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Background: Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The ketogenic diet (KD), a diet high in fat and low in carbohydrates, has been applied clinically for the treatment of obese women with PCOS. We have previously demonstrated that KD improved the reproductive phenotype in an androgen-induced PCOS mouse model, yet the underlying molecular mechanisms remain largely unclear. The aim of the present study was to investigate the effect of KD on the reproductive phenotype of a letrozole-induced PCOS mouse model. Methods: Female C57BL/6N mice were divided into three groups, designated control, letrozole, and letrozole + KD groups. Mice of control and letrozole groups were fed the control diet, whereas letrozole + KD mice were fed a KD with 89.9% (kcal) fat for 3 weeks after the PCOS mouse model was generated. β-hydroxybutyrate (BHB), the most abundant ketone body in the body, was used to treat KGN cells with testosterone (T) to simulate the KD effect on PCOS mouse ovaries in vitro. Results: Our data showed that KD treatment significantly increased blood ketone levels and reduced body weight. Ovarian functions were improved in some letrozole + KD mice. Results from in vitro experiments indicated mitochondrial damage owing to high T levels, which resulted in the leakage of cytochrome C and mitochondrial DNA into the cytosol and thus induced the activation of the intracellular caspase cascade and the cGAS-STING-NF-κB pathway, leading to granulosa cell inflammation and apoptosis. BHB exhibited certain protective effects on mitochondria of T-treated KGN cells via inhibiting the cGAS-STING pathway. Moreover, the cGAS-STING pathway was activated in ovaries of letrozole mice and was down-regulated in letrozole + KD mice. Conclusion: These findings, for the first time, revealed that hyperandrogenism induced ovarian dysfunction possibly through activation of the cGAS-STING pathway, which could be partially inhibited by ketone bodies produced from KD administration. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs (miRNAs) play crucial roles in regulating inflammation and cellular senescence. Among them, miR-146a has emerged as a key modulator of inflammation, but its role in obesity-induced senescence remains unexplored. This study investigates the involvement of miR-146a in high-fat diet (HFD)-induced hypothalamic senescence and in protective effects of elocalcitol (Elo), a non-hypercalcemic, fluorinated vitamin D analog on HFD-induced senescence. Results: Wild-type (WT) HFD-fed mice exhibited increased body weight, impaired locomotor activity, and cognitive decline compared to low-fat diet (LFD) controls. In the brain, HFD induced senescence markers (p16, p21), β-galactosidase activity (β-gal) of microglia, and increased expression of senescence associated secretory phenotype (SASP) cytokines (Il1b, Il18, Tnf, Il6) in activated hypothalamic microglia. In the liver, increased p21 and SASP cytokines were detected, although p16 and β-gal levels remained unchanged. Importantly, miR-146a expression was significantly downregulated in the hypothalamus following HFD exposure in WT mice, while miR-146a knockout (Mir146a-/-) mice subjected to HFD showed augmented hypothalamic senescence characterized by higher levels of p16, p21, and β-gal + microglial cells as compared to WT mice. The SASP profile remained similar between Mir146a-/- HFD and WT HFD mice. Among miR-146a target genes, smad4 was upregulated the hypothalamus of HFD-fed mice, with a more pronounced increase in the hypothalamus of HFD-fed Mir146a-/- mice. Further, treatment with Elo upregulated miR-146a expression in both the hypothalamus and the liver, lowered body weight and improved cognitive function, while reducing senescence markers and SASP cytokines in WT HFD mice. These effects were absent in Mir146a-/- HFD mice when treated with Elo, indicating the dependence of Elo's therapeutic efficacy on miR-146a. Conclusion: Elocalcitol prevents development of senescence in microglia via modulation of miR-146a expression, while miR-146a provides protection against HFD-induced cellular senescence in the hypothalamus most probably via inhibition of TGF/Smad4 pathway. These findings highlight Elo and miR-146a as promising therapeutic candidates for ameliorating obesity-related neuroinflammation and senescence. [ABSTRACT FROM AUTHOR]

The experiment aimed to investigate the effects of pomelo fruit polysaccharide on reducing fat deposition and improving liver health in Epinephelus coioides. Selected Epinephelus coioides with a body weight of about 11 g, divided into five groups. There were three replicates in each group: Control group (fat content 11.06%), low-fat group (fat content 7.49%), low-fat + pomelo fruit polysaccharide group (low-fat diet +400 mg/kg pomelo fruit polysaccharide), high-fat group (fat content 15.32%) and high-fat + pomelo fruit polysaccharide group (high-fat diet +400 mg/kg pomelo fruit polysaccharide). 20 fish per repeat. The pre-test period was two weeks, the formal test period was eight weeks. The results showed that the weight gain rate (WGR) and specific growth rate (SGR) of Epinephelus coioides in the low-fat group were significantly lower than those in the control group (P<0.05). The low-fat + pomelo fruit polysaccharide group and the high-fat + pomelo fruit polysaccharide group were higher than the low-fat group and the high-fat group, respectively, but without significant differences (P>0.05). Compared to the high-fat group, the whole fish and muscle crude fat content and hepatosomatic index (HSI) in the high-fat + pomelo fruit polysaccharide group were significantly reduced (P<0.05). The low-fat group and high-fat group showed liver damage, but the low-fat + pomelo fruit polysaccharide group and the high-fat + pomelo fruit polysaccharide group exhibited significant improvements in liver tissue structure damage, and the liver lipid droplet content in the high-fat + pomelo fruit polysaccharide group was significantly lower than that in the high-fat group. The high-fat + pomelo fruit polysaccharide group significantly inhibited the upregulation of inflammation and apoptosis-related genes interleukin-1β (IL-1β), interleukin-8 (IL-8), caspase protease-3 (caspase-3), and caspase protease-8 (caspase-8). The study indicates that the addition of pomelo polysaccharide in low fat and high fat diets had no effect on the growth performance of Epinephelus coioides, but it could reduce the increase of crude fat content in whole fish and muscle and fat deposition in liver caused by high fat diet, enhance immune function and improve liver health. [ABSTRACT FROM AUTHOR]

Background/Objectives: Emerging data support evidence of the essential role of glucagon for lipid metabolism. However, data on the role of dietary fat intake for glucagon secretion is limited. This analysis investigated whether altering nutritional fat intake affects glucagon levels in healthy subjects. Methods: A total of 92 twins (age: 31 ± 14 years, BMI: 23 ± 3 kg/m2) consumed two 6-week diets: first a low-fat, high-carbohydrate diet (LFD) followed by an isocaloric high-fat, low-carbohydrate diet (HFD). In total, 24 twins (age: 39 ± 15 years, BMI: 24 ± 2 kg/m2) continued with a high-protein diet (HPD). Clinical investigations were performed after 6 weeks of the LFD, after 1 and 6 weeks of the HFD and after 6 weeks of the HPD. Results: The LFD caused a significant decrease in fasting glucagon (−27%, p < 0.001) compared to baseline. After 6 weeks of the HFD, glucagon increased (117%, p < 0.001 vs. LFD), while free fatty acids decreased. Six weeks of the HPD further increased glucagon levels (72%, p = 0.502 vs. HFD), although fasting amino acid levels remained constant. Fasting insulin and HOMA-IR moderately increased after one week of the HFD, while six weeks of the HPD significantly decreased both. The fasting glucagon-to-insulin ratio decreased during the LFD (p < 0.001) but increased after the HFD (p < 0.001) and even further increased after the HPD (p = 0.018). Liver fat, triglycerides and blood glucose did not increase during the HFD. The heritability of glucagon levels was 45% with the LFD. Conclusions: An HFD increases glucagon levels and the glucagon-to-insulin ratio under isocaloric conditions compared to an LFD in healthy lean subjects. This rise in glucagon may represent a metabolic response to prevent hepatic steatosis, as glucagon increases have been previously shown to induce hepatic fat oxidation. [ABSTRACT FROM AUTHOR]

Time-restricted feeding (TRF) has emerged as a promising dietary approach for improving metabolic parameters associated with obesity. However, it remains largely unclear whether TRF offers benefits for obesity related to exposure to light at night. This study examined whether lean and obese mice under chronic light exposure could benefit from TRF intervention. Six-week-old C57BL/6 male mice were fed either a low-fat diet or a high-fat diet under a 12 h light/12 h dark cycle for 6 weeks. They were then divided into three subgroups: control light, chronic 24 h light, and chronic light with a daily 10 h TRF. Chronic light exposure led to increased weight gain and higher expression of inflammatory and fibrotic markers in the adipose tissue of both lean and obese mice. It also increased hepatic triglyceride content in mice, regardless of their weight status. TRF protected both lean and obese mice from weight gain, normalized inflammatory and fibrotic gene expression, and reduced adipose tissue collagen and liver triglyceride accumulation caused by light exposure alone or in combination with obesity. These results suggest that TRF could have clinical implications for preventing obesity associated with night shift work, regardless of current weight status. [ABSTRACT FROM AUTHOR]

Epidemiological studies demonstrate that maternal obesity and maternal allergy are major risk factors for asthma in offspring. However, the impact of maternal allergy and obesity on offspring lung insulin signaling and allergen responsiveness is not known. To evaluate this, allergic and nonallergic female mice were fed a high-fat diet or low-fat diet from 7 wk before pregnancy until weaning. Neonatal pups were allergen-sensitized and allergen-challenged and then were assessed for obesity, insulin signaling, and allergic inflammation. Compared with pups of nonobese nonallergic mothers, allergen-challenged pups of obese nonallergic mothers, nonobese allergic mothers, and obese allergic mothers had bronchoalveolar lavage (BAL) eosinophilia, with the pups of obese allergic mothers having the highest BAL eosinophilia. These pups also had lower insulin-induced lung AKT phosphorylation, indicating a decrease in lung parenchymal insulin sensitivity. In cross-fostering experiments, allergen-challenged pups exposed to both pre- and postnatal obese allergic mothers had the highest level of BAL eosinophilia. Maternal obesity or allergy increased offspring serum allergen-specific IgE and interleukin-5 that was highest when the mother was both obese and allergic. Also, allergen-challenged pups exposed to both pre- and postnatal obese allergic mothers had the highest level of interleukin-5. In summary, offspring born to obese allergic mothers have decreased lung insulin sensitivity and increased lung allergic inflammation. Interestingly, our data also demonstrate that there is both a pregnancy and postpregnancy aspect of maternal allergy and obesity that enhances allergen responsiveness in offspring. [ABSTRACT FROM AUTHOR]

Excessive dietary fat intake increases plasma lipid levels and has been associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fracture, especially in older postmenopausal women. The objective of this study was to investigate whether there are sex-related differences in lipid metabolism that could have an impact on large-scale bone regeneration. Because ribs provide a unique exception as the only bones capable of completely regenerating large-scale defects, we used a rib resection mouse model in which human features are recapitulated. After 10 days of exposure to a low-fat diet or high-fat diet (HFD), we performed large-scale rib resection surgeries on male and female mice (6–7 weeks old) with deletion of the low-density lipoprotein (LDL) receptor (Ldlr−/−) and age- and sex-matched wild-type (WT) mice were used as controls. Plasma analysis showed that short-term exposure to HFD significantly increases total cholesterol, LDL cholesterol, and triglycerides levels in Ldlr−/− mice but not in WT, with no differences between males and females. However, under HFD, callus bone volume was significantly reduced exclusively in male Ldlr−/− mice when compared to WT, although these differences were no longer apparent by 21 days after resection. Regardless of diet or genotype, BMD of regenerated ribs did not differ significantly between groups, although male mice typically had lower average BMD values. Together, these results suggest that short-term hyperlipidemia has transient effects on large-scale bone regeneration exclusively in male mice. [ABSTRACT FROM AUTHOR]

Ghrelin is an orexigenic peptide released by gastric ghrelin cells that contributes to obesity and hepatic steatosis. The mechanosensitive ion channel Piezo1 in gastric ghrelin cells inhibits the synthesis and secretion of ghrelin in response to gastric mechanical stretch. We sought to modulate hepatic lipid metabolism by manipulating Piezo1 in gastric ghrelin cells. Mice with a ghrelin cell–specific deficiency of Piezo1 (Ghrl-Piezo1−/−) had hyperghrelinemia and hepatic steatosis when fed a low-fat or high-fat diet. In these mice, hepatic lipid accumulation was associated with changes in gene expression and in protein abundance and activity expected to increase hepatic fatty acid synthesis and decrease lipid β-oxidation. Pharmacological inhibition of the ghrelin receptor improved hepatic steatosis in Ghrl-Piezo1−/− mice, thus confirming that the phenotype of these mice was due to overproduction of ghrelin caused by inactivation of Piezo1. Gastric implantation of silicone beads to induce mechanical stretch of the stomach inhibited ghrelin synthesis and secretion, thereby helping to suppress fatty liver development induced by a high-fat diet in wild-type mice but not in Ghrl-Piezo1−/− mice. Our study elucidates the mechanism by which Piezo1 in gastric ghrelin cells regulate hepatic lipid accumulation, providing insights into potential treatments for fatty liver. Editor's summary: The appetite-stimulating hormone ghrelin promotes hepatic lipid accumulation. Zhang et al. investigated the regulation of hepatic lipid homeostasis by Piezo1, a mechanosensitive ion channel that is activated when food ingestion stretches the stomach and that suppresses ghrelin production. Mice lacking Piezo1 in ghrelin-producing cells in the stomach developed hepatic steatosis, which was reversed by pharmacologically blocking the ghrelin receptor. Gastric bead implantation, which mimicked the mechanical stretch induced by food intake, reduced hepatic steatosis in control mice on a normal diet or with diet-induced obesity but not in the conditional knockout mice. Thus, Piezo1 in ghrelin-producing cells could be targeted to treat metabolic dysfunction–associated steatotic liver disease, the most prevalent liver disorder worldwide. —Wei Wong [ABSTRACT FROM AUTHOR]

Background: Obesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed "metabolic endotoxemia." We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women. Methods: Fifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm2) and n = 25 with high VAT area (177.5 ± 31.3 cm2). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks. Results: Women in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet. Conclusions: Increased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms. 7yVbQmTTfsF9b4Af3tznWN Video Abstract [ABSTRACT FROM AUTHOR]

In the study of obesity and diabetes, mice are widely used for experimental research, and fasting is a common procedure used to reset metabolism in mouse models. The fasting duration for experimental mice varies greatly in nutritional and metabolic studies, ranging from 2 to 48 h. This study aims to assess the optimal fasting duration for mice fed low- and high-fat diets over a short period of time. C57BL/6J mice were fed a low-fat diet (LFD) or high-fat diet (HFD) and fasted for 4, 6, 8, 10, 12, or 24 h. The effects of different conditions after fasting on the metabolic level of mice were explored, and the data were collected for analysis. Our data indicate that fasting has inconsistent effects on mice fed a low-fat or high-fat diet. To compare the metabolic differences between mice in different dietary levels and thereby secure better scientific data, mice should fast for 6 h in animal experiments. Fasting for 6 h is also recommended when comparing glucose tolerance with insulin tolerance. [ABSTRACT FROM AUTHOR]

Some health disorders, such as obesity and type 2 diabetes, are associated with a poor diet and low quality of the fat in it. The type and duration of the diet have an impact on the liver. This investigation uses the proteomic approach to identify changes in the mouse liver protein profile in adaptation to high-fat diets with different saturated fatty acid contents and linoleic acid (18:2n-6) to α-linolenic acid (18:3n-3) fatty acid ratios. Four groups of male mice were fed different diets: one standard diet and three high-fat diets were investigated. After six months on these diets, the animals were sacrificed for liver dissection. Two-dimensional electrophoresis was used to separate the complex liver protein mixture, which enabled the separation of proteins against a wide, 3–10 range of pH and molecular weights of 15–250 kDa. Protein profiles were analysed in the PDQuest Advanced 8.0.1 program. Differentially expressed spots were identified using matrix-assisted laser desorption/ionisation–time-of-flight tandem mass spectrometry and peptide mass fingerprinting. The levels of identified proteins were validated using Western blotting. Transcript levels were evaluated using a real-time quantitative PCR. The analysis of mouse liver protein profiles enabled the identification of 32 protein spots differing between nutritional groups. A diet high in polyunsaturated fatty acids modulated the levels of liver proteins involved in critical metabolic pathways, including amino acid metabolism, carbohydrate metabolism and cellular response to oxidative stress. [ABSTRACT FROM AUTHOR]

Maternal obesity during pregnancy is associated with adverse pregnancy outcomes. This might be due to undesired obesity-induced changes in the maternal gut microbiota and related changes in the maternal immune adaptations during pregnancy. The current study examines how obesity affects gut microbiota and immunity in pregnant obese and lean mice during mid-pregnancy (gestational day 12 (GD12)). C57BL/6 mice were fed a high-fat diet or low-fat diet from 8 weeks before mating and during pregnancy. At GD12, we analyzed the gut microbiota composition in the feces and immune responses in the intestine (Peyer's patches, mesenteric lymph nodes) and the peripheral circulation (spleen and peripheral blood). Maternal obesity reduced beneficial bacteria (e.g., Bifidobacterium and Akkermansia) and changed intestinal and peripheral immune responses (e.g., dendritic cells, Th1/Th2/Th17/Treg axis, monocytes). Numerous correlations were found between obesity-associated bacterial genera and intestinal/peripheral immune anomalies. This study shows that maternal obesity impacts the abundance of specific bacterial gut genera as compared to lean mice and deranges maternal intestinal immune responses that subsequently change peripheral maternal immune responses in mid-pregnancy. Our findings underscore the opportunities for early intervention strategies targeting maternal obesity, ideally starting in the periconceptional period, to mitigate these obesity-related pregnancy effects. [ABSTRACT FROM AUTHOR]

It had been observed that homozygous albumin knockout mice (Alb−/−) exhibit low plasma free fatty acid (FFA) concentration and improved blood glucose regulation. However, it was not yet known to what extent heterozygous albumin knockout (Alb+/−) mice would display a similar phenotype. Alb−/−, Alb+/−, and wild-type (WT) female mice were studied on a low-fat diet (LFD) or high-fat diet (HFD). On both diets, decreased plasma FFA concentration, and improved glucose tolerance test were observed in Alb−/−, but not in Alb+/−, compared to WT. Plasma adiponectin concentration showed greater elevation in Alb−/− than Alb+/−. Consistent with that, adiponectin gene expression was significantly higher in Alb−/− mice than in Alb+/− and WT mice. A dose-dependent response was observed for hepatic Acadl gene expression showing higher Acadl gene expression in Alb−/− mice than in Alb+/− and WT mice. In conclusion, although female Alb+/− mice exhibited some slight differences from WT mice (e.g., increased plasma adiponectin and hepatic Acadl gene expression), Alb+/− mice did not exhibit improved glucoregulation in comparison to WT mice, indicating that a minor suppression of albumin expression is not sufficient to improve glucoregulation. Furthermore, it is now clear that although the response of female mice to HFD might be unique from how males generally respond, still the complete albumin deficiency in Alb−/− mice and the associated FFA reduction is capable of improving glucoregulation in females on this diet. The present results have implications for the role of albumin and FFA in the regulation of metabolism. [ABSTRACT FROM AUTHOR]

Aims: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. Materials and Methods: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9–5.8) years follow‐up. Results: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107–1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035–1.531) p = 0.0213), albuminuria (OR 1.277 (1.124–1.454), p = 0.0002; HR 1.608 (1.208–2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006–1.037) p = 0.0068; HR 1.324 (1.089–1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non‐diabetic individuals (HR 1.402 (1.081–1.818), p = 0.0109). Conclusions: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP‐fold peptides in the pathophysiology of diabetes complications and vascular risk stratification. [ABSTRACT FROM AUTHOR]

Aim: Type 1 diabetes results from autoimmune events influenced by environmental variables, including changes in diet. This study investigated how feeding refined versus unrefined (aka 'chow') diets affects the onset and progression of hyperglycaemia in non‐obese diabetic (NOD) mice. Methods: Female NOD mice were fed either unrefined diets or matched refined low‐ and high‐fat diets. The onset of hyperglycaemia, glucose tolerance, food intake, energy expenditure, circulating insulin, liver gene expression and microbiome changes were measured for each dietary group. Results: NOD mice consuming unrefined (chow) diets developed hyperglycaemia at similar frequencies. By contrast, mice consuming the defined high‐fat diet had an accelerated onset of hyperglycaemia compared to the matched low‐fat diet. There was no change in food intake, energy expenditure, or physical activity within each respective dietary group. Microbiome changes were driven by diet type, with chow diets clustering similarly, while refined low‐ and high‐fat bacterial diversity also grouped closely. In the defined dietary cohort, liver gene expression changes in high‐fat‐fed mice were consistent with a greater frequency of hyperglycaemia and impaired glucose tolerance. Conclusion: Glucose intolerance is associated with an enhanced frequency of hyperglycaemia in female NOD mice fed a defined high‐fat diet. Using an appropriate matched control diet is an essential experimental variable when studying changes in microbiome composition and diet as a modifier of disease risk. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates of diabesity. The Western diet's abundance of fat and fructose significantly contributes to MASLD, disrupting hepatic glucose metabolism. We previously demonstrated that a high-fat and high-fructose diet (HFHFD) led to increased body and liver weight compared to the low-fat diet (LFD) group, accompanied by glucose intolerance and liver abnormalities, indicating an intermediate state between fatty liver and liver fibrosis in the HFHFD group. Sirtuins are crucial epigenetic regulators associated with energy homeostasis and play a pivotal role in these hepatic dysregulations. Our investigation revealed that HFHFD significantly decreased Sirt1 and Sirt7 gene and protein expression levels, while other sirtuins remained unchanged. Additionally, glucose 6-phosphatase (G6Pase) gene expression was reduced in the HFHFD group, suggesting a potential pathway contributing to fibrosis progression. Chromatin immunoprecipitation analysis demonstrated a significant increase in histone H3 lysine 18 acetylation within the G6Pase promoter in HFHFD livers, potentially inhibiting G6Pase transcription. In summary, HFHFD may inhibit liver gluconeogenesis, potentially promoting liver fibrosis by regulating Sirt7 expression. This study offers an epigenetic perspective on the detrimental impact of fructose on MASLD progression. [ABSTRACT FROM AUTHOR]

Background: Obesity is a critical public health concern with its prevalence growing at an alarming rate worldwide. The Western diet that typically includes high-fat or high-fructose components is one of the leading contributing factors of obesity. Recent findings demonstrate the essential role of BAT in regulating whole-body metabolism. However, the explicit mechanism through which BAT maintains homeostasis is still unknown. Methods: Six-week-old C57BL/6 male mice were fed either a low-fat diet (LFD) or a high-fat high-fructose diet (HFHFD) for 4, 12, and 20 weeks. Results: We observed a significant increase in BAT weight under HFHFD along with BAT whitening in a time-dependent manner. This was also accompanied by a significant decrease in UCP1 and PGC1α protein, as well as a significant increase in the Bax/Bcl-2 ratio as early as 12 weeks, indicating increased apoptosis under HFHFD. Interestingly, miRNA-103 expression that holds a seed sequence within the miRNA biogenesis machinery, Dicer, was significantly upregulated after 12 and 20 weeks of HFHFD. Dicer and another biogenesis regulator, TRBP2, exhibited significant upregulation at 4 weeks of HFHFD. Conversely, those gene expressions were significantly downregulated at 12 and 20 weeks of HFHFD, followed by a significant decrease in the protein level at 12 weeks. To confirm the mechanistic connection, miRNA-103 knockdown in vitro significantly upregulated Dicer and the TRBP2 gene. However, only Dicer exhibited a significant increase at the translational level. Conclusion: Overall, we conclude that HFHFD may elicit BAT dysfunction by inhibiting Dicer via miRNA-103. [ABSTRACT FROM AUTHOR]

Obesity is a major public health problem for all age groups across the world. Diet, rather than hereditary alterations, is thought to have a significant role in the obesity pandemic. Obesity can considerably harm male reproductive health, resulting in lower libido, erectile dysfunction, and subfertility or infertility. Tocotrienols (T3s) are among the compounds that have metabolic effects due to their nutritional properties as a food supplement. The study aimed to identify the role of tocotrienol in ameliorating the risks of a high-fat diet on some reproductive hormones and efficiency. The eighteen male adult rats were randomly assigned to three separate sets of six each. The control group was fed a low-fat diet (LF ten percent kcal from fat), the high-fat diet (HFD) group was fed a high-fat diet (HF sixty percent kcal from fat), and the high-fat diet with tocotrienol (HFDT) group was fed a high-fat diet administered tocotrienol (60 mg/kg BW) dissolved in olive oil (1 mL/kg) for 12 weeks. LH hormone showed a significant decrease in concentration for the HFD and HFDT groups when compared with the control group. Tocotrienol supplement introduced its ability to improve motility and account for dead and abnormal sperm values. The histopathological examination of testes in rats fed a high-fat diet and supplemented with tocotrienol revealed normal spermatogenesis. The tocotrienol supplement ameliorated the deleterious effect of obesity in the experiment and appeared significantly less than the control group. [ABSTRACT FROM AUTHOR]

Obesity is a fast-growing epidemic affecting more than 40% of the US population and leads to co-morbidities such as type 2 diabetes and cancer. More importantly, there is a rapid increase in childhood obesity associated with obesity in parents. Further, offspring are encoded with approximately half of their genetic information from the paternal side. Obesity in fathers at the preconceptional period likely influences the intergenerational development of obesity. This study focuses on the role of fish oil supplementation as a non-pharmacological intervention in fathers and its impact on childhood obesity using animal models. Male mice were fed a low-fat diet or high-fat diet with or without fish oil for 10 weeks and mated with female mice on a chow diet. Offspring were then continued on a chow diet until 8 or 16 weeks. In vivo insulin tolerance was tested to assess the metabolic health of offspring. Further, adipose tissue was harvested upon sacrifice, and genetic markers of inflammation and lipid metabolism in the tissue were analyzed. Offspring of males supplemented with fish oil showed lower body weight, improved insulin tolerance, and altered inflammatory markers. Markers of fatty acid oxidation were higher, while markers of fatty acid synthesis were lower in offspring of fathers fed fish oil. This supports fish oil as an accessible intervention to improve offspring metabolic health. [ABSTRACT FROM AUTHOR]

Fat in the form of cracked rapeseed and 3-nitrooxypropanol (3-NOP, market as Bovaer) were fed alone or in combination to 4 Danish Holstein multicannulated dairy cows, with the objective to investigate effects on gas exchange, dry matter intake (DMI), nutrient digestion, and nutrient metabolism. The study design was a 4 × 4 Latin square with a 2 × 2 factorial treatment arrangement with 2 levels of fat supplementation; 33 g of crude fat per kg of dry matter (DM) or 64 g of crude fat per kg of DM for low and high fat diets, respectively, and 2 levels of 3-NOP; 0 mg/kg DM or 80 mg/kg DM. In total, 4 diets were formulated: low fat (LF), high fat (HF), 3-NOP and low fat (3LF), and 3-NOP and high fat (3HF). Cows were fed ad libitum and milked twice daily. The adaptation period lasted 11 d, followed by 5 d with 12 diurnal sampling times of digesta and ruminal fluid. Thereafter, gas exchange was measured for 5 d in respiration chambers. Chromic oxide and titanium dioxide were used as external flow markers to determine intestinal nutrient flow. No interactions between fat supplementation and 3-NOP were observed for methane yield (g/kg DM), total-tract digestibility of nutrients or total volatile fatty acid (VFA) concentration in the rumen. Methane yield (g/kg DMI) was decreased by 24% when cows were fed 3-NOP. In addition, 3-NOP increased carbon dioxide and hydrogen yield (g/kg DM) by 6% and 3,500%, respectively. However, carbon dioxide production was decreased when expressed on a daily basis. Fat supplementation did not affect methane yield but tended to reduce methane in percent of gross energy intake. A decrease (11%) in DMI was observed, when cows were fed 3-NOP. Likely, the lower DMI mediated a lower passage rate causing the tendency to higher rumen and total-tract neutral detergent fiber digestibility, when the cows were fed 3-NOP. Total VFA concentrations in the rumen were negatively affected both by 3-NOP and fat supplementation. Furthermore, 3-NOP caused a shift in the VFA fermentation profile, with decreased acetate proportion and increased butyrate proportion, whereas propionate proportion was unaffected. Increased concentrations of the alcohols methanol, ethanol, propanol, butanol, and 2-butanol were observed in the ruminal fluid when cows were fed 3-NOP. These changes in rumen metabolites indicate partial re-direction of hydrogen into other hydrogen sinks, when methanogenesis is inhibited by 3-NOP. In conclusion, fat supplementation did not reduce methane yield, whereas 3-NOP reduced methane yield, irrespective of fat level. However, the concentration of 3-NOP and diet composition and resulting desired mitigation effect must be considered before implementation. The observed reduction in DMI with 80 mg 3-NOP/kg DM was intriguing and may indicate that a lower dose should be applied in a Northern European context; however, the mechanism behind needs further investigation. [ABSTRACT FROM AUTHOR]

The current study was conducted to assess the effect of HFD (40%) on estrous cycle regularity and body weight in female rats. Fourteen female Wistar albino rats were randomly divided into two groups. The control group (I) received the standard chow diet, and the HFD group (II) received the HFD (55% basal diet, 3% sesame oil, 25% beef tallow, 5% milk powder, 5% roasted peanuts, 5% egg, and 2% NaCl) daily for 10 successive weeks. Bodyweight was recorded every week from the beginning of the study to the end, where, at the 8 th week after dietary exposure, the assessment of the estrous cycle was performed daily for ten successive days using visual assessment and vaginal cytology procedures. The HFD group revealed a statistically higher proportion of rats with an irregular estrous cycle (p = 0.031) and a significantly increased diestrus index vs. the control group (p = 0.025). The HFD group revealed a nonsignificant decrease in the cycle frequency, a significant decrease in the total days of the proestrus stage (p ≤ 0.001), and a nonsignificant shortening in the estrus and metestrus stages vs. control. In contrast, the HFD group revealed a significantly longer diestrus stage than the control group (p = 0.025). Weight gain and body weight were significantly increased throughout the experiment in the HFD group when compared with the control group (p < 0.001). In conclusion, HFD results in increased body weight and increased estrous cycle irregularities, which may impair the female reproductive function. [ABSTRACT FROM AUTHOR]

Western diets are becoming increasingly common around the world. Western diets have high omega 6 (ω-6) and omega 3 (ω-3) fatty acids and are linked to bone loss in humans and animals. Dietary fats are not created equal; therefore, it is vital to understand the effects of specific dietary fats on bone. We aimed to determine how altering the endogenous ratios of ω-6:ω-3 fatty acids impacts bone accrual, strength, and fracture toughness. To accomplish this, we used the Fat-1 transgenic mice, which carry a gene responsible for encoding a ω-3 fatty acid desaturase that converts ω-6 to ω-3 fatty acids. Male and female Fat-1 positive mice (Fat-1) and Fat-1 negative littermates (WT) were given either a high-fat diet (HFD) or low-fat diet (LFD) at 4 wk of age for 16 wk. The Fat-1 transgene reduced fracture toughness in males. Additionally, male BMD, measured from DXA, decreased over the diet duration for HFD mice. In males, neither HFD feeding nor the presence of the Fat-1 transgene impacted cortical geometry, trabecular architecture, or whole-bone flexural properties, as detected by main group effects. In females, Fat-1 -LFD mice experienced increases in BMD compared to WT-LFD mice; however, cortical area, distal femur trabecular thickness, and cortical stiffness were reduced in Fat-1 mice compared to pooled WT controls. However, reductions in stiffness were caused by a decrease in bone size and were not driven by changes in material properties. Together, these results demonstrate that the endogenous ω-6:ω-3 fatty acid ratio influences bone material properties in a sex-dependent manner. In addition, Fat-1 mediated fatty acid conversion was not able to mitigate the adverse effects of HFD on bone strength and accrual. [ABSTRACT FROM AUTHOR]

Maternal overnutrition during lactation predisposes offspring to develop metabolic diseases and exacerbates the relevant syndromes in males more than females in later life. The hypothalamus is a heterogenous brain region that regulates energy balance. Here we combined metabolic trait quantification of mother and offspring mice under low and high fat diet (HFD) feeding during lactation, with single nucleus transcriptomic profiling of their offspring hypothalamus at peak lacation to understand the cellular and molecular alterations in response to maternal dietary pertubation. We found significant expansion in neuronal subpopulations including histaminergic (Hdc), arginine vasopressin/retinoic acid receptor-related orphan receptor β (Avp/Rorb) and agouti-related peptide/neuropeptide Y (AgRP/Npy) in male offspring when their mothers were fed HFD, and increased Npy-astrocyte interactions in offspring responding to maternal overnutrition. Our study provides a comprehensive offspring hypothalamus map at the peak lactation and reveals how the cellular subpopulations respond to maternal dietary fat in a sex-specific manner during development. Maternal high fat diet during lactation predisposes offspring to develop obesity in males more than females. Here, authors show expansion of key metabolic related hypothalamic neuron populations in male but not female mice, in response to maternal fat intake. [ABSTRACT FROM AUTHOR]

Obesity is often accompanied by heightened circulating and tissue inflammation along with an increase in sphingolipids (e.g., ceramides) in metabolically active and insulin-sensitive organs. Whey protein isolate (WPI) has been shown to decrease inflammation and increase insulin sensitivity when given during a high-fat diet (HFD) intervention in rodents. The whey protein bioactive peptide glycomacropeptide (GMP) has also been linked to having anti-inflammatory properties and regulating lipogenesis. Therefore, the purpose of the study was to determine the effect of dietary GMP within the whey protein matrix on tissue inflammation, adiposity, and tissue ceramide accumulation in an obesogenic rodent model. Young adult male mice (10 wk old) underwent a 10-wk 60% HFD intervention. Glycomacropeptide was absent in the control low-fat diet and HFD WPI (−GMP) groups. The HFD WPI (1×GMP) treatment contained a standard amount of GMP, and HFD WPI (2×GMP) had double the amount. We observed no differences in weight gain or reductions in adiposity when comparing the GMP groups to HFD WPI (−GMP). Similarly, insulin resistance and glucose intolerance were not offset with GMP, and skeletal muscle and liver tissue ceramide content was unaltered with the GMP intervention. In contrast, the additional amount of GMP (2×GMP) might adversely affect tissue obesity-related pathologies. Together, dietary GMP given in a whey protein matrix during an HFD intervention does not alter weight gain, insulin resistance, glucose intolerance, and sphingolipid accumulation in the liver and skeletal muscle. [ABSTRACT FROM AUTHOR]

• High-fat diet consumption before surgery extends duration of long-term memory deficits. • High-fat diet consumption potentiates the neuroinflammatory response to surgery. • TLR4 mediates the development of HFD + surgery-induced neuroinflammation & memory impairments. • Dietary DHA supplementation prevents HFD + surgery-induced neuroinflammation & memory deficits. Post-operative cognitive dysfunction (POCD) is an abrupt decline in neurocognitive function arising shortly after surgery and persisting for weeks to months, increasing the risk of dementia diagnosis. Advanced age, obesity, and comorbidities linked to high-fat diet (HFD) consumption such as diabetes and hypertension have been identified as risk factors for POCD, although underlying mechanisms remain unclear. We have previously shown that surgery alone, or 3-days of HFD can each evoke sufficient neuroinflammation to cause memory deficits in aged, but not young rats. The aim of the present study was to determine if HFD consumption before surgery would potentiate and prolong the subsequent neuroinflammatory response and memory deficits, and if so, to determine the extent to which these effects depend on activation of the innate immune receptor TLR4, which both insults are known to stimulate. Young-adult (3mo) & aged (24mo) male F344xBN F1 rats were fed standard chow or HFD for 3-days immediately before sham surgery or laparotomy. In aged rats, the combination of HFD and surgery caused persistent deficits in contextual memory and cued-fear memory, though it was determined that HFD alone was sufficient to cause the long-lasting cued-fear memory deficits. In young adult rats, HFD + surgery caused only cued-fear memory deficits. Elevated proinflammatory gene expression in the hippocampus of both young and aged rats that received HFD + surgery persisted for at least 3-weeks after surgery. In a separate experiment, rats were administered the TLR4-specific antagonist, LPS-RS, immediately before HFD onset, which ameliorated the HFD + surgery-associated neuroinflammation and memory deficits. Similarly, dietary DHA supplementation for 4 weeks prior to HFD onset blunted the neuroinflammatory response to surgery and prevented development of persistent memory deficits. These results suggest that HFD 1) increases risk of persistent POCD-associated memory impairments following surgery in male rats in 2) a TLR4-dependent manner, which 3) can be targeted by DHA supplementation to mitigate development of persistent POCD. [ABSTRACT FROM AUTHOR]

Background: Recent decades have seen an exponential rise in global obesity prevalence, with rates nearly doubling in a span of 40 years. A comprehensive knowledge base regarding the systemic effects of obesity is required to create new preventative and therapeutic agents effective at combating the current obesity epidemic. Previous studies of diet-induced obesity utilizing mouse models have demonstrated a difference in bodyweight gain by sex. In such studies, female mice gained significantly less weight than male mice when given the same high fat (HF) diet, indicating a resistance to diet-induced obesity. Research has also shown sex differences in gut microbiome composition between males and females, indicated to be in part a result of sex hormones. Understanding metabolic differences between sexes could assist in the development of new measures for obesity prevention and treatment. This study aimed to characterize sex differences in weight gain, plasma lipid profiles, fecal microbiota composition, and fecal short chain fatty acid levels. We hypothesized a role for the gut microbiome in these sex differences that would be normalized following microbiome depletion. Methods: A mouse model was used to study these effects. Mice were divided into treatment groups by sex, diet, and presence/absence of an antibiotic cocktail to deplete genera in the gut microbiome. We hypothesized that sex differences would be present both in bodyweight gain and systemic measures of obesity, including hormone and circulating free fatty acid levels. Results: We determined statistically significant differences for sex and/or treatment for the outcome measures. We confirm previous findings in which male mice gained significantly more weight than female mice fed the same high fat diet. However, sex differences persisted following antibiotic administration for microbiome depletion. Conclusions: We conclude that sex differences in the gut microbiome may contribute to sex differences in obesity, but they do not explain all of the differences. Highlights: Analyzed the fecal microbiome at the genus level for male and female C57Bl/6 mice on a low fat diet, high fat diet, with and without antibiotic treatment. Measured ten short chain fatty acids in fecal samples for male and female C57Bl/6 mice on a low fat diet, high fat diet, with and without antibiotic treatment. Measured circulating free fatty acids for male and female C57Bl/6 mice on a low fat diet, high fat diet, with and without antibiotic treatment. Male mice gained the most weight on a high fat diet, following antibiotic treatment, compared to all other groups. Significant depletion of the microbiome via antibiotic treatment does not decrease body weight and does not normalize sex differences in obesity. [ABSTRACT FROM AUTHOR]

Currently, over 88 million people are estimated to have adopted a vegan or vegetarian diet. Cysteine is a semi-essential amino acid, which availability is largely dependent on dietary intake of meat, eggs and whole grains. Vegan/vegetarian diets are therefore inherently low in cysteine. Sufficient uptake of cysteine is crucial, as it serves as substrate for protein synthesis and can be converted to taurine and glutathione. We found earlier that intermolecular cystine bridges are essential for the barrier function of the intestinal mucus layer. Therefore, we now investigate the effect of low dietary cystine on the intestine. Mice (8/group) received a high fat diet with a normal or low cystine concentration for 2 weeks. We observed no changes in plasma methionine, cysteine, taurine or glutathione levels or bile acid conjugation after 2 weeks of low cystine feeding. In the colon, dietary cystine restriction results in an increase in goblet cell numbers, and a borderline significant increase mucus layer thickness. Gut microbiome composition and expression of stem cell markers did not change on the low cystine diet. Remarkably, stem cell markers, as well as the proliferation marker Ki67, were increased upon cystine restriction in the small intestine. In line with this, gene set enrichment analysis indicated enrichment of Wnt signaling in the small intestine of mice on the low cystine diet, indicative of increased epithelial proliferation. In conclusion, 2 weeks of cystine restriction did not result in apparent systemic effects, but the low cystine diet increased the proliferative capacity specifically of the small intestine and induced the number of goblet cells in the colon. [ABSTRACT FROM AUTHOR]

Objective: To address the relationship between the proportions of carbohydrates and fat and hyperglycaemia in the Chinese population. Design: A cross-section research involving data from the China Health and Nutrition Survey in 2009, and nutritional status and health indicators were mainly focused. Setting: China. Participants: 8197 Chinese individuals aged over 16 years, including 1345 subjects who had a low-carbohydrate and high-fat diet, 3951 individuals who had a medium proportion of carbohydrate and fat diet, 2660 participants who had a high-carbohydrate and low-fat diet and 241 people who had a very-high-carbohydrate and low-fat diet. Results: Subjects with the high-carbohydrate and low-fat diet were significantly associated with an increased risk of hyperglycaemia (OR: 1·142; 95 % CI: 1·022, 1·276) when compared with the individuals with the medium proportion of carbohydrate and fat diet. Meanwhile, people with a very-high-carbohydrate and low-fat diet had a higher risk of hyperglycaemia (OR: 1·829; 95 % CI: 1·377, 2·429). In contrast, the association between participants with a low-carbohydrate and high-fat diet and hyperglycaemia was NS (OR: 1·082; 95 % CI: 0·942, 1·243) with adjusting a series of confounding factors. Furthermore, people with a very-high-carbohydrate and low-fat diet were significantly associated with a higher risk of hyperglycaemia in the major energy levels and social characteristics subgroup. Conclusions: We found the high-carbohydrate and low-fat and very-high-carbohydrate and low-fat diets were significantly associated with a high risk of hyperglycaemia. And, the association between low-carbohydrate and high-fat diets and the risk of hyperglycaemia was NS. [ABSTRACT FROM AUTHOR]

Background: The presence of type 2 diabetes mellitus increases the risk of developing the colon cancer. The main objective of this study was to determine the role of sodium orthovanadate (SOV) in colon cancer associated with diabetes mellitus by targeting the competitive inhibition of PTP1B. Methods: For in vivo study, high fat diet with low dose streptozotocin model was used for inducing the diabetes mellitus. Colon cancer was induced by injecting 1,2-dimethylhydrazine (25 mg/kg, sc) twice a week. TNM staging and immunohistochemistry (IHC) was carried out for colon cancer tissues. In vitro studies like MTT assay, clonogenic assay, rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry were performed on HCT-116 cell line. CAM assay was performed to examine the anti-angiogenic effect of the drug. Results: Sodium orthovanadate reduces the blood glucose level and tumor parameters in the animals. In vitro studies revealed that SOV decreased cell proliferation dose dependently. In addition, SOV induced apoptosis as depicted from rhodamine-123 dye assay and annexin V-FITC assay using flow cytometry as well as p53 IHC staining. SOV showed reduced angiogenesis effect on eggs which was depicted from CAM assay and also from CD34 and E-cadherin IHC staining. Conclusions: Our data suggest that SOV exhibits protective role in colon cancer associated with diabetes mellitus. SOV exhibits anti-proliferative, anti-angiogenic and apoptotic inducing effects hence can be considered for therapeutic switching in diabetic colon cancer. [ABSTRACT FROM AUTHOR]

Objective: The impact of early‐life stress on weight‐loss maintenance is unknown. Methods: Mice underwent neonatal maternal separation (NMS) from 0 to 3 weeks and were weaned onto a high‐fat sucrose diet (HFSD) from 3 to 20 weeks. Calorie‐restricted weight loss on a low‐fat sucrose diet (LFSD) occurred over 2 weeks to induce a 20% loss in body weight, which was maintained for 6 weeks. After weight loss, half of the mice received running wheels, and the other half remained sedentary. Mice were then fed ad libitum on an HFSD or LFSD for 10 weeks and were allowed to regain body weight. Results: NMS mice had greater weight regain, total body weight, and adiposity compared with naïve mice. During the first week of refeeding, NMS mice had increased food intake and were in a greater positive energy balance than naïve mice. Female mice were more susceptible to NMS‐induced effects, including increases in adiposity. NMS and naïve females were more susceptible to HFSD‐induced weight regain. Exercise was beneficial in the first week of regain in male mice, but, long‐term, only those on the LFSD benefited from exercise. As expected, HFSD led to greater weight regain than LFSD. Conclusions: Early‐life stress increases weight regain in mice. [ABSTRACT FROM AUTHOR]

We sought to evaluate the association between diet and angiogenic biomarkers in KpB mice, and the association between these markers, body mass index (BMI), and overall survival (OS) in high-grade serous cancers (HGSC). Tumors previously obtained from KpB mice subjected to high-fat diets (HFD, n = 10) or low-fat diets (LFD, n = 10) were evaluated for angiogenesis based on CD-31 microvessel density (MVD). Data from prior microarray analysis (Agilent 244 K arrays) conducted in 10 mice were utilized to assess associations between diet and angiogenetic biomarkers. Agilent (mouse) and Affymetrix Human Genome U133a probes were linked to 162 angiogenic-related genes. The associations between biomarkers, BMI, and OS were evaluated in an HGSC internal database (IDB) (n = 40). Genes with unadjusted p < 0.05 were evaluated for association with OS in the TCGA-OV database (n = 339). There was no association between CD-31 and diet in mice (p = 0.66). Sixteen angiogenic-related genes passed the p < 0.05 threshold for association with HFD vs. LFD. Transforming growth factor-alpha (TGFA) demonstrated 72% higher expression in HFD vs. LFD mice (p = 0.04). Similar to the mouse study, in our HGSC IDB, higher TGFA expression correlated with higher BMI (p = 0.01) and shorter survival (p = 0.001). In the TCGA-OV dataset, BMI data was not available and there was no association between TGFA and OS (p = 0.48). HFD and obesity may promote tumor progression via differential modulation of TGFA. We were unable to confirm this finding in the TCGA dataset. Further evaluation of TGFA is needed to determine if this is a target unique to obesity-driven HGSC. • Transforming growth factor-alpha (TGFA) demonstrated 72% higher expression in mice fed high-fat diets. • Higher tumor TGFA expression was associated with higher BMI and shorter survival in patients with serous ovarian cancers. • High-fat diet and obesity may promote tumor progression via differential modulation of TGFA. [ABSTRACT FROM AUTHOR]

Consumption of a modern Western-type high-fat low-fiber diet increases the risk of obesity. However, how a host responds to such a diet, especially during the early period of dietary transition from a previous low-fat and fiber-rich diet, remains poorly explored. Wild-type C57BL/6 mice were fed a normal chow diet or a high-fat diet. Enteric glial cell (EGC) activation was detected through quantitative real-time PCR (qRT-PCR), immunoblotting and immunohistology analysis. Fluorocitrate or genetic deletion of glial fibrillary acidic protein (GFAP)-positive glial-intrinsic myeloid differentiation factor 88 (Myd88) was used to inhibit EGC activation, and the effect of a high-fat diet on obesity was further investigated. The role of MYD88-dependent sensing of commensal products in adipocyte was observed to analyze the effect of obesity. A dietary shift from a normal chow diet to a high-fat diet in mice induced a transient early-phase emergence of a GFAP-positive EGC network in the lamina propria of the ileum, accompanied with an increase in glial-derived neurotrophic factor production. Inhibition of glial cell activity blocked this response. GFAP-positive glial Myd88 knockout mice gained less body weight after high-fat diet (HFD) feeding than littermate controls. In contrast, adipocyte deletion of Myd88 in mice had no effect on weight gain but instead exacerbated glucose intolerance. Furthermore, short-term fluorocitrate intervention during HFD feeding attenuated body weight gain. Our findings indicate that EGCs are early responders to intestinal ecosystem changes and the GFAP-positive glial Myd88 signaling participates in regulating obesity. [ABSTRACT FROM AUTHOR]

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the tricarboxylic acid (TCA) cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvatealanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis. These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders. [ABSTRACT FROM AUTHOR]

This study investigates the effects of fish oil supplementation during the periconceptional period in male mice. Specifically, it examines the impact of fish oil on intergenerational health, as determined by skeletal muscle markers. To mimic paternal obesity, thirty mice were separated into three groups with distinct dietary regimes for 10 weeks: a high-fat diet (HF), a high-fat diet supplemented with fish oil (FO), and a low-fat diet (LF). Then, these mice mated with control female mice. Dams and offspring consumed a chow diet during gestation and lactation, and the offspring continued on a chow diet. To study short-term (8 weeks) and long-term (16 weeks) effects of FO, skeletal muscle was isolated at the time of sacrifice, and gene analyses were performed. Results suggest that offspring born to FO-supplemented sires exhibited a significant, short-term upregulation of genes associated with insulin signaling, fatty acid oxidation, and skeletal muscle growth with significant downregulation of genes involved in fatty acid synthesis at 8 weeks. Prominent differences in the above markers were observed at 8 weeks compared to 16 weeks. These findings suggest the potential benefits of FO supplementation for fathers during the periconceptional period in reducing the health risks of offspring due to paternal obesity. [ABSTRACT FROM AUTHOR]

Researches are gradually drifting towards adoption of food as therapies for the management of diseases that result from metabolic derangement, in extension genetical diseases can as well be managed by functional and nutritional diet that will maintain health of an individual through life. Diabetes mellitus is not an exception, there are several functional meals designed for the management of diabetes, many of these have unripe plantain as the base, with emphasis on just glycemic response limiting the antioxidant and anti-inflammatory influence. The aim of this study is to formulate a functional and optimized diet of unripe plantain base containing soycake and rice bran and compare the antidiabetic potentials of the well known cerolina and unripe plantain with the formulated optimized blend which will be in both flour and dough forms. Determine the effects that cooking of the flour samples could have on the antioxidant and overall antidiabetic potentials, through the comparison of the dough and flour. The uripe mature plantain, rice bran and soybean cake were obtained, response surface methodology (RSM) was used to establish the combination of the flour samples, and the runs generated were screened by proximate analysis and sensory evaluation to select the best blend regarded as the optimized flour blend. Dough meal (PSRD) was prepared from the optimized flour blend (PSRF) and the antidiabetic (α-amylase and α-glucosidase) and antioxidant (DPPH and hydroxyl scavenging, metal chelating activities and ferric reducing antioxidant power) effects were evaluated (in vitro). Male Wistar rats were obtained and subjected to 4-week high fat diet and low dose of streptozotocin (35 mg/kg i.p.), the animals were screened for manifestation of hyperglycemic signs and divided into eight (8) groups which included the positive control, and groups treated with PSRD, PSRF, PLTF, PLTD, CERF, CERD and glybenclamide, the ninth group is the negative control. The doughs and flours, and glybenclamide were administered orally for twenty-eight (28) days. The pancreas and liver were excised from anesthetized rats and subjected to histological and biochemical evaluations. The biochemical evaluations could be divided into antioxidant (activities of GST, GPx, catalase and superoxide dismutase and concentrations of NP-SH, GSH and MDA) and anti-inflammation (MPO, XO, TNF-α, IL-1β and IL-6). The results confirmed the relationship between diabetes mellitus, oxidative stress, inflammation and pro-inflammatory cytokines. The optimized dough sample had higher inhibition of α-amylase and α-glucosidase activities than the flour blend. The optimized dough sample further demonstrated antioxidant and anti-inflammatory protection against pancreatic and hepatic dysfunctions that could ensue as a result of type-2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Consumption of a high-fat diet (HFD) is associated with an increased risk of metabolic diseases, cancer, and neurological disorders, which are major global health concerns. In the present study, mice were fed a HFD containing 40% fat and 0.5% or 1.0% acylated steryl-β-glucosides (ASG) and their gut microbiota was compared to that of mice fed with a low-fat diet (LFD). After 55 d, the epididymal fat weight was higher in the HFD and ASG groups than in the LFD group; however, the epididymal fat weight was lower in the ASG group than in the HFD group. The abundance of gut microbiota increased with HFD in obese micespecific Bacillota, but decreased when ASG was added to the HFD. The number of intestinal bacteria involved in the production of carcinogenic secondary bile acids was increased by the consumption of HFD, but decreased by the addition of ASG to HSD. This finding may indicate the gut bacteria-mediated health benefits of ASG. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to observe the changes of glucolipid metabolic indexes and intestinal flora structure in high-fat diet combined with streptozotocin-induced diabetic rats, and the effect of lowfat diet on their intervention. Methods The rats fed with normal diet and high-fat diet were used as the control and model groups, respectively, and were subjected to low-fat diet intervention for 8 weeks. Body weights of all rats were recorded, orbital blood was taken from the rats to detect glucolipid metabolism indexes, and feces were retained for the detection of intestinal microbial diversity before and after the start of the experiment. Results In the experimental group, weight and LDL-C decreased significantly after the low-fat diet intervention, and the difference was statistically significant (P0.05). The phylum Bacteroidetes and Actinobacteria were elevated in diabetic rats, and the TM7 and Firmicutes/Bacteroidetes ratio were significantly higher after low-fat diet control. The key genera in diabetic rats were Prevotella and Bacteroides, but they changed to Ruminococc and Clostridium after the low-fat diet intervention. The key pathways of low-fat diet intervention were lipopolysaccharide biosynthesis, glycosaminoglycan degradation, other glycan degradation, and sphingolipid metabolis. Conclusion Low-fat diet significantly reduces body weight and alters intestinal flora structure in diabetic rats. Low-fat diet may interfere with the progression of diabetes by altering intestinal lipid metabolic pathways.

It has been reported that Akkermansia muciniphila improves host metabolism and reduces inflammation; however, its potential effects on bile acid metabolism and metabolic patterns in metabolic‐associated fatty liver disease (MAFLD) are unknown. In this study, we have analysed C57BL/6 mice under three feeding conditions: (i) a low‐fat diet group (LP), (ii) a high‐fat diet group (HP) and (iii) a high‐fat diet group supplemented with A. muciniphila (HA). The results found that A. muciniphila administration relieved weight gain, hepatic steatosis and liver injury induced by the high‐fat diet. A. muciniphila altered the gut microbiota with a decrease in Alistipes, Lactobacilli, Tyzzerella, Butyricimonas and Blautia, and an enrichment of Ruminiclostridium, Osclibacter, Allobaculum, Anaeroplasma and Rikenella. The gut microbiota changes correlated significantly with bile acids. Meanwhile, A. muciniphila also improved glucose tolerance, gut barriers and adipokines dysbiosis. Akkermansia muciniphila regulated the intestinal FXR‐FGF15 axis and reshaped the construction of bile acids, with reduced secondary bile acids in the caecum and liver, including DCA and LCA. These findings provide new insights into the relationships between probiotics, microflora and metabolic disorders, highlighting the potential role of A. muciniphila in the management of MAFLD. [ABSTRACT FROM AUTHOR]

In the past few decades, many researchers believed that a high-fat and high-calorie diet is the most critical factor leading to metabolic diseases. However, increasing evidence shows a high-carbohydrate and low-fat diet may also be a significant risk factor. It needs a comprehensive evaluation to prove which viewpoint is more persuasive. We systematically compared the effects of high-fat and high-calorie diets and high-carbohydrate and low-fat ones on glycolipid metabolism in mice to evaluate and compare the effects of different dietary patterns on metabolic changes in mice. Sixty 8-week-old male C57BL/6 mice were divided into four groups after acclimatization and 15% (F-15), 25% (F-25), 35% (F-35), and 45% (F-45) of their dietary energy was derived from fat for 24 weeks. The body weight, body-fat percentage, fasting blood glucose, lipid content in the serum, and triglyceride content in the livers of mice showed a significantly positive correlation with dietary oil supplementation. Interestingly, the total cholesterol content in the livers of mice in the F-15 group was significantly higher than that in other groups (p < 0.05). Compared with the F-45 group, the mRNA expression of sterol synthesis and absorption-related genes (e.g., Asgr1, mTorc1, Ucp20, Srebp2, Hmgcr, and Ldlr), liver fibrosis-related genes (e.g., Col4a1 and Adamts1) and inflammation-related genes (e.g., Il-1β and Il-6) were significantly higher in the F-15 group. Compared with the F-45 group, the relative abundance of unclassified_f_Lachnospiraceae and Akkermansia was decreased in the F-15 group. While unclassified_f_Lachnospiraceae and Akkermansia are potentially beneficial bacteria, they have the ability to produce short-chain fatty acids and modulate cholesterol metabolism. In addition, the relative abundance of unclassified_f_Lachnospiraceae and Akkermansia was significantly positively correlated with fatty acid transporters expression and negatively correlated with that of cholesteryl acyltransferase 1 and cholesterol synthesis-related genes. In conclusion, our study delineated how a high-fat and high-calorie diet (fat supplied higher than or equal to 35%) induced obesity and hepatic lipid deposition in mice. Although the high-carbohydrate and low-fat diet did not cause weight gain in mice, it induced cholesterol deposition in the liver. The mechanism is mainly through the induction of endogenous synthesis of cholesterol in mice liver through the ASGR1-mTORC1-USP20-HMGCR signaling pathway. The appropriate oil and carbon water ratio (dietary energy supply from fat of 25%) showed the best gluco-lipid metabolic homeostasis in mice. [ABSTRACT FROM AUTHOR]

The overall prevalence of metabolic diseases such as type 2 diabetes (T2D) and associated co-morbidities have increased at an alarming rate in the United States and worldwide. There is a growing body of epidemiological evidence implicating exposure to persistent organic pollutants (POPs), including legacy organochlorine (OC) pesticides and their bioaccumulative metabolites, in the pathogenesis of metabolic diseases. Therefore, the goal of the present study was to determine if exposure to trans-nonachlor, a bioaccumulative OC pesticide contaminant, in concert with high fat diet intake induced metabolic dysfunction. Briefly, male Sprague Dawley rats were exposed to trans-nonachlor (.5 or 5 ppm) in either a low fat (LFD) or high fat diet (HFD) for 16 weeks. At 8 weeks of intake, trans-nonachlor decreased serum triglyceride levels in LFD and HFD fed animals and at 16 weeks compared to LFD fed animals. Interestingly, serum glucose levels were decreased by trans-nonachlor (5 ppm) in LFD fed animals at 16 weeks. Serum free fatty acids were increased by trans-nonachlor exposure (5 ppm) in LFD fed animals at 16 weeks. HFD fed animals displayed signs of hepatic steatosis including elevated liver triglycerides, liver enzymes, and liver lipid peroxidation which were not significantly altered by trans-nonachlor exposure. However, there was a trans-nonachlor mediated increase in expression of fatty acid synthase in livers of LFD fed animals and not HFD fed animals. Thus, the present data indicate exposure to trans-nonachlor in conjunction with LFD or HFD intake produces both diet and exposure dependent effects on lipid and glucose metabolism. [ABSTRACT FROM AUTHOR]

Chronic low-grade inflammation is associated with a state of diet-induced obesity that impacts systemic tissues and can cross the blood–brain barrier to act directly on the brain. The extent to which pro-inflammatory cytokines released in these conditions affect dopamine presynaptic neurotransmission has not been previously investigated. The purpose of this study was to examine how dopamine terminals are affected by pro-inflammatory cytokines, and to determine if dietary fat consumption potentiates cytokine effects on dopamine release and reuptake rate in the nucleus accumbens (NAc). Male and female C57BL/6J mice were fed high, medium, or low-fat diets (60%, 30%, or 10% total kcals from fat, respectively) for six weeks. Fast scan cyclic voltammetry (FSCV) was used to measure dopamine release and reuptake rate in the NAc core from ex vivo coronal brain slices. Electrically evoked dopamine release and the maximal rate of dopamine reuptake (Vmax) were significantly lower in mice fed the 30% and 60% high-fat diets compared to the 10% low-fat group (p < 0.05). IL-6 5 or 10 nM or TNFα 30 or 300 nM was added to artificial cerebrospinal fluid (aCSF) bathed over brain slices during FSCV. No effect on dopamine release or Vmax was observed with lower concentrations. However, 10 nM IL-6 and 300 nM TNFα significantly reduced dopamine release in the 60% fat group (p < 0.05). No effect of added cytokine was observed on Vmax. Overall, these data provide evidence that dietary fat increases neural responsiveness to cytokines, which may help inform comorbidities between diet-induced obesity and depression or other mood disorders. [ABSTRACT FROM AUTHOR]

Introduction: Among all cancers, endometrial cancer is most strongly associated with obesity, withmore than 65% of endometrial cancers attributable to obesity and being overweight. Fatty acid synthase (FAS), a key lipogenic enzyme, is expressed in endometrial cancer tumors and is associated with aworse prognosis for this disease. Orlistat, an FAS inhibitor, is an FDA-approved weight loss medication that has demonstrated anti-tumor activity in a variety of preclinical cancer models. Methods: In this study, the Lkb1fl/flp53fl/fl mouse model of endometroid endometrial cancer was exposed to three diet interventions, including a high fat diet (obese), a low fat diet (lean) and switch from a high fat to a low fat diet, and then exposed to orlistat or placebo. Results: The mice fed a high-fat diet had significantly increased body weight and tumor weight compared to mice fed a low-fat diet. Switching from a high-fat diet to a low fat diet led to a reduction in mouse weight and suppressed tumor growth, as compared to both the high fat diet and low fat diet groups. Orlistat effectively decreased body weight in obese mice and inhibited tumor growth in obese, lean, and the high fat diet switch to low fat diet mouse groups through induction of apoptosis. Orlistat also showed anti-proliferative activity in nine of 11 primary cultures of human endometrial cancer. Discussion: Our findings provide strong evidence that dietary intervention and orlistat have anti-tumor activity in vivo and supports further investigation of orlistat in combination with dietary interventions for the prevention and treatment of endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. Methods: In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (< 20 E% carbohydrates, 50–60 E% fat) or a control diet (50–60 E% carbohydrates, 20–30 E% fat) for six months. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were assessed by ultrasound in the brachial artery together with plasma interleukin-6 (IL-6) and serum high-sensitivity C-reactive protein (hsCRP) in the participants at baseline (n = 70) and after six months (n = 64). Results: The FMD and NID were unaltered in both groups after six months, and there were no between-group differences in change of either FMD (p = 0.34) or NID (p = 0.53) in response to the interventions. The circulating hsCRP and IL-6 levels decreased only in response to LCD (both p < 0.05). However, comparing changes over time with the control diet, the LCD did not reduce either IL-6 (p = 0.25) or hsCRP (p = 0.07) levels. The lack of changes in FMD and NID in response to LCD persisted after adjustment for cardiovascular risk factors. Conclusion: A LCD high in fat for six months does not adversely affect endothelial function or selected markers of low-grade inflammation, which suggests that this nutritional approach does not increase the risk of cardiovascular disease. Trial registration ClinicalTrials.gov (NCT03068078). [ABSTRACT FROM AUTHOR]

Simple Summary: Fat content is critical to milk quality, health and economic value. Fat content can be affected by diet composition. Diet-induced milk fat depression (MFD) is a specific reduction in milk fat synthesis caused by feeding cows high contents of rapidly fermentable carbohydrates or polyunsaturated fatty acid (PUFA). However, the mechanisms involved in MFD have not been fully elucidated and substantial controversy remains. Therefore, the aim of this study was to provide reference data for exploration of the relationship between milk fat synthesis and nutrient digestion as well as hindgut microbials. In this study, changes in milk performance, nutrient digestibility, hindgut fermentation parameters and microflora were observed by inducing milk fat depression (MFD) in dairy cows fed with a high-starch or a high-fat diet. Eight Holstein cows were paired in a completely randomized cross-over design within two 35 d periods (18 d control period and 17d induction period). During the control period, all cows were fed the low-starch and low-fat diet (CON), and at the induction period, four of the cows were fed a high-starch diet with crushed wheat (IS), and the other cows were fed a high-fat diet with sunflower fat (IO). The results showed that, compared to when the cows were fed the CON diet, when cows were fed the IS or IO diet, they had lower milk fat concentrations, energy corrected milk, 3.5% fat-corrected milk yield, feed efficiency and apparent digestibility of NDF and ADF. However, cows fed the IO diet had a lower apparent digestibility of ether extracts. In addition, we observed that when cows were fed the high-starch (IS) or high-fat (IO) diet, they had a higher fecal concentration of propionate and acetate, and a lower NH3-N. Compared to when the cows were fed the CON diet, cows fed the IS diet had a lower pH, and cows fed the IO diet had a lower concentration of valerate in feces. In the hindgut microbiota, the relative abundance of Oscillospiraceae_UCG-005 was increased, while the Verrucomicrobiota and Lachnospiraceae_AC2044_group were decreased when cows were fed the IO diet. The relative abundance of Prevotellaceae_UCG-003 was increased, while the Alistipes and Verrucomicrobiota decreased, and the Treponema, Spirochaetota and Lachnospiraceae_AC2044_group showed a decreasing trend when cows were fed the IS diet. In summary, this study suggested that high-starch or high-fat feeding could induce MFD in dairy cows, and the high-fat diet had the greatest effect on milk fat; the high-starch or high-fat diet affected hindgut fermentation and apparent fiber digestibility. The changes in hindgut flora suggested that hindgut microbiota may be associated with MFD in cows. [ABSTRACT FROM AUTHOR]

Gluten, which is found in cereals such as wheat, rye and barley, makes up a major dietary component in most western nations, and has been shown to promote body mass gain and peripheral inflammation in mice. In the current study, we investigated the impact of gluten on central inflammation that is typically associated with diet‐induced obesity. While we found no effect of gluten when added to a low‐fat diet (LFD), male mice fed high fat diet (HFD) enriched with gluten increased body mass and adiposity compared with mice fed HFD without gluten. We furthermore found that gluten, when added to the LFD, increases circulating C‐reactive protein levels. Gluten regardless of whether it was added to LFD or HFD led to a profound increase in the number of microglia and astrocytes in the arcuate nucleus of the hypothalamus, as detected by immunohistochemistry for ionised calcium binding adaptor molecule 1 (Iba‐1) and glial fibrillary acidic protein (GFAP), respectively. In mice fed LFD, gluten mimicked the immunogenic effects of HFD exposure and when added to HFD led to a further increase in the number of immunoreactive cells. Taken together, our results confirm a moderate obesogenic effect of gluten when fed to mice exposed to HFD and for the first‐time report gluten‐induced astro‐ and microgliosis suggesting the development of hypothalamic injury in rodents. [ABSTRACT FROM AUTHOR]

Background: Syndecan-4 (SDC4) is a member of the heparan sulfate proteoglycan family of cell-surface receptors. We and others previously reported that variation in the SDC4 gene was associated with several components of the metabolic syndrome, including intra-abdominal fat, fasting glucose and triglyceride levels, and hypertension, in human cohorts. Additionally, we demonstrated that high fat diet (HFD)-induced obese female mice with a Sdc4 genetic deletion had higher visceral adiposity and a worse metabolic profile than control mice. Here, we aimed to first investigate whether the mouse Sdc4 null mutation impacts metabolic phenotypes in a sex- and diet-dependent manner. We then tested whether SDC4 polymorphisms are related to the metabolic syndrome (MetS) in humans. Methods: For the mouse experiment, Sdc4-deficient (Sdc4−/−) and wild-type (WT) mice were treated with 14-weeks of low-fat diet (LFD). Body composition, energy balance, and selected metabolic phenotypes were assessed. For the human genetic study, we used logistic regression models to test 11 SDC4 SNPs for association with the MetS and its components in a cohort of 274 (113 with MetS) elderly subjects from southern Italy. Results: Following the dietary intervention in mice, we observed that the effects of the Sdc4 null mutation on several phenotypes were different from those previously reported in the mice kept on an HFD. Nonetheless, LFD-fed female Sdc4−/− mice, but not males, displayed higher levels of triglycerides and lower insulin sensitivity at fasting than WT mice, as seen earlier in the HFD conditions. In the parallel human study, we found that carriers of SDC4 rs2228384 allele C and rs2072785 allele T had reduced risk of MetS. The opposite was true for carriers of the SDC4 rs1981429 allele G. Additionally, the SNPs were found related to fasting triglyceride levels and triglyceride glucose (TyG) index, a reliable indicator of insulin resistance, with sex-stratified analysis detecting the association of rs1981429 with these phenotypes only in females. Conclusions: Altogether, our results suggest that SDC4 is an evolutionary conserved genetic determinant of MetS and that its genetic variation is associated with fasting triglyceride levels in a female-specific manner. [ABSTRACT FROM AUTHOR]

The application of fatty acid (FA) isotopic analysis has great potential in elucidating food web structure, but it has not experienced the same wide-spread use as amino acid isotopic analyses. The failure to adopt FA isotopic methods is almost certainly linked to a lack of reliable information on trophic fractionation of FA, particularly in higher predators. In this work, we attempt to address this shortfall, through comparison of FA δ13C values in captive Atlantic pollock (Pollachius virens) liver and their known diets. Since catabolism is likely the main cause of fractionation and it may vary with dietary fat content, we investigated the impact of dietary fat concentration on isotopic discrimination in FA. We fed Atlantic pollock three formulated diets with similar FA isotopic compositions but different fat concentrations (5–9% of diet), representative of the range found in natural prey, for 20 weeks. At the conclusion of the study, δ13C values of liver FA were very similar to the FA within the corresponding diets, with most discrimination factors < 1. For all FA except 22:6n-3, dietary fat had no effect on discrimination factors. Only for 22:6n-3 did fish fed the highest fat diet have lower δ13C values than the diet consumed. Thus, these FA-specific discrimination factors can be applied to evaluate diets in marine fish consuming natural diets and will serve as additional and valuable biomarkers in fish feeding ecology. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Ageing leads to a loss of mass in skeletal muscle, but the effect of obesity on ageing‐related muscle wasting is unclear. In this study, we aimed to demonstrate the specific effect of obesity on fast‐twitch skeletal muscle in ageing.What is the main finding and its importance?Our findings show that the obesity induced by long‐term ingestion of a high‐fat diet does not aggravate muscle wasting in fast‐twitch skeletal muscle of aged mice, indicating that the present study provides morphological characteristics for skeletal muscle of sarcopenic obesity. Obesity and ageing reduce muscle mass and lead to deficits in muscle maintenance, but it is not known whether obesity accelerates muscle wasting additively in the setting of ageing. We investigated morphological characteristics in fast‐twitch extensor digitorum longus (EDL) muscle of mice fed a low‐fat diet (LFD) or a high‐fat diet (HFD) for 4 or 20 months. The fast‐twitch EDL muscle was harvested, and the muscle fibre‐type composition, individual muscle cross‐sectional area and myotube diameter were measured. We found an increase in the percentage of type IIa and IIx myosin heavy chain fibres in the whole EDL muscle, but a decrease in type IIB myosin heavy chain in both HFD protocols. The cross‐sectional area and myofibre diameter were lower in both groups of aged mice (after 20 months of LFD or HFD) compared with young mice (after 4 months of the diets), but there were no differences between mice fed LFD or HFD for 20 months. These data suggest that long‐term feeding of HFD does not aggravate muscle wasting in fast‐twitch EDL muscle of male mice. [ABSTRACT FROM AUTHOR]

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance and mitochondrial lipid oxidation and also enhances insulin sensitivity (IS). It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests with tracers were conducted in mice ranging from 4 to 21 months of age, fed a low-fat diet (LFD) or high-fat diet (HFD) with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Values for an IS index derived for peripheral tissues (IS-P) and one for the liver (IS-L) were steeply decreased by aging and an HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In young animals fed an LFD, RW access enhanced the IS-P concomitantly with the muscle β-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease; however this only occurred in animals fed an LFD. Therefore, this study indicates that endurance exercise can improve the age-dependent decline in organ-specific IS if paired with a healthy diet. Article Highlights: Exercise is a known strategy to improve insulin sensitivity (IS), whereas aging and a lipid-rich diet decrease IS. Using a tracer-based oral glucose tolerance test, we investigated how exercise, age, and diet interact in the development of tissue-specific insulin resistance. Exercise (voluntary access to a running wheel) mainly improved IS in animals fed a low-fat diet. In these animals, exercise improved peripheral IS only at young age but fully prevented the age-dependent decline of hepatic IS. The prevention of age-dependent decline in IS by exercise is tissue-specific and blunted by a lipid-rich diet. [ABSTRACT FROM AUTHOR]

Background/Objectives: Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context. Methods: Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined. Results: In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity. Conclusions: T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity. [ABSTRACT FROM AUTHOR]