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n − 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n − 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n − 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n − 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. High-dose n − 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

OBJECTIVE The objective of this study was to evaluate the relationship between blood levels of adiponectin and leptin with lean body and trunk adipose mass in women with and without type 2 diabetes mellitus (T2DM). METHODS This cross-sectional study analyzed baseline data from five previous clinical studies involving postmenopausal women (n = 95). Body composition was assessed by dual-energy x-ray absorptiometry, and appendicular lean mass was calculated based on body mass index (ALMBMI). Adipokines and cytokines were measured by enzyme-linked immunosorbent assay. Linear mixed-effect models with a random study effect were used to investigate the relationship between predictors (eg, adiponectin, leptin), outcomes (eg, ALMBMI, trunk adipose mass), and co-variables (T2DM status, age, interleukin-6, and C-reactive protein). RESULTS Postmenopausal women with T2DM had lower ALMBMI than those without T2DM. There was a positive association between blood adiponectin and ALMBMI in postmenopausal women without T2DM, but no association in those with T2DM. Blood leptin was negatively associated with ALMBMI for women regardless of T2DM diagnosis. Blood adiponectin was negatively associated, whereas blood leptin was positively associated with trunk adipose mass for the entire cohort. CONCLUSIONS T2DM status moderated the relationship between blood adiponectin and ALMBMI, where blood adiponectin was positively associated with ALMBMI in postmenopausal women without T2DM, but not those with T2DM. Dysregulated metabolism in T2DM may contribute to lower muscle mass in women with T2DM, but future research is required to elucidate this mechanistic link. The negative association between blood leptin and ALMBMI was a novel finding. Future studies will need to more clearly define the relationship between these variables.

OBJECTIVES: Increasing linoleic acid (LA) in the diet through supplementation with LA-rich oils can increase muscle mass and decrease fat mass in adults. Unfortunately, many US dietary oils once high in LA are now high in oleic acid (OA) and low in LA, making it challenging for adults to increase LA intake. This study examines the extent in which consumption of healthy cookies enriched with LA for two weeks can increase plasma, erythrocytes and peripheral blood mononuclear cells (PBMC) LA levels. METHODS: In a randomized double-blinded placebo-controlled study, healthy adults (N = 84) were randomly assigned to consume one healthy cookie rich in LA or one healthy cookie rich in OA (placebo) per day for two weeks. The healthy cookies were high in unsaturated fat with 10 grams of either grapeseed oil (high in LA) or safflower oil (high in OA). Additionally, the healthy cookies were 100% whole grain and had about one half the amount of added sugar compared to traditional cookie recipes. Fasting blood was taken before (pre) and after (post) healthy cookie consumption. Fatty acids in the plasma, erythrocytes and PBMC were analyzed using gas chromatography. Because LA supplementation has been shown to reduce inflammation, plasma levels of total and high molecular weight (HMW) adiponectin and tumor necrosis factor receptor 2 (TNFr2) were assessed. A t-test of post values at a 5% significance level was used to determined differences between the two groups. RESULTS: Of the 84 participants enrolled, 42 were randomly assigned to each group and all but one participant completed the study. 66% (n = 55) of the participants were female. The mean age was 32.6 years and the mean BMI was 25.8. After two weeks of consuming one healthy cookie per day, LA was significantly higher in plasma, erythrocytes and PBMC in the group consuming the LA-rich healthy cookies compared to the group consuming the placebo healthy cookies. Levels of total and HMW adiponectin and TNFr2 were not different between the groups after healthy cookie consumption. CONCLUSIONS: Healthy cookies are a food-based approach to increasing LA in the diet that also alter the amount of LA in the blood. Future long-term studies are needed to assess the ability of healthy cookie consumption to alter body composition and markers of inflammation. FUNDING SOURCES: Funding was provided by the Carol S. Kennedy Professorship and the Ohio Agriculture Research and Development Center.

OBJECTIVES: Cancer contributes to adverse changes in body composition that may increase risk of cardiometabolic diseases. Skeletal muscle is a main driver of cardiometabolic health. We hypothesize that higher intake of long chain omega-3 polyunsaturated fatty acids (LCn3PUFAs) is associated with muscle health. This study evaluates whether LCn3PUFA exposure assessed in diet and in blood is associated with markers of muscle health in women with breast cancer. METHODS: This is a cross-sectional analysis evaluating LCn3PUFA exposure and markers of muscle health in women (N = 150) prior to treatment for breast cancer. Exposure to LCn3PUFAs was assessed by a diet history questionnaire (DHQ), a question specifically about supplement usage and biomarker of LCn3PUFAs in red blood cells (RBC). Body composition were measured at the same visit using dual x-ray absorptiometry. Linear regression models were used to test for associations. RESULTS: 13% (N = 19) of women reported using fish oil supplements (e.g., Supplement Users) and had significantly higher levels of RBC LCn3PUFAs than Supplement Non-users. In Supplement Non-users, there was a positive association between reported dietary exposure by DHQ and RBC LCn3PUFA levels. The n3 index (e.g., sum of RBC EPA + DHA) and DHA (22:6n3) were positively associated with appendicular lean mass/BMI. There were no significant correlations between RBC LCn3PUFAs with grip strength and or other measurements of body composition. CONCLUSIONS: As a biomarker of intake, RBC LCn3PUFAs are positively associated with appendicular lean mass, a measure of skeletal muscle mass. A future study should prospectively evaluate whether higher LCn3PUFA exposure (as measured in blood) is associated with maintaining better muscle health during and following cancer treatment. FUNDING SOURCES: Funding was provided by the National Cattleman's Beef Association, NIH (JKG) CA186720, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship.

OBJECTIVES: Compare the effects of high-fat diets containing linoleic-acid (LA)-rich oil and lard on measures of whole-body energy metabolism and skeletal muscle function in a mouse model of diet-induced obesity. METHODS: 9-week old male C57BL6/J mice (n = 24) were assigned to high fat isocaloric diets (24% fat by wt) containing LA-rich safflower oil (SO) or lard (LD) for 18 weeks. Food intake and body weight were measured every 2 days. EchoMRI was used at Days 0, 65, and 100 to determine the effects of each diet on body composition. Grip strength was measured to assess muscle strength at Day 113. Fasting blood glucose was measured and an insulin tolerance test (ITT) was performed on Day 85 to measure insulin sensitivity and glucose uptake. After 130 days, quadriceps muscle mitochondrial and cardiolipin remodeling gene expression was measured by qRT-PCR. Cardiolipin (CL) speciation of muscle was measured by normal phase liquid chromatography coupled to electrospray ionization mass spectrometry. RESULTS: Although LD-fed mice gained body mass at a faster rate, there was no difference in body mass or cumulative food intake after 130 days. Similarly, % adiposity of LD-fed mice increased at Day 65 compared to those fed the SO diet, but not at Day 100. Mice consuming the SO diet exhibited increased hindlimb grip strength. SO-fed mice exhibited lower blood glucose levels at 90 and 120 minutes post-insulin injection, demonstrating improved glucose clearance over time. Significant differences in CL speciation, particularly that of LA-containing species, were observed. CONCLUSIONS: When compared to the LD diet, mice consuming the SO diet exhibited early reductions in adiposity that were undistinguishable after 130 days of dietary intervention. However, mice fed SO diet exhibited improved grip strength, insulin-stimulated glucose clearance and significant differences in skeletal muscle cardiolipin speciation. Future studies will address the relationship between LA-derived metabolites, CL speciation, and improved muscle function. FUNDING SOURCES: Funding was provided by NIH, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship. DBS received support from the AOCS Thomas H. Smouse Memorial Fellowship.

cope Supplementation with linoleic acid (LA; 18:2Ω6)-rich oils increases lean mass and decreases trunk adipose mass in people. Erythrocyte fatty acids reflect the dietary pattern of fatty acid intake and endogenous metabolism of fatty acids. The aim of this study is to determine the relationship of erythrocyte LA, with aspects of body composition, insulin resistance, and inflammation. Additionally, we tested for relationships of oleic acid (OA) and the sum of long chain omega-three fatty acids (LC-Ω3-SUM), on the same outcomes. Methods and results Men and women (N = 139) were evaluated for body composition, insulin resistance, and serum inflammatory markers, IL-6, and c-reactive protein (CRP) and erythrocyte fatty acid composition after an overnight fast. LA was positively related to appendicular lean mass/body mass index and inversely related to trunk adipose mass. Additionally, LA was inversely related to insulin resistance and IL-6. While there was an inverse relationship between OA or LC-Ω3-SUM with markers of inflammation, there were no relationships between OA or LC-Ω3-SUM with body composition or HOMA-IR. Conclusion Higher erythrocyte LA was associated with improved body composition, insulin resistance, and inflammation. Erythrocyte OA or LC-Ω3-SUM was unrelated to body composition and insulin resistance. There is much controversy about whether all unsaturated fats have the same benefits for metabolic syndrome and weight gain. We sought to test the strength of the relationships between three unsaturated fatty acid in erythrocytes with measurements of body composition, metabolism, and inflammation in healthy adults. Linoleic acid, but not oleic acid or the sum of long-chain omega 3 fatty acids (w3), was associated with increased appendicular lean mass and decreased trunk adipose mass and insulin resistance.

Cachexia is a multifactorial syndrome characterized by weight loss and tissue wasting, which is associated with reduced quality of life, responsiveness to chemotherapy, and decreased survival. We aim to determine whether changes in plasma fatty acid content in pancreatic ductal adenocarcinoma (PDAC): 1) are predictive of developing cachexia, and 2) whether these changes are influenced by other clinical parameters, like diabetes, that could contribute to malnutrition. Treatment-naïve metastatic PDAC subjects (n=51) were enrolled in NCT01280058 in which plasma samples and clinical data were collected prior to treatment. Subjects were assigned to either weight stable ( Citation Format: Kristyn Gumpper, Phil A. Hart, Martha Belury, Olivia Crowe, Rachel M. Cole, Niharika Badi, Alice Hinton, Mitchell L. Ramsey, Anne Noonan, Darwin L. Conwell, Zobeida Cruz-Monserrate. Plasma fatty acid levels in treatment-naïve metastatic pancreatic cancer patients are associated with clinical indicators of cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-022.

OBJECTIVES: Investigate the impact of LA-rich oil (LO) on measures of energy metabolism in a mouse model of metabolic syndrome. METHODS: Ob/ob mice were fed diets containing 6% wt LO, oleic acid-rich (OO) or palmitic acid-rich (PO) for 6 weeks. Body composition was measured at weeks 0 and 6. Plasma was collected at necropsy to measure adiponectin, insulin, and glucose. Grip strength and muscle fiber cross-sectional area (CSA) of total and succinate dehydrogenase-positive (SDH) fibers were quantified in quadriceps. In white adipose tissue, mRNA was measured for markers of beiging and lipid storage. RESULTS: Mice fed OO and LO diets (vs. PO diet) had reduced % adipose. There was no difference of oils on plasma adiponectin or HOMA-IR. Decreases in grip strength were observed in PO-fed mice, while OO and LO-fed mice maintained strength throughout the study. LO-fed mice exhibited smaller skeletal muscle fibers compared to the PO-fed mice. OO-fed mice had fewer intermediate-sized SDH fibers. In white adipose tissue, LO-fed mice exhibited increased PGC1a, and decreased PPARy and LPL mRNA compared to PO-fed mice. CONCLUSIONS: These findings suggest that dietary LA may alter lipid mobilization and metabolism in obese mice. These preliminary results showcase the importance of future investigation of lipid storage and mitochondrial phospholipid biology in skeletal muscle. FUNDING SOURCES: Funding was provided by NIH R21CA185140, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship. DBS received support from the AOCS Thomas H. Smouse Memorial Fellowship.

OBJECTIVES: Due to the established cardioprotective effects of fish oil in pressure-induced models of heart failure, we hypothesize that fish oil could also be cardioprotective in anthracycline-induced heart failure. METHODS: In a mouse model of anthracycline cardiotoxicity male mice were assigned to one of four groups: anthracycline injection + control diet, saline injection + control diet, anthracycline injection + fish oil diet, or saline injection + fish oil diet. The control diet contained 90 g/kg soybean oil while the fish oil diet contained 40 g/kg soybean oil and 50 g/kg fish oil (8% fat by weight). The differences between groups were assessed by two-way ANOVA. Sidak's multiple comparison test was used to determine differences from the control group. RESULTS: Controlling for body weight, anthracycline treatment increased heart weight in both diet groups suggesting cardiac hypertrophy. Compared with control diet, fish oil diet attenuated anthracycline-induced increases in pro-inflammatory Il6 and pro-fibrotic collagen III mRNA. In addition, dietary fish oil increased bcl2 (anti-apoptosis) and heme oxygenase-1 (antioxidant) mRNA in heart muscle in mice treated with anthracycline. CONCLUSIONS: Our data suggest that dietary fish oil may attenuate some of the cardiotoxic effects of anthracyclines. Fish oil is generally found to be safe in cancer patients, and if effective in clinical trials could provide a widely available therapy for cancer patients undergoing anthracycline chemotherapy. FUNDING SOURCES: Funding was provided by NIH R21CA185140, Ohio Agriculture Research and Development Center, the Carol S. Kennedy Professorship, and the Ohio State University Education and Human Ecology Dissertation Research Fellowship.

OBJECTIVES: Higher blood levels of the essential fatty acid, linoleic acid (LA), are associated with a decreased risk of type 2 diabetes. However, many dietary oils once high in LA are now low in LA and high in oleic acid (OA). We have previously shown in healthy adults that supplementation with a high LA oil can increase plasma LA levels and decrease plasma OA levels. The current study examines the relationship of habitual levels of plasma LA and OA with markers of body composition, inflammation and glycemia in healthy adults. METHODS: Data from baseline visit were analyzed from 127 health adults participating in a 2-week study of the effect of dietary oils on blood fatty acid profiles. Plasma fatty acid composition was measured by gas chromatography. Insulin, glucose, total and high molecular weight (HMW) adiponectin, tumor necrosis factor receptor 2 (TNF-r2) and lipopolysaccharide binding protein (LBP) were measured in fasting plasma samples. Body mass index (BMI) and sagittal diameter (SAD) were measured as markers of body composition. Grip strength was measured as a marker of muscle strength and gait speed was measured as a marker of muscle function. Linear regression was used to assess the association of study measurements to plasma LA or OA. Results were adjusted for sex, age, physical activity and BMI. RESULTS: Plasma LA was negatively associated with both BMI and SAD while plasma OA was positively associated with both insulin and grip strength. In males, but not females, higher plasma LA was associated with higher HMW adiponectin while higher plasma OA was positively associated with fasting glucose. Neither plasma LA or OA were associated with total adiponectin, TNF-r2, LBP or gait speed. CONCLUSIONS: Higher levels of plasma LA predicted for lower measures of adiposity in both males and females and higher HMW adiponectin levels in males. Higher levels of plasm OA predicted for increased grip strength and higher glycemia, particularly in men. To our knowledge no randomized controlled trial has compared LA or OA supplementation on body composition, glycemia, and adiponectin in healthy men and women. FUNDING SOURCES: Funding was provided by the Carol S. Kennedy Professorship and the Ohio Agriculture Research and Development Center.

Chemotherapeutic agents such as doxorubicin may negatively affect long-term brain functioning in cancer survivors, neuroinflammation may play a causal role. Dietary approaches that reduce inflammation, such as lowering sucrose and increasing eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA), may attenuate chemotherapy-induced neuroinflammation and synaptic damage, thereby improving quality of life. Ovariectomized, C57BL/6 mice were assigned to a chemotherapy (9 mg/kg doxorubicin + 90 mg/kg cyclophosphamide) or vehicle two-injection regimen, with injections two and four weeks after starting diets. In Study 1, mice received low sucrose diets with EPA + DHA or No EPA + DHA for four to six weeks, tissues were collected four, seven, or 14 days after the second injection. Compared to vehicle, chemotherapy increased pro-inflammatory cytokine IL-1&beta, at day seven in the cortex and hippocampus, and reduced gene expression of synaptic marker Shank 3 at all timepoints in cortex, while EPA + DHA increased expression of Shank 3. In Study 2, high or low sucrose/EPA + DHA or No EPA + DHA diets were fed for five weeks, tissues were collected ten days after the second injection. Among chemotherapy-treated mice, brain DHA was higher with low sucrose feeding. Furthermore, low sucrose increased gene expression of Shank 1, while EPA + DHA increased expression of Shank 3 and reduced protein concentrations of pro-inflammatory markers IL-5, IL-6 and KC/GRO in the cortex, but not the hippocampus. Low sucrose, EPA + DHA diets may attenuate neuroinflammation and synaptic damage induced by doxorubicin-based chemotherapy in specific brain regions.

Dietary fat quality, especially the intake of specific types of fatty acids, impacts the risk of many chronic diseases, including cardiovascular diseases, certain cancers and type 2 diabetes (T2DM). A recent pooled analysis involving 20 studies from around the world revealed that higher linoleic acid (18:2n-6 LA) biomarker is associated with dose-dependent decreases in the incidence of T2DM. This latest study corroborates earlier cross-sectional studies and intervention trials showing that biomarkers of LA intake are associated with reduced risk of T2DM and better glycemic control and/or insulin sensitivity. This review highlights key clinical trials that have evaluated the role of LA in glycemia and the related condition, insulin sensitivity.

There is increasing evidence that chronic inflammation is associated with increased breast cancer risk. Long-chain omega-3 polyunsaturated fatty acids (LCω-3PUFA) may reduce circulating biomarkers of inflammation; however associations of blood LCω-3PUFA with breast tissue LCω-3PUFA and breast tissue biomarkers of inflammation are not well understood. We conducted a cross-sectional analysis of breast tissue and blood samples from n = 85 women with no history of breast cancer, who underwent breast reduction surgery. Fatty acids of erythrocytes and undissected breast tissues were analyzed by gas chromatography; C-reactive protein (CRP), interleukin (IL)-6 and IL-8 in plasma and tissue were measured by ELISA. Multivariable-adjusted regression models were used to estimate associations between erythrocyte LCω-3PUFA and breast tissue biomarkers. Women in the highest erythrocyte LCω-3PUFA tertile had LCω-3PUFA concentrations in the breast 73% (95% CI: 31-128%; p trend

How composition of egg yolk (EY) influences NF-κB, a key transcription pathway in inflammation, remains unclear. We performed partial delipidation of EY that removed 20-30% of cholesterol and triglycerides. The resulting polar and nonpolar fractions were termed EY-P and EY-NP. NF-κB activation in response to EY from different suppliers and their fractions was examined in 3T3-L1 adipocytes using a NF-κB response element reporter assay and by analyzing expression of 248 inflammatory genes. Although EY-P and EY contained similar level of vitamins, carotenoids, and fatty acids, only delipidated EY-P fraction suppressed NF-κB via down-regulation of toll like receptor-2 and up-regulation of inhibitory toll interacting protein (Tollip) and lymphocyte antigen 96 (Ly96). Our data suggest that anti-inflammatory activity of lutein and retinol were blunted by nonpolar lipids in EY, likely via crosstalk between SREBP and NF-κB pathways in adipocytes. Thus, moderate delipidation may improve the beneficial properties of regular eggs.

As the incidence of obesity continues to increase, identifying novel nutritional therapies to enhance weight loss are needed. Raspberry ketone (RK; 4-(4-hydroxyphenyl) butan-2-one) is a bioactive phytochemical that is marketed as a weight loss supplement in the United States, yet there is scant scientific evidence demonstrating that RK promotes weight loss. The aim of the current study was to investigate the effect of RK on accumulation of adipose mass, hepatic lipid storage, and levels of plasma adiponectin in mice fed a high-fat (HF) diet. Mice were individually housed and fed a HF control diet (45% kcal from fat) for two weeks to induce weight gain, then assigned to HF control, high-dose (1.74% wt/wt) raspberry ketone (HRK), low-dose (0.25% wt/wt) raspberry ketone (LRK), or a pair-fed group (PF) fed similar food intake to LRK mice. Following five weeks of feeding, mice fed LRK and HRK diets showed reduced food intake and body weight compared to mice maintained on control diet. When normalized to body weight, mice fed HRK diet exhibited decreased inguinal fat mass and increased liver mass compared to the control group. Hepatic steatosis was lowest in mice fed HRK diet, whereas LRK diet did not have an effect when compared to the PF group. Plasma adiponectin concentration was unaffected by RK and pair-feeding. Our findings demonstrate that RK supplementation has limited benefit to adipose loss beyond reducing energy intake in mice fed a high-fat diet. The present study supports the need for appropriate study design when validating weight-loss supplements.

Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexia – before severe fat loss – in the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34–42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A - activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition.

OBJECTIVES: Investigate the impact of dietary linoleic acid (LA) on whole-body energy metabolism, fatty acid uptake, oxylipin metabolites, and energy production machinery in skeletal muscle. METHODS: Mice were fed modified AIN-93 M diets containing 6% wt of LA or palmitic acid (PA) for 5 weeks. To address energy balance, grip strength, blood glucose, and body composition were measured weekly and indirect calorimetry was performed after 4.5 weeks of diet. To address skeletal muscle architecture, cross-sectional area was quantified in quadriceps. To determine the effect of LA diet on skeletal muscle lipids, fatty acid composition was measured in quadriceps using GC. Targeted lipidomics using LC-MS/MS was utilized to measure LA-derived oxylipins in mitochondria isolated from gastrocnemius. RESULTS: No difference in food intake, body weight, blood glucose, or body composition were observed between diet groups. Mice fed the LA diet exhibited higher heat production and lower respiratory exchange ratio, independent of ambulatory activity compared to mice fed the PA diet. Cross sectional area analysis in quadriceps muscle revealed that mice fed the LA diet had smaller muscle fibers compared to mice fed the PA diet. The LA diet increased LA level in quadriceps. Using hierarchal cluster analysis, we identified several unique patterns of oxylipins that impact insulin sensitivity and may be associated with increased mitochondrial capacity. Mice fed the LA diet exhibited a three-fold increase of oxylipin metabolites 9- and 13-HODE, and 12,13-diHOME. CONCLUSIONS: Mice fed a diet fortified in LA have increased LA in skeletal muscle, changes to skeletal muscle architecture, favorable changes to whole body energy metabolism, and increases in LA-derived oxylipins in skeletal muscle mitochondria. Our discovery that LA generates 9-HODE and 13-HODE in muscle mitochondria suggests that downstream pathways, including PPARg transactivation, may be linked with effects on muscle energy metabolism. FUNDING SOURCES: Funding was provided by the National Institutes of Health (NIH) R21CA185140, Ohio Agriculture Research and Development Center and the Carol S. Kennedy Professorship. DBS is supported by the Center for Muscle Health and Neuromuscular Disorders Predoctoral Research Fellowship.

cope Obesity-related metabolic dysregulation may be a link between obesity and postmenopausal breast cancer. Naringenin, a flavonoid abundant in grapefruits, displays beneficial effects on metabolic health and tumorigenesis. Here, we assessed the effects of naringenin on mammary tumor cell growth in vitro and in obese ovariectomized mice. Methods and results Naringenin inhibited cell growth, increased phosphorylation of AMP-activated protein kinase (AMPK), down-regulated CyclinD1 expression, and induced cell death in E0771 mammary tumor cells. Obese ovariectomized mice were fed a high-fat (HF), high-fat diet with low naringenin (LN; 1% naringenin) or high-fat diet with high naringenin (HN; 3% naringenin) for 2 weeks and then implanted with E0771 cells in mammary adipose tissue. Three weeks after tumor cell implantation, naringenin accumulation in tumor was higher than that in mammary adipose tissue in HN mice. HN decreased body weight, adipose mass, adipocyte size, α-smooth muscle actin mRNA in mammary adipose tissue, and mRNA of inflammatory cytokines in both mammary and perigonadal adipose tissues. Compared with mice fed HF diet, HN delayed growth of tumors early but did not alter final tumor weight. Conclusion Naringenin reduces adiposity and ameliorates adipose tissue inflammation, with a moderate inhibitory effect on tumor growth in obese ovariectomized mice.

Summary Background & aims Metabolic effects of dietary fat quality in people with type 2 diabetes are not well-understood. The study objective was to evaluate effects of conjugated linoleic acid (CLA) and safflower (SAF) oils on glycemia, blood lipids, and inflammation. The hypothesis we tested is that dietary oils improve glycemia, lipids, and inflammatory markers in a time-dependent way that follows accumulation of linoleic acid and CLA isomers in serum of subjects supplemented with dietary oils. Methods Fifty-five post-menopausal, obese women with type 2 diabetes enrolled, and 35 completed this randomized, double-masked crossover study. Treatments were 8 g daily of CLA and SAF for 16 weeks each. We used a multiple testing procedure with pre-determined steps analysis to determine the earliest time that a significant effect was detected. Results CLA did not alter measured metabolic parameters. SAF decreased HbA1c (−0.64 ± 0.18%, p = 0.0007) and C-reactive protein (−13.6 ± 8.2 mg/L, p = 0.0472), increased QUICKI (0.0077 ± 0.0035, p = 0.0146) with a minimum time to effect observed 16 weeks after treatment. SAF increased HDL cholesterol (0.12 ± 0.05 mmol/L, p = 0.0228) with the minimum time to detect an effect of SAF at 12 weeks. The minimum time to detect an increase of c9t11-CLA, t10c12-CLA, and linoleic acid in serum of women supplemented CLA or SAF, respectively, was four weeks. Conclusions We conclude that 8 g of SAF daily improved glycemia, inflammation, and blood lipids, indicating that small changes in dietary fat quality may augment diabetes treatments to improve risk factors for diabetes-related complications.

Scope Estrogen deficiency has been associated with central obesity, muscle loss and metabolic syndrome in postmenopausal women. This study assessed naringenin accumulation in tissues and investigated the hypothesis that naringenin reverses diet-induced metabolic disturbances in obese ovariectomized mice. Methods and results In study 1, we measured naringenin concentrations in plasma, liver, perigonadal and subcutaneous adipose tissues, and muscle of ovariectomized C57BL/6J female mice after 11 weeks of naringenin supplementation. Naringenin accumulated 5–12 times more in mice fed a 3% naringenin diet than in mice fed a 1% naringenin diet. In study 2, ovariectomized mice were fed a high-fat diet (60 kcal% fat) for 11 weeks and half of the mice were then supplemented with 3% naringenin for another 11 weeks. Dietary naringenin suppressed weight gain, lowered hyperglycemia and decreased intra-abdominal adiposity evaluated by magnetic resonance imaging. Naringenin-fed mice exhibited elevated locomotor activity monitored by infrared beam breaks, maintained muscle mass and reduced muscle diacylglycerol content. Real-time PCR analysis in muscle revealed decreased mRNA level for genes involved in de novo lipogenesis, lipolysis and triglyceride synthesis/storage. Conclusion Long-term 3% naringenin supplementation resulted in significant naringenin accumulation in plasma and tissues, associated with attenuated metabolic dysregulation and muscle loss in obese ovariectomized mice.

There is increasing evidence that chronic inflammation is associated with increased breast cancer risk. Long-chain omega-3 polyunsaturated fatty acids (LCω-3PUFA) may reduce circulating biomarkers of inflammation; however associations of blood LCω-3PUFA with breast tissue LCω-3PUFA and breast tissue biomarkers of inflammation are not well understood. We conducted a cross-sectional analysis of breast tissue and blood samples from n = 85 women with no history of breast cancer, who underwent breast reduction surgery. Fatty acids of erythrocytes and undissected breast tissues were analyzed by gas chromatography; C-reactive protein (CRP), interleukin (IL)-6 and IL-8 in plasma and tissue were measured by ELISA. Multivariable-adjusted regression models were used to estimate associations between erythrocyte LCω-3PUFA and breast tissue biomarkers. Women in the highest erythrocyte LCω-3PUFA tertile had LCω-3PUFA concentrations in the breast 73% (95% CI: 31-128%; p trend 0.0001) higher than women in the lowest tertile. Associations for each individual LCω-3PUFA were similar in magnitude. No significant association was found for the shorter ω-3 PUFA, α-linolenic acid. Although compatible with no association, women in the highest tertile of erythrocyte eicosapentaenoic acid had a nonsignificant 32% (95% CI: -23 to 62%) reduced breast tissue CRP. No correlation was observed between erythrocyte ω-3 PUFA and tissue IL-6 or IL-8 concentrations. Our findings provide evidence that erythrocyte ω-3 fatty acids are valid measures of breast tissue concentrations, and limited evidence that inverse associations from prospective epidemiologic studies of blood LCω-3PUFA and breast cancer risk may be partly explained by reductions in breast tissue inflammation; however, these findings require replication.

Rodents are commonly used in food restriction-refeeding studies to investigate weight regain. Mice that are rationed food every 24 hours may consume all allocated food in a short time (gorge) and therefore undergo a brief well-fed period followed by an extended fasted period until the next day’s food allotment. These exaggerated metabolic states are not typical in ad-libitum fed (nibbling) mice. The aim of the current study was to elucidate the intraday and cumulative metabolic consequences of gorging (induced by food restriction) in mice during controlled refeeding. Accordingly, following a temporary food restriction, mice were fed rations similar to intakes of ad-libitum fed controls. Temporary food restriction initiated gorging behavior that persisted during refeeding; consequently, metabolism-related measurements were obtained in the gorging mice during their daily fed and fasted metabolic states. Robust differences in adipose tissue lipogenic and inflammatory gene expression were found in the gorging mice by metabolic state (fed versus fasted). Additionally, despite a reduced cumulative food intake compared to ad-libitum fed mice, restriction-induced gorging mice had increased intra-abdominal fat accumulation, diminished hepatic and peripheral insulin sensitivity, and a gene expression profile favoring lipid deposition. Our findings highlight the intraday differences in gene expression in gorging mice before and after feeding that confound comparisons with ad-libitum fed, or nibbling, mice. The present study also provides evidence that weight regain following food restriction is associated with cumulative metabolic and behavioral abnormalities in mice.

Scope The fatty acid profile of dietary lipids is reflected in mammary adipose tissue and may influence mammary gland biology and cancer risk. To determine the effects of fish consumption on breast adipose tissue fatty acids, we conducted a study of fish versus n-3 PUFA supplements in women at increased risk of breast cancer. Methods and results High risk women were randomized to comparable doses of marine n-3 PUFAs as canned salmon + albacore or capsules for 3 months. Pre- and posttreatment fatty acid profiles were obtained by GC. Dietary fish (n = 12) and n-3 PUFA capsules (n = 13) yielded increased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in plasma (p < 0.0001), erythrocyte membranes (p < 0.0001), and breast fat (p < 0.01) at 3 months. Women taking capsules had higher plasma and erythrocyte membrane EPA changes (∼four versus twofold, p = 0.002), without significant differences in DHA. Increases in breast adipose EPA, DHA were similar for both groups. Higher BMI correlated with smaller changes in plasma, erythrocyte membrane EPA, and breast adipose EPA, DHA. Adherence was excellent at 93.9% overall and higher in the fish arm (p = 0.01). Conclusion Fish provides an excellent source of n-3 PUFAs that increases breast adipose EPA, DHA similar to supplements and represents a well-tolerated intervention for future studies of the impact of n-3 PUFAs and dietary patterns on breast cancer.

Objective Adverse metabolic changes associated with loss of ovarian function increase the risk of developing metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) in postmenopausal women. Naringenin improves metabolic disturbances in vitro and in vivo. In the present study, we tested the effects of naringenin on metabolic disturbances resulting from estrogen deficiency in ovariectomized mice. Materials/methods Ovariectomized C57BL/6 J female mice were fed a control diet (10% calories from fat) for 11 weeks. Mice either continued on the control diet (n = 9) or were switched to the control diet supplemented with 3% naringenin (n = 10) for the next 11 weeks. Energy expenditure was measured by indirect calorimetry and activity was monitored by infrared beam breaks. Intra-abdominal and subcutaneous adiposity was evaluated by magnetic resonance imaging (MRI). Blood biochemical measures of metabolic response included glucose, insulin, adipokines, and lipids. Lipid content in liver and muscle and expression of relevant genes in adipose tissue, liver, and muscle were quantified. Results Ovariectomized mice fed naringenin exhibited lower fasting glucose and insulin levels compared to controls, with over 50% reduction of intra-abdominal and subcutaneous adiposity. Plasma leptin and leptin mRNA in adipose depots were also decreased in mice fed a naringenin diet. Monocyte chemoattractant protein-1 (MCP1/Ccl2) and interleukin 6 (IL-6/Il6) mRNA expression levels were significantly lower in perigonadal adipose tissue of naringenin-supplemented mice. We also observed that mice fed a naringenin diet had less hepatic lipid accumulation with corresponding alterations of hepatic gene expression associated with de novo lipogenesis, fatty acid oxidation, and gluconeogenesis. Conclusion Dietary naringenin attenuates many of the metabolic disturbances associated with ovariectomy in female mice. Electronic supplementary material The online version of this article (doi:10.1186/1743-7075-12-1) contains supplementary material, which is available to authorized users.

Mechanistic pathways linking maternal polyunsaturated fatty acid (PUFA) status with gestational length are poorly delineated. This study examined whether inflammation and sleep quality serve as mediators, focusing on the antiinflammatory ω-3 docosahexaenoic acid (DHA; 22:6n3) and proinflammatory ω-6 arachidonic acid (AA; 20:4n6). Pregnant women (n = 135) provided a blood sample and completed the Pittsburgh Sleep Quality Index (PSQI) at 20-27 weeks gestation. Red blood cell (RBC) fatty acid levels were determined by gas chromatography and serum inflammatory markers [interleukin (IL)-6, IL-8, tumor necrosis factor-α, IL-1β, and C-reactive protein] by electrochemiluminescence using high sensitivity kits. Both higher serum IL-8 (95% CI = 0.10,3.84) and poor sleep (95% CI = 0.03,0.28) served as significant mediators linking lower DHA:AA ratios with shorter gestation. Further, a serial mediation model moving from the DHA:AA ratio → sleep → IL-8 → length of gestation was statistically significant (95% CI = 0.02, 0.79). These relationships remained after adjusting for depressive symptoms, age, BMI, income, race, and smoking. No interactions with race were observed in relation to length of gestation as a continuous variable. However, a significant interaction between race and the DHA:AA ratio in predicting preterm birth was observed (p = 0.049); among African Americans only, odds of preterm birth decreased as DHA:AA increased (p = 0.048). These data support a role for both inflammatory pathways and sleep quality in linking less optimal RBC PUFA status with shorter gestation in African American and European American women and suggest that African-Americans have greater risk for preterm birth in the context of a low DHA:AA ratio.

Objective Mechanistic pathways linking maternal long-chain polyunsaturated fatty acid (LC-PUFA) status with gestational length are poorly delineated. Key LC-PUFAs implicated in this association are the antiinflammatory omega-3 docosahexaenoic acid (DHA) and proinflammatory omega-6 arachidonic acid (AA). We hypothesized that (1) lower red blood cell (RBC) DHA:AA ratios would predict shorter gestation and (2) this effect would be mediated by both inflammation and sleep quality. Methods Pregnant women (n = 135) provided blood and completed the Pittsburg Sleep Quality Index at 20–27 weeks gestation. RBC fatty acids were determined by gas chromatography and serum inflammatory markers (IL-6, IL-8, TNF- α , IL-1 β , CRP) were determined by high-sensitivity ELISA. Results Lower DHA:AA ratios predicted higher serum IL-8 (r = −0.20, p = 0.02) and poorer sleep quality (b = −13.8, p = 0.02). These relationships remained after adjusting for depressive symptoms, age, BMI, income, race, and smoking. Mediational analyses demonstrated indirect effects linking lower RBC DHA:AA with shorter gestation via higher IL-8 (95% CI = 0.10, 3.84) and poor sleep (95% CI = 0.35, 3.99). A significant race X DHA:AA interaction in predicting preterm birth (PTB) was observed (p = 0.049); among African Americans only, the odds of PTB decreased significantly as DHA:AA increased (OR for 0.1 unit increase = 0.25 (95% CI = 0.06, 0.99, p = 0.048). Discussion These data support both inflammatory pathways and sleep quality as significant mediators linking maternal DHA:AA status and length of gestation. African Americans may be at greater risk for PTB related to suboptimal DHA levels.

Background: The type of fat consumed in the diet may influence mammary tissue biology and breast cancer risk, with preclinical evidence for inhibitory effects of n-3 versus n-6 polyunsaturated fatty acids (PUFAs) on mammary carcinogenesis. Fish consumption and fish oil supplements are two strategies to increase dietary n-3 fatty acids. Objective: To determine the effects of increased fish consumption on breast adipose tissue fatty acids, we conducted a study of dietary fish versus an n-3 fatty acid supplement in women at increased risk for developing breast cancer. Design: In this three month randomized study, women at high risk for breast cancer received either (a) dietary fish in the form of canned salmon and albacore tuna at a dose of four 6 ounce servings/week or (b) two n-3 fatty acid capsules (1.68 g EPA+DHA)/day for three months. Subjects underwent fasting blood draws monthly and breast adipose tissue samples at baseline and three months for fatty acid profiling by gas chromatography. Results: Both study interventions of dietary fish and n-3 PUFA capsule yielded increased EPA and DHA content in plasma (p Conclusions: Dietary fish and n-3 PUFA capsules significantly increase breast adipose tissue EPA and DHA content and represent two well tolerated strategies for future clinical trials of dietary n-3 PUFAs for breast cancer prevention. Citation Format: Shana Straka, Joanne L. Lester, Sarah Puchala, Angela Rose, Rachel Cole, Rebecca R. Andridge, Steven K. Clinton, Martha A. Belury, Lisa D. Yee. A pilot trial of dietary fish and ω-3 fatty acid supplements in women at high risk for breast cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B45.