High-fat Diet Challenge Research Articles

Muscle-specific TGR5 overexpression improves glucose clearance in glucose-intolerant mice

TGR5, a G protein–coupled bile acid receptor, is expressed in various tissues and regulates several physiological processes. In the skeletal muscle, TGR5 activation is known to induce muscle hypertrophy; however, the effects on glucose and lipid metabolism are not well understood, despite the fact that the skeletal muscle plays a major role in energy metabolism. Here, we demonstrate that skeletal muscle–specific TGR5 transgenic (Tg) mice exhibit increased glucose utilization, without altering the expression of major genes related to glucose and lipid metabolism. Metabolite profiling analysis by capillary electrophoresis time-of-flight mass spectrometry showed that glycolytic flux was activated in the skeletal muscle of Tg mice, leading to an increase in glucose utilization. Upon long-term, high-fat diet challenge, blood glucose clearance was improved in Tg mice without an accompanying increase in insulin sensitivity in skeletal muscle and a reduction of body weight. Moreover, Tg mice showed improved age-associated glucose intolerance. These results strongly suggest that TGR5 ameliorated glucose metabolism disorder that is caused by diet-induced obesity and aging by enhancing the glucose metabolic capacity of the skeletal muscle. Our study demonstrates that TGR5 activation in the skeletal muscle is effective in improving glucose metabolism and may be beneficial in developing a novel strategy for the prevention or treatment of hyperglycemia.

Container-aided integrative QTL and RNA-seq analysis of Collaborative Cross mice supports distinct sex-oriented molecular modes of response in obesity

BackgroundThe Collaborative Cross (CC) mouse population is a valuable resource to study the genetic basis of complex traits, such as obesity. Although the development of obesity is influenced by environmental factors, underlying genetic mechanisms play a crucial role in the response to these factors. The interplay between the genetic background and the gene expression pattern can provide further insight into this response, but we lack robust and easily reproducible workflows to integrate genomic and transcriptomic information in the CC mouse population.ResultsWe established an automated and reproducible integrative workflow to analyse complex traits in the CC mouse genetic reference panel at the genomic and transcriptomic levels. We implemented the analytical workflow to assess the underlying genetic mechanisms of host susceptibility to diet induced obesity and integrated these results with diet induced changes in the hepatic gene expression of susceptible and resistant mice. Hepatic gene expression differs significantly between obese and non-obese mice, with a significant sex effect, where male and female mice exhibit different responses and coping mechanisms.ConclusionIntegration of the data showed that different genes but similar pathways are involved in the genetic susceptibility and disturbed in diet induced obesity. Genetic mechanisms underlying susceptibility to high-fat diet induced obesity are different in female and male mice. The clear distinction we observed in the systemic response to the high-fat diet challenge and to obesity between male and female mice points to the need for further research into distinct sex-related mechanisms in metabolic disease.

The Autophagy Protein Becn1 Improves Insulin Sensitivity by Promoting Adiponectin Secretion Via Exocyst Binding

Beclin 1/Becn1 is an essential protein in autophagy, a stress-induced lysosomal degradation pathway. Autophagy dysregulation is implicated in the pathogenesis of metabolic diseases such as type 2 diabetes. However, the mechanism of the autophagy machinery in metabolic regulation is poorly understood. In this study, we discovered a metabolically important secretory function of Becn1 in adipose tissue, which is distinct from its role in degradation. In response to high-fat diet challenge, autophagy-hyperactive Becn1F121A mice, caused by a constitutively active Becn1F121A mutation, show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell autonomous mechanism. We further identified that the circulating factor that activates AMPK systemically in Becn1F121A mice is adiponectin, a metabolic hormone secreted from adipocytes. The Becn1-facilitated adiponectin secretion is regulated by upstream autophagy modulators, and is mediated by binding of the coiled-coil domain of Becn1 with subunits of the exocyst complex. In addition, adipose tissue-specific Becn1F121A expression is sufficient to activate liver AMPK and improve systemic insulin sensitivity by increasing adiponectin secretion. Altogether, we demonstrated that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through interacting with the exocyst in adipose tissue. Our study highlights a novel non-cell autonomous, non-degradative, mechanism by which the autophagy machinery regulates metabolism.

Gut Microbiota Resilience: Definition, Link to Health and Strategies for Intervention.

The gut microbiota is a new frontier in health and disease. Not only many diseases are associated with perturbed microbiota, but an increasing number of studies point to a cause-effect relationship. Defining a healthy microbiota is not possible at the current state of our knowledge mostly because of high interindividual variability. A resilient microbiota could be used as surrogate for healthy microbiota. In addition, the gut microbiota is an “organ” with frontline exposure to environmental changes and insults. During the lifetime of an individual, it is exposed to challenges such as unhealthy diet, medications and infections. Impaired ability to bounce back to the pre-challenge baseline may lead to dysbiosis. It is therefore legitimate to postulate that maintaining a resilient microbiota may be important for health. Here we review the concept of resilience, what is known about the characteristics of a resilient microbiota, and how to assess microbiota resilience experimentally using a model of high fat diet challenge in humans. Interventions to maintain microbiota resilience can be guided by the knowledge of what microbial species or functions are perturbed by challenges, and designed to replace diminished species with probiotics, when available, or boost them with prebiotics. Fibers with multiple structures and composition can also be used to increase microbiota diversity, a characteristic of the microbiota that may be associated with resilience. We finally discuss some open questions and knowledge gaps.

Hypolipidaemic, hypoglycaemic and antioxidant effects of a tropical highland blackberry beverage consumption in healthy individuals on a high-fat, high-carbohydrate diet challenge

BACKGROUND: Blackberries have a high content of bioactive compounds such as anthocyanins and ellagitannins, which are associated with health benefits against cardiovascular diseases, cancer, diabetes, and other inflammatory conditions. OBJECTIVE: This study evaluated the effect of a tropical highland blackberry (Rubus adenotrichos Schltdl.) beverage (50% v/v) on lipids, glucose and antioxidant parameters of healthy individuals. METHODS: Thirteen healthy individuals of both sexes were assigned into two groups in a randomized crossover design. Each participant was subjected to a high fat and high carbohydrate diet challenge and drank 250 mL of either blackberry beverage or water with every meal, three times a day for 14 days. Total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, glucose level, superoxide dismutase (SOD), and catalase (CAT) enzymatic activities were assessed from plasma. RESULTS: Plasma levels of triglycerides, total cholesterol, and glucose levels significantly decreased (p < 0.05) after consuming the blackberry beverage. Changes in LDL and HDL cholesterol levels were not statistically significant (p > 0.05). CAT and SOD enzymatic activities increased slightly, although not statistically significant (p > 0.05). CONCLUSION: Drinking a beverage from a blackberry micro-filtered juice improved plasma lipid and glucose profiles, as well as CATand SOD enzymatic activities in healthy participants.

NOD1 deficiency promotes an imbalance of thyroid hormones and microbiota homeostasis in mice fed high fat diet

The contribution of the nucleotide-binding oligomerization domain protein NOD1 to obesity has been investigated in mice fed a high fat diet (HFD). Absence of NOD1 accelerates obesity as early as 2 weeks after feeding a HFD. The obesity was due to increases in abdominal and inguinal adipose tissues. Analysis of the resting energy expenditure showed an impaired function in NOD1-deficient animals, compatible with an alteration in thyroid hormone homeostasis. Interestingly, free thyroidal T4 increased in NOD1-deficient mice fed a HFD and the expression levels of UCP1 in brown adipose tissue were significantly lower in NOD1-deficient mice than in the wild type animals eating a HFD, thus contributing to the observed adiposity in NOD1-deficient mice. Feeding a HFD resulted in an alteration of the proinflammatory profile of these animals, with an increase in the infiltration of inflammatory cells in the liver and in the white adipose tissue, and an elevation of the circulating levels of TNF-α. In addition, alterations in the gut microbiota in NOD1-deficient mice correlate with increased vulnerability of their ecosystem to the HFD challenge and affect the immune-metabolic phenotype of obese mice. Together, the data are compatible with a protective function of NOD1 against low-grade inflammation and obesity under nutritional conditions enriched in saturated lipids. Moreover, one of the key players of this early obesity onset is a dysregulation in the metabolism and release of thyroid hormones leading to reduced energy expenditure, which represents a new role for these hormones in the metabolic actions controlled by NOD1.

Effects of Acute Cocoa Supplementation on Postprandial Apolipoproteins, Lipoprotein Subclasses, and Inflammatory Biomarkers in Adults with Type 2 Diabetes after a High-Fat Meal.

Dyslipidemia and inflammation exacerbate postprandial metabolic stress in people with diabetes. Acute dietary supplementation with polyphenols shows promise in improving postprandial metabolic stress in type 2 diabetes (T2D). Cocoa is a rich source of dietary polyphenols with demonstrated cardioprotective effects in adults without diabetes. To date, the acute effects of cocoa on postprandial lipids and inflammation have received little attention in the presence of T2D. This report expands on our earlier observation that polyphenol-rich cocoa, given as a beverage with a fast-food-style, high-fat breakfast, increased postprandial high-density lipoprotein-cholesterol (HDL-C) in adults with T2D. We now test whether polyphenol-rich cocoa modulated postprandial apolipoproteins (Apo-A1, B), non-esterified fatty acids, nuclear magnetic resonance (NMR)-derived lipoprotein subclass profiles, and select biomarkers of inflammation following the same dietary challenge. We found that cocoa decreased NMR-derived concentrations of total very low-density lipoprotein and chylomicron particles and increased the concentration of total HDL particles over the 6-hour postprandial phase. Serum interleukin-18 was decreased by cocoa vs. placebo. Thus, polyphenol-rich cocoa may alleviate postprandial dyslipidemia and inflammation following a high-fat dietary challenge in adults with T2D. The study was registered at clinicaltrials.gov as NCT01886989.

520-P: Exenatide Ameliorates Diabetic Kidney Disease by Inhibiting Apoptosis via SIRT1/TXNIP Signal Pathway

Recent studies have indicated apoptosis to be a major contributor to the progression of Diabetic Kidney Disease. GLP-1 agonist such as Exenatide, which counteracts insulin resistance in humans with type 2 diabetes, has been shown to ameliorate Diabetic Kidney Disease in experimental models. In this study, we investigated whether exenatide could alleviate Diabetic Kidney Disease by apoptosis through SIRT1/TXNIP signal pathway. Male C57BL/6J mice challenged with a high-fat diet (HFD) for 12weeks were then treated with exenatide (HFD+exe) or normal saline(HFD+sal) by intraperitoneal injection for 8 weeks. The results revealed that Exenatide notably decreased body weight, urine albumin-to-creatinine ratio(ACR) and apoptosis in the kidney induced by HFD challenge. Western blot revealed the level of apoptosis were notably downregulated after exenatide treatment. In addition, the protein expression of SIRT1 was upregulated, whereas TXNIP was downregulated in the HFD+exe group. Collectively, the data indicate that Exenatide ameliorates Diabetic Kidney Disease by inhibiting apoptosis via SIRT1/TXNIP signal pathway. Disclosure M. Wang: None. R. Liang: None. F. Xu: None. M. Cai: None.

259-OR: Epigenetic Coregulation of Beta-Cell Function and Survival in Postnatal Life

Both type 1 and type 2 diabetes are caused by inadequate functional beta-cells. Loss of beta-cells in diabetes is preceded by progressive beta-cell failure due to impaired beta-cell function and adaptive capacity, driven by cellular stress. While plenty of evidence suggests that beta-cell function and mass are co-regulated to dictate adaptive capacity, the molecular mechanisms that direct such co-regulation and are disrupted by cellular stress remain unclear. In the present study, we show that the CCCTC binding factor, CTCF is a novel epigenetic regulator of beta-cell functional maturity and mass. CTCF is a zinc finger protein that regulates 3D chromatin architecture and epigenetic stability towards transcriptional regulation, and plays an important role in cell differentiation, self-renewal, and survival. In addition, the levels of CTCF are sensitive to cellular-stress. Our data show that the beta-cell specific CTCF knockout mice (CTCF-BKO) become diabetic by 4-5 months of age, due to a progressive loss of beta-cell maturity and viability that mirrors evolving T2D. The CTCF-BKO mice have impaired glucose stimulated insulin secretion (GSIS), with metabolic, epigenetic, and gene expression profiles that resemble functionally immature neonatal beta-cells, around 1-2 months of age. This is followed by progressive loss of beta-cell mass due to p53 dependent apoptosis. In addition, mice with haplo-insufficiency of CTCF in their beta-cells display impaired GSIS and a deficit in the adaptive beta-cell expansion in response to high-fat diet challenge. Finally, we show that the CTCF program is disrupted in islets of diabetic mice. Taken together, these studies provide a novel insight into the epigenetic regulation of functional beta-cell mass and adaptive capacity in postnatal life. Disclosure S. Dhawan: None. T. Gurlo: None. J.K. Wang: None.

Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of cirrhosis and major risk factors for hepatocellular carcinoma and liver-related death. Despite substantial clinical and basic research, the pathogenesis of obesity-related NAFLD remains poorly understood. In this study, we show that perforin can act as an immune regulator to prevent the progression of NAFLD. Aged perforin-deficient (Prf−/−) mice have increased lipid accumulation in the liver compared to WT mice. With high-fat diet (HFD) challenge, Prf−/− mice have increased liver weight, more severe liver damage, and increased liver inflammation when compared with WT controls. Mechanistic studies revealed that perforin specifically regulates intrinsic IFN-γ production in CD4 T cells, not CD8 T cells. We found that CD4 T cell depletion reduces liver injury and ameliorates the inflammation and metabolic morbidities in Prf−/− mice. Furthermore, improved liver characteristics in HFD Prf−/− and IFN-γR−/− double knockout mice confirmed that IFN-γ is a key factor for mediating perforin regulation of NAFLD progression. Overall, our findings reveal the important regulatory role perforin plays in the progression of obesity-related NAFLD and highlight novel strategies for treating NAFLD.

Maternal exercise programs skeletal muscle metabolic dysfunction in offspring mice challenged with high fat diet.

Exercise, including maternal exercise becomes increasingly less common. Though improper maternal nutrition and obesity are known to affect fetal muscle development and predisposes offspring to metabolic dysfunction, the effects of maternal exercise (ME) on fetal muscle development and offspring metabolic health are largely undefined.PURPOSETo investigate the effects of maternal exercise on mitochondrial biogenesis during fetal muscle development, and muscle function and metabolic health in offspring following high fat diet (HFD) challenge.METHODSFemale C57BL/6J mice were randomized and assigned into a control (CON) or an exercise (EX) group (n = 6 per group) fed a normal chow. Exercise was performed every morning for 60 min during pregnancy. Then, the animals were mated, and the skeletal muscle samples were collected at embryonic day 18.5, weaning, and after 8 weeks of high fat diet (HFD; 60 kcal% from fat) challenge in both females and males. Statistical analysis were conducted using student’s t‐test and/or one/two way analysis of variance (ANOVA).RESULTSME muscle fiber diameters and enhanced muscle endurance capacity in offspring (P < 0.05), which were positively associated with switching muscle fibers from type IIb/x to type I and IIa and mitochondrial biogenesis (P < 0.05), but negatively correlated with atrophy‐related Atrogin‐1 and Murf1 gene expression (P < 0.05). Mechanistically, ME enhanced DNA demethylation of Pgc‐1a promoter and its expression during fetal muscle development. Importantly, such changes in DNA methylation maintained in offspring muscle before and after HFD challenge, resulting in elevated Pgc‐1a mRNA expression and increased contents of PGC‐1a1 and 4 isoforms, which improved metabolic health.CONCLUSIONSThis study identifies that ME enhances DNA demethylation of the Pgc‐1a promoter during fetal muscle development, which has programming effects on the exercise endurance capacity and metabolic health of muscle in offspring.Support or Funding InformationThis work was supported by National Institutes of Health Grants R01‐HD067449.Maternal exercise (ME) enhances adaptation to endurance training of offspring mice (A,B) and the proportion of muscle type I fiber composition before and following HFD challenge (C). ME decreases muscle atrophy‐related genes following HFD challenge (D,E). Data are mean ± s.e.m. and each dot represents one litter.; two‐sided P values by unpaired Student’s t‐test (D,E) or two‐way repeated measures ANOVA followed by Tukey’s test (B).Figure 1

FAM13A affects body fat distribution and adipocyte function

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.

Endothelial-specific deficiency of megalin in the brain protects mice against high-fat diet challenge

BackgroundThe increasing risk of obesity and diabetes among other metabolic disorders are the consequence of shifts in dietary patterns with high caloric-content food intake. We previously reported that megalin regulates energy homeostasis using blood-brain barrier (BBB) endothelial megalin-deficient (EMD) mice, since these animals developed obesity and metabolic syndrome upon normal chow diet administration. Obesity in mid-life appears to be related to greater dementia risk and represents an increasing global health issue. We demonstrated that EMD phenotype induced impaired learning ability and recognition memory, neurodegeneration, neuroinflammation, reduced neurogenesis, and mitochondrial deregulation associated with higher mitochondrial mass in cortical tissues.MethodsEMD mice were subjected to normal chow and high-fat diet (HFD) for 14 weeks and metabolic changes were evaluated.ResultsSurprisingly, BBB megalin deficiency protected against HFD-induced obesity improving glucose tolerance and preventing hepatic steatosis. Compared to wild type (wt), the brain cortex in EMD mice showed increased levels of the mitochondrial biogenesis regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2), a thermogenic protein involved in the regulation of energy metabolism. This agreed with the previously found increased mitochondrial mass in the transgenic mice. Upon HFD challenge, we demonstrated these two proteins were found elevated in wt mice but reported no changes over the already increased levels in EMD animals.ConclusionWe propose a protective role for megalin on diet-induce obesity, suggesting this could be related to metabolic disturbances found in dementia through brain endocrine system communications.

Yarrow Supercritical Extract Ameliorates the Metabolic Stress in a Model of Obesity Induced by High-Fat Diet.

Nowadays, obesity and its associated metabolic disorders, including diabetes, metabolic syndrome, cardiovascular disease, or cancer, continue to be a health epidemic in westernized societies, and there is an increased necessity to explore anti-obesity therapies including pharmaceutical and nutraceutical compounds. Considerable attention has been placed on the identification of bioactive compounds from natural sources to manage the metabolic stress associated with obesity. In a previous work, we have demonstrated that a CO2 supercritical fluid extract from yarrow (Yarrow SFE), downregulates the expression of the lipogenic master regulator SREBF1 and its downstream molecular targets FASN and SCD in a tumoral context. Since obesity and diabetes are strongly considered high-risk factors for cancer development, herein, we aimed to investigate the potential therapeutic role of Yarrow SFE in the metabolic stress induced after a high-fat diet in mice. For this purpose, 32 C57BL/6 mice were distributed in four groups according to their diets: standard diet (SD); SD supplemented with Yarrow SFE (SD + Yarrow); high-fat diet (HFD); and HFD supplemented with Yarrow SFE (HFD + Yarrow). Fasting glycemia, insulin levels, homeostasis model assessment for insulin resistance (HOMA-IR), lipid profile, gene expression, and lipid content of liver and adipose tissues were analyzed after three months of treatment. Results indicate improved fasting glucose levels in plasma, enhanced insulin sensitivity, and diminished hypercholesterolemia in the HFD + Yarrow group compared to the HFD group. Mechanistically, Yarrow SFE protects liver from steatosis after the HFD challenge by augmenting the adipose tissue buffering capacity of the circulating plasma glucose.

Effects of a probiotic intervention on Escherichia coli and high-fat diet-induced intestinal microbiota imbalance.

Obesity is often associated with intestinal microbiota imbalance and increased Gram-negative bacteria characterized by higher endotoxin levels. Therefore, a study on the joint effects of a high-fat diet and Gram-negative bacteria prechallenge might provide further information on the interactive effects of intestinal microbiota and obesity as well as the effects of a probiotic intervention on these processes. This study focused on the joint effects of a high-fat diet and Escherichia coli on mouse inflammatory cytokines, intestinal microbiota, hepatic pathological changes, and the alleviating capacity of probiotics (Lactobacillus plantarum, Bifidobacterium breve, and Lactobacillus fermentum). Our results showed that E. coli administration and the high-fat diet exacerbated the inflammatory syndrome by increasing the visceral fat content, the inflammatory cell infiltration, and intestinal microbiota disorder in mice. E. coli administration caused a decrease in short-chain fatty acids in mouse feces, and probiotics effectively improved this phenomenon. Compound probiotic intervention reduced LPS and IL-1β levels, while increased IL-10 levels in mice improved the degeneration and inflammatory infiltration of mouse liver cells. The intestinal microbiota showed great differences at 3weeks and 6weeks post-administration. High fat and E. coli alone or in combination caused intestinal microbiota disorder, with increased harmful bacteria, and the probiotics effectively improved the intestinal flora structure and increased the fecal short-chain fatty acid (SCFA) content. In conclusion, a high-fat diet and Gram-negative bacteria challenge exacerbated the inflammatory syndrome, which can be alleviated by compound probiotic intervention.

Enhancing cardiac glycolysis causes an increase in PDK4 content in response to short-term high-fat diet

The healthy heart has a dynamic capacity to respond and adapt to changes in nutrient availability. Metabolic inflexibility, such as occurs with diabetes, increases cardiac reliance on fatty acids to meet energetic demands, and this results in deleterious effects, including mitochondrial dysfunction, that contribute to pathophysiology. Enhancing glucose usage may mitigate metabolic inflexibility and be advantageous under such conditions. Here, we sought to identify how mitochondrial function and cardiac metabolism are affected in a transgenic mouse model of enhanced cardiac glycolysis (GlycoHi) basally and following a short-term (7-day) high-fat diet (HFD). GlycoHi mice constitutively express an active form of phosphofructokinase-2, resulting in elevated levels of the PFK-1 allosteric activator fructose 2,6-bisphosphate. We report that basally GlycoHi mitochondria exhibit augmented pyruvate-supported respiration relative to fatty acids. Nevertheless, both WT and GlycoHi mitochondria had a similar shift toward increased rates of fatty acid-supported respiration following HFD. Metabolic profiling by GC-MS revealed distinct features based on both genotype and diet, with a unique increase in branched-chain amino acids in the GlycoHi HFD group. Targeted quantitative proteomics analysis also supported both genotype- and diet-dependent changes in protein expression and uncovered an enhanced expression of pyruvate dehydrogenase kinase 4 (PDK4) in the GlycoHi HFD group. These results support a newly identified mechanism whereby the levels of fructose 2,6-bisphosphate promote mitochondrial PDK4 levels and identify a secondary adaptive response that prevents excessive mitochondrial pyruvate oxidation when glycolysis is sustained after a high-fat dietary challenge.

Propionate alleviates high-fat diet-induced lipid dysmetabolism by modulating gut microbiota in mice.

The aims were to examine whether oral sodium propionate supplementation regulate lipid metabolism through modulating gut microbiota. ICR male mice (26·98±0·30g) were randomly assigned to three groups (n=10) and fed control diet (Con), high-fat diet (HFD) and HFD plus propionate (Pro) respectively. In this study, we found that HFD increased the weight of final body, inguinal white adipose tissues (iWAT), epididymal white adipose tissue (eWAT) and perirenal white adipose tissue (pWAT), as well as the adipocyte mean area of iWAT and eWAT in mice (P<0·05), whereas sodium propionate treatment reduced the weight of iWAT and pWAT as well as adipocyte mean area of iWAT in mice fed a HFD (P<0·05). Moreover, in the iWAT, the mRNA expression of lipogenesis genes, including peroxisome proliferator activated receptor γ, acetyl-CoA carboxylase and carnitine palmitoyl transferase-1β, was upregulated by HFD challenge (P<0·05), and the elevation of these genes was nearly reversed to the level of control diet-fed mice by sodium propionate treatment. Meanwhile, sodium propionate treatment increased the hormone-sensitive lipase mRNA expression in the iWAT of HFD-fed mice (P<0·05). High-throughput pyrosequencing of the 16S rRNA demonstrated that sodium propionate treatment significantly recovered the gut microbiota dysbiosis in HFD-fed mice, including the richness and diversity of microbiota and the ratio of Firmicutes to Bacteroidetes. Furthermore, the HFD-induced reductions in colonic levels of butyrate and valerate were reversed by sodium propionate treatment, which also normalized the serum LPS level seen in HFD-fed mice to the levels of the control diet-fed mice. Collectively, these results indicated that sodium propionate treatment could improve lipid metabolism in HFD-fed mice, and the potential mechanisms might be via regulating gut microbiota. We demonstrated for the first time that oral sodium propionate significantly improved HFD-induced dysbiosis of gut microbiota, indicating that the mitigative effect of propionate for HFD-induced lipid dysmetabolism might be mediated by gut microbiota in mice.

The developmental Wnt signaling pathway effector β-catenin/TCF mediates hepatic functions of the sex hormone estradiol in regulating lipid metabolism.

The bipartite transcription factor β-catenin (β-cat)/T cell factor (TCF), formed by free β-cat and a given TCF family member, serves as the effector of the developmental Wnt signaling cascade. β-cat/TCFs also serve as effectors of certain peptide hormones or growth factors during adulthood. We reported that liver-specific expression of dominant-negative Transcription factor 7 like 2 (TCF7L2DN) led to impaired glucose disposal. Here we show that, in this LTCFDN transgenic mouse model, serum and hepatic lipid contents were elevated in male but not in female mice. In hepatocytes, TCF7L2DN adenovirus infection led to stimulated expression of genes that encode lipogenic transcription factors and lipogenic enzymes, while estradiol (E2) treatment attenuated the stimulation, associated with Wnt-target gene activation. Mechanistically, this E2-mediated activation can be attributed to elevated β-cat Ser675 phosphorylation and TCF expression. In wild-type female mice, ovariectomy (OVX) plus high-fat diet (HFD) challenge impaired glucose disposal and insulin tolerance, associated with increased hepatic lipogenic transcription factor sterol regulatory element-binding protein 1-c (SREBP-1c) expression. In wild-type mice with OVX, E2 reconstitution attenuated HFD-induced metabolic defects. Some of the attenuation effects, including insulin intolerance, elevated liver-weight gain, and hepatic SREBP-1c expression, were not affected by E2 reconstitution in HFD-fed LTCFDN mice with OVX. Finally, the effects of E2 in hepatocytes on β-cat/TCF activation can be attenuated by the G-protein-coupled estrogen receptor (GPER) antagonist G15. Our study thus expanded the scope of functions of the Wnt pathway effector β-cat/TCF, as it can also mediate hepatic functions of E2 during adulthood. This study also enriches our mechanistic understanding of gender differences in the risk and pathophysiology of metabolic diseases.

Maternal high fat diet programs hypothalamic-pituitary-adrenal function in adult rat offspring

Abstract Maternal environmental factors such as diet have profound effects on offspring development and later health. The hypothalamic-pituitary-adrenal (HPA) axis is an important stress neuroendocrine system that is subject to programming by early life challenges. The present study was further to investigate whether maternal high fat diet (HFD) exposure during rat pregnancy and lactation can alter the HPA axis activity in adult male offspring. We observed that maternal HFD consumption exerted long-term effects on the basal activity of the HPA axis in adult offspring, with increased mean plasma corticosterone levels that result from elevated steroid pulse frequence and pulse amplitude. More importantly, maternal HFD offspring displayed enhanced corticosterone responses to restraint (1 h) and lipopolysaccharide (25 μg/kg, iv) but not insulin-induced hypoglycemia (0.3U/kg, iv) stress, suggesting a stressor-specific effect of maternal diet on the hyperresponsiveness of the HPA axis to stress. Additionally, maternal HFD exposure markedly attenuated the habituation of HPA responses to repeated restraint stress. These findings demonstrate that perinatal HFD exposure has a potent and long-lasting influence on development of neuroendocrine regulatory mechanisms. Maternal HFD consumption significantly increased basal corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus; nevertheless, similar increments in CRF mRNA levels following restraint were observed between maternal HFD offspring and control rats. Furthermore, the medial and central nuclei of amygdala played a pivotal role in maternal HFD-induced sensitization of the HPA response to psychological and systemic stress, respectively, suggesting that different neural pathways may mediate maternal HFD-induced HPA hyperresponsivity to different types of stressors. Take together, the long-term effects of maternal HFD challenge on the central regulation of the HPA axis, therefore, expose the adult offspring to greater HPA function throughout lifespan, in stressor-specific and region-specific manner.

Tanycytic TSPO inhibition induces lipophagy to regulate lipid metabolism and improve energy balance

ABSTRACT Hypothalamic glial cells named tanycytes, which line the 3rd ventricle (3V), are components of the hypothalamic network that regulates a diverse array of metabolic functions for energy homeostasis. Herein, we report that TSPO (translocator protein), an outer mitochondrial protein, is highly enriched in tanycytes and regulates homeostatic responses to nutrient excess as a potential target for an effective intervention in obesity. Administration of a TSPO ligand, PK11195, into the 3V, and tanycyte-specific deletion of Tspo reduced food intake and elevated energy expenditure, leading to negative energy balance in a high-fat diet challenge. Ablation of tanycytic Tspo elicited AMPK-dependent lipophagy, breaking down lipid droplets into free fatty acids, thereby elevating ATP in a lipid stimulus. Our findings suggest that tanycytic TSPO affects systemic energy balance through macroautophagy/autophagy-regulated lipid metabolism, and highlight the physiological significance of TSPO in hypothalamic lipid sensing and bioenergetics in response to overnutrition. Abbreviations 3V: 3rd ventricle; ACAC: acetyl-Coenzyme A carboxylase; AGRP: agouti related neuropeptide; AIF1/IBA1: allograft inflammatory factor 1; AMPK: AMP-activated protein kinase; ARC: arcuate nucleus; Atg: autophagy related; Bafilo: bafilomycin A1; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CNS: central nervous system; COX4I1: cytochrome c oxidase subunit 4I1; FFA: free fatty acid; GFAP: glial fibrillary acidic protein; HFD: high-fat diet; ICV: intracerebroventricular; LAMP2: lysosomal-associated membrane protein 2; LD: lipid droplet; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MBH: mediobasal hypothalamus; ME: median eminence; MEF: mouse embryonic fibroblast; NCD: normal chow diet; NEFM/NFM: neurofilament medium; NPY: neuropeptide Y; OL: oleic acid; POMC: pro-opiomelanocortin-alpha; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; Rax: retina and anterior neural fold homeobox; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; RER: respiratory exchange ratio; siRNA: small interfering RNA; SQSTM1: sequestosome 1; TG: triglyceride; TSPO: translocator protein; ULK1: unc-51 like kinase 1; VCO2: carbon dioxide production; VMH: ventromedial hypothalamus; VO2: oxygen consumption