A high methionine and low folate diet alters glucose homeostasis and gut microbiome

Hyperhomocysteinemia (HHcy) is considered as a risk factor for several complications, including cardiovascular and neurological disorders. A high methionine low folate (HMLF) diet chronically causes HHcy by accumulating homocysteine in the systemic circulation. Elevated Hcy level is also associated with the incidence of diabetes mellitus. However, very few studies focus on the impact of HMLF diet on glucose homeostasis, and that on gut microbiome profile. HHcy was induced by feeding C57BL/6 mice a HMLF diet for 8 weeks. The HMLF diet feeding resulted in a progressive body weight loss, and development of slight glucose intolerance and insulin resistance in HHcy mice. Notably, the HMLF diet alters the gut microbiome profile and increases the relative abundance of porphyromonadaceae family of bacteria in HHcy mice. These findings provide new insights into the roles of dysregulated glucose homeostasis and gut flora in the pathogenesis of HHcy-related complications.     

Liraglutide modulates gut microbiota and reduces NAFLD in obese mice

Metabolic disorders such as insulin resistance and diabetes are associated with obesity and nonalcoholic fatty liver disease (NAFLD). The aggressive form of a fatty liver disease may progress to cirrhosis and hepatocellular carcinoma. Furthermore, recent studies demonstrated that there is a dysbiosis in the gut microbiota associated with early stages of metabolic disease. Therefore, the identification and repurposing of drugs already used to treat insulin resistance may be an excellent option for other disorders. We evaluated the effect of liraglutide on obesity, NAFLD and gut microbiota modulation in two different animal models of obesity: the ob/ob mice and the high-fat diet (HFD)-fed mice. Liraglutide treatment induced significant weight loss in both obesity models, showed improvements in glycemic parameters and reduced inflammatory cell infiltration in the cecum and the liver. In ob/ob mice, the liraglutide treatment was able to reduce the accumulation of liver fat by 78% and reversed steatosis in the HFD mice. The gut microbiota analysis showed that liraglutide changed the overall composition as well as the relative abundance of weight-relevant phylotypes such as a reduction of Proteobacteria and an increase of Akkermansia muciniphila in the treated HFD group. We show that liraglutide can lead to weight loss and gut microbiota modulations, and is associated with an improvement of NAFLD. Furthermore, by generating a profile of the intestinal microbiota, we compiled a list of potential bacterial targets that may modulate metabolism and induce a metabolic profile that is considered normal or clinically controlled.     

Gut microbiota-mediated xanthine metabolism is associated with resistance to high-fat diet-induced obesity

Resistance to high-fat diet-induced obesity (DIR) has been observed in mice fed a high-fat diet and may provide a potential approach for anti-obesity drug discovery. However, the metabolic status, gut microbiota composition, and its associations with DIR are still unclear. Here, ultraperformance liquid chromatography-tandem mass spectrometry-based urinary metabolomic and 16S rRNA gene sequencing-based fecal microbiome analyses were conducted to investigate the relationship between metabolic profile, gut microbiota composition, and body weight of C57BL/6J mice on chow or a high-fat diet for 8 weeks. PICRUSt analysis of 16S rRNA gene sequences predicted the functional metagenomes of gut bacteria. The results demonstrated that feeding a high-fat diet increased body weight and fasting blood glucose of high-fat diet-induced obesity (DIO) mice and altered the host-microbial co-metabolism and gut microbiota composition. In DIR mice, high-fat diet did not increase body weight while fasting blood glucose was increased significantly compared to chow fed mice. In DIR mice, the urinary metabolic pattern was shifted to a distinct direction compared to DIO mice, which was mainly contributed by xanthine. Moreover, high-fat diet caused gut microbiota dysbiosis in both DIO and DIR mice, but in DIR mice, the abundance of Bifidobacteriaceae, Roseburia, and Escherichia was not affected compared to mice fed a chow diet, which played an important role in the pathway coverage of FormylTHF biosynthesis I. Meanwhile, xanthine and pathway coverage of FormylTHF biosynthesis I showed significant positive correlations with mouse body weight. These findings suggest that gut microbiota-mediated xanthine metabolism correlates with resistance to high-fat DIO.     

Table grape consumption reduces adiposity and markers of hepatic lipogenesis and alters gut microbiota in butter fat-fed mice

Our objective was to determine if consuming table grapes reduces adiposity and its metabolic consequences and alters gut microbiota in mice fed a high-fat (HF), butter-rich diet. C57BL/6 J mice were fed a low-fat (LF) diet or HF diet with 3% or 5% grapes for 11 weeks. Total body and inguinal fat were moderately but significantly reduced in mice fed both levels of grapes compared to their controls. Mice fed 5% grapes had lower liver weights and triglyceride levels and decreased expression of glycerol-3-phosphate acyltransferase (Gpat1) compared to the 5% controls. Mice fed 3% grapes had lower hepatic mRNA levels of peroxisome proliferator-activated receptor gamma 2, sterol-CoA desaturase 1, fatty-acid binding protein 4 and Gpat1 compared to the 3% controls. Although grape feeding had only a minor impact on markers of inflammation or lipogenesis in adipose tissue or intestine, 3% of grapes decreased the intestinal abundance of sulfidogenic Desulfobacter spp. and the Bilophila wadsworthia-specific dissimilatory sulfite reductase gene and tended to increase the abundance of the beneficial bacterium Akkermansia muciniphila compared to controls. In addition, Bifidobacterium, Lactobacillus, Allobaculum and several other genera correlated negatively with adiposity. Allobaculum in particular was increased in the LF and 3% grapes groups compared to the HF-fed controls. Notably, grape feeding attenuated the HF-induced impairment in epithelial localization of the intestinal tight junction protein zonula occludens. Collectively, these data indicate that some of the adverse health consequences of consuming an HF diet rich in saturated fat can be attenuated by table grape consumption.     

Low-Dose Aspartame Consumption Differentially Affects Gut Microbiota-Host Metabolic Interactions in the Diet-Induced Obese Rat

Aspartame consumption is implicated in the development of obesity and metabolic disease despite the intention of limiting caloric intake. The mechanisms responsible for this association remain unclear, but may involve circulating metabolites and the gut microbiota. Aims were to examine the impact of chronic low-dose aspartame consumption on anthropometric, metabolic and microbial parameters in a diet-induced obese model. Male Sprague-Dawley rats were randomized into a standard chow diet (CH, 12% kcal fat) or high fat (HF, 60% kcal fat) and further into ad libitum water control (W) or low-dose aspartame (A, 5–7 mg/kg/d in drinking water) treatments for 8 week (n = 10–12 animals/treatment). Animals on aspartame consumed fewer calories, gained less weight and had a more favorable body composition when challenged with HF compared to animals consuming water. Despite this, aspartame elevated fasting glucose levels and an insulin tolerance test showed aspartame to impair insulin-stimulated glucose disposal in both CH and HF, independently of body composition. Fecal analysis of gut bacterial composition showed aspartame to increase total bacteria, the abundance of Enterobacteriaceae and Clostridium leptum. An interaction between HF and aspartame was also observed for Roseburia ssp wherein HF-A was higher than HF-W (P<0.05). Within HF, aspartame attenuated the typical HF-induced increase in the Firmicutes:Bacteroidetes ratio. Serum metabolomics analysis revealed aspartame to be rapidly metabolized and to be associated with elevations in the short chain fatty acid propionate, a bacterial end product and highly gluconeogenic substrate, potentially explaining its negative affects on insulin tolerance. How aspartame influences gut microbial composition and the implications of these changes on the development of metabolic disease require further investigation.     

Prevention and Reversal of Obesity and Glucose Intolerance in Mice by DHA Derivatives

The n‐3 polyunsaturated fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert hypolipidemic effects and prevent development of obesity and insulin resistance in animals fed high‐fat diets. We sought to determine the efficacy of α‐substituted DHA derivatives as lipid‐lowering, antiobesity, and antidiabetic agents. C57BL/6 mice were given a corn oil‐based high‐fat (35% weight/weight) diet (cHF), or cHF with 1.5% of lipids replaced with α‐methyl DHA ethyl ester (Substance 1), α‐ethyl DHA ethyl ester (Substance 2), α,α‐di‐methyl DHA ethyl ester (Substance 3), or α‐thioethyl DHA ethyl ester (Substance 4) for 4 months. Plasma markers of glucose and lipid metabolism, glucose tolerance, morphology, tissue lipid content, and gene regulation were characterized. The cHF induced obesity, hyperlipidemia, impairment of glucose homeostasis, and adipose tissue inflammation. Except for Substance 3, all other substances prevented weight gain and Substance 2 exerted the strongest effect (63% of cHF‐controls). Glucose intolerance was significantly prevented (～67% of cHF) by both Substance 1 and Substance 2. Moreover, Substance 2 lowered fasting glycemia, plasma insulin, triacylglycerols, and nonesterified fatty acids (73, 9, 47, and 81% of cHF‐controls, respectively). Substance 2 reduced accumulation of lipids in liver and skeletal muscle, as well as adipose tissue inflammation associated with obesity. Substance 2 also induced weight loss in dietary obese mice. In contrast to DHA administered either alone or as a component of the EPA/DHA concentrate (replacing 15% of dietary lipids), Substance 2 also reversed established glucose intolerance in obese mice. Thus, Substance 2 represents a novel compound with a promising potential in the treatment of obesity and associated metabolic disturbances.     

The Intra- or Extracellular Redox State Was Not Affected by a High vs. Low Glycemic Response Diet in Mice

A low glycemic response (LGR) vs. high glycemic response (HGR) diet helps curtail the development of obesity and diabetes, though the mechanisms are unknown. We hypothesized that consumption of a HGR vs. a LGR diet would lead to a more oxidized circulating redox state and predicted that a HGR diet would increase fat accumulation, reduce insulin sensitivity, and impair metabolic acclimation to a high fat diet in a mouse model. Hence, male C57BL/6 mice consumed a HGR or LGR diet for 16 weeks and a subset of the mice subsequently consumed a high fat diet for 4 weeks. We found that body mass increased at a faster rate for those consuming the HGR diet. Percent body fat was greater and percent lean mass was lesser in the HGR group starting at 12 weeks. However, the groups did not differ in terms of glucose tolerance at week 14 and metabolic parameters (respiratory exchange ratio, heat production, activity) at weeks 4 or 15. Moreover, mice on either diet did not show differences in metabolic acclimation to the high fat leg of the study. At the termination of the study, the groups did not differ in terms of redox pairs (lactate/pyruvate and β-hydroxybutyrate/acetoacetate) or thioredoxin reductase activity in blood. Also, total and oxidized glutathione levels and lipid peroxidation were similar in blood and liver. Correlations between baseline measures, longitudinal parameters, environmental conditions, and terminal metrics revealed that individual mice have innate propensities to metabolic regulation that may be difficult to perturb with diet alone; for example, starting mass correlated negatively with energy expenditure 4 weeks into the study and total hepatic glutathione at the end of the study. In conclusion, these data suggest that the mechanism by which HGR carbohydrates contributes to obesity is not via prolonged oxidation of the circulating redox state.     

Daesiho-Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota

BackgroundObesity has become a major global health challenge due to its increasing prevalence, and the associated health risk. It is the main cause of various metabolic diseases including diabetes, hypertension, cardiovascular disease, stroke and certain forms of cancer.

Methods and Results

In the present study we evaluated the anti-obesity property of Daesiho-tang (DSHT), an herbal medicine, using high fat diet (HFD)-induced obese mice as a model. Our results showed that DSHT ameliorated body weight gain, decreased total body fat, regulated expression of leptin and adiponectin genes of adipose tissue and exerted an anti-diabetic effect by attenuating fasting glucose level and serum insulin level in HFD-fed animals. In addition, DSHT-treatment significantly reduced total cholesterol (TC), triglycerides (TG) and increased high density lipoprotein-cholesterol (HDL), glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) levels in serum and reduced deposition of fat droplets in liver. DSHT treatment resulted in significantly increased relative abundance of bacteria including Bacteroidetes, Bacteroidetes/Firmicutes ratio, Akkermansia Bifidobacterium., Lactobacillus, and decreased the level of Firmicutes. Using RT2 profiler PCR array, 39 (46%) genes were found to be differentially expressed in HFD-fed mice compared to normal control. However, normal gene expressions were restored in 36 (92%) genes of HFD-fed mice, when co-exposed to DSHT.

Conclusion/Major Findings

The results of this study demonstrated that DSHT is an effective herbal formulation in attenuation of obesity in HFD-fed mice through alteration of gene expressions and modulation of intestinal microbiota.     

Differences in Hematopoietic Stem Cells Contribute to Sexually Dimorphic Inflammatory Responses to High Fat Diet-induced Obesity

Women of reproductive age are protected from metabolic disease relative to postmenopausal women and men. Most preclinical rodent studies are skewed toward the use of male mice to study obesity-induced metabolic dysfunction because of a similar protection observed in female mice. How sex differences in obesity-induced inflammatory responses contribute to these observations is unknown. We have compared and contrasted the effects of high fat diet-induced obesity on glucose metabolism and leukocyte activation in multiple depots in male and female C57Bl/6 mice. With both short term and long term high fat diet, male mice demonstrated increased weight gain and CD11c⁺ adipose tissue macrophage content compared with female mice despite similar degrees of adipocyte hypertrophy. Competitive bone marrow transplant studies demonstrated that obesity induced a preferential contribution of male hematopoietic cells to circulating leukocytes and adipose tissue macrophages compared with female cells independent of the sex of the recipient. Sex differences in macrophage and hematopoietic cell in vitro activation in response to obesogenic cues were observed to explain these results. In summary, this report demonstrates that male and female leukocytes and hematopoietic stem cells have cell-autonomous differences in their response to obesity that contribute to an amplified response in males compared with females.     

Sex-Specific Effects of High Fat Diet on Indices of Metabolic Syndrome in 3xTg-AD Mice: Implications for Alzheimer's Disease

Multiple factors of metabolic syndrome have been implicated in the pathogenesis of Alzheimer''s disease (AD), including abdominal obesity, insulin resistance, endocrine dysfunction and dyslipidemia. High fat diet, a common experimental model of obesity and metabolic syndrome, has been shown to accelerate cognitive decline and AD-related neuropathology in animal models. However, sex interacts with the metabolic outcomes of high fat diet and, therefore, may alter neuropathological consequences of dietary manipulations. This study examines the effects of sex and high fat diet on metabolic and AD-related neuropathological outcomes in 3xTg-AD mice. Three month-old male and female 3xTg-AD mice were fed either standard or high fat diets for 4 months. Obesity was observed in all high fat fed mice; however, ectopic fat accumulation, hyperglycemia and hyperinsulinemia were observed only in males. Interestingly, despite the different metabolic outcomes of high fat diet, the neuropathological consequences were similar: both male and female mice maintained under high fat diet exhibited significant worsening in behavioral performance and hippocampal accumulation of β-amyloid protein. Because high fat diet resulted in obesity and increased AD-like pathology in both sexes, these data support a role of obesity-related factors in promoting AD pathogenesis.     

Divergent effects of eicosapentaenoic and docosahexaenoic acid ethyl esters, and fish oil on hepatic fatty acid oxidation in the rat

The physiological activity of fish oil, and ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) affecting hepatic fatty acid oxidation was compared in rats. Five groups of rats were fed various experimental diets for 15 days. A group fed a diet containing 9.4% palm oil almost devoid of n-3 fatty acids served as a control. The test diets contained 4% n-3 fatty acids mainly as EPA and DHA in the form of triacylglycerol (9.4% fish oil) or ethyl esters (diets containing 4% EPA ethyl ester, 4% DHA ethyl ester, and 1% EPA plus 3% DHA ethyl esters). The lipid content of diets containing EPA and DHA ethyl esters was adjusted to 9.4% by adding palm oil. The fish oil diet and ethyl ester diets, compared to the control diet containing 9.4% palm oil, increased activity and mRNA levels of hepatic mitochondrial and peroxisomal fatty acid oxidation enzymes, though not 3-hydroxyacyl-CoA dehydrogenase activity. The extent of the increase was, however, much greater with the fish oil than with EPA and DHA ethyl esters. EPA and DHA ethyl esters, compared to the control diet, increased 3-hydroxyacyl-CoA dehydrogenase activity, but fish oil strongly reduced it. It is apparent that EPA and DHA in the form of ethyl esters cannot mimic the physiological activity of fish oil at least in affecting hepatic fatty acid oxidation in rat.     

Activation of Kupffer Cells Is Associated with a Specific Dysbiosis Induced by Fructose or High Fat Diet in Mice

The increase consumption of fructose in diet is associated with liver inflammation. As a specific fructan substrate, fructose may modify the gut microbiota which is involved in obesity-induced liver disease. Here, we aimed to assess whether fructose-induced liver damage was associated with a specific dysbiosis, especially in mice fed a high fat diet (HFD). To this end, four groups of mice were fed with normal and HFD added or not with fructose. Body weight and glucose sensitivity, liver inflammation, dysbiosis and the phenotype of Kupffer cells were determined after 16 weeks of diet. Food intake was increased in the two groups of mice fed with the HFD. Mice fed with HFD and fructose showed a higher infiltration of lymphocytes into the liver and a lower inflammatory profile of Kupffer cells than mice fed with the HFD without fructose. The dysbiosis associated with diets showed that fructose specifically prevented the decrease of Mouse intestinal bacteria in HFD fed mice and increased Erysipelotrichi in mice fed with fructose, independently of the amount of fat. In conclusion, fructose, used as a sweetener, induced a dysbiosis which is different in presence of fat in the diet. Consequently, the activation of Kupffer cells involved in mice model of HFD-induced liver inflammation was not observed in an HFD/fructose combined diet. These data highlight that the complexity of diet composition could highly impact the development of liver lesions during obesity. Specific dysbiosis associated with the diet could explain that the progressions of liver damage are different.     

Age-dependent alterations of glucose clearance and homeostasis are temporally separated and modulated by dietary fat

Diet- and age-dependent changes in glucose regulation in mice occur, but the temporal development, mechanisms and influence of dietary fat source remain to be defined.We followed metabolic changes in three groups of mice including a low-fat diet (LFD) reference group and two high-fat, high-sucrose diets based on either fish oil (FOD) or soybean oil (SOD), rich in ω3- and ω6-polyunsaturated fatty acids, respectively, to closely monitor the age-dependent development in glucose regulation in both obese (SOD-fed) and lean (LFD- and FOD-fed) mice. We assessed glucose homeostasis and glucose clearance at week 8, 12, 16, 24, 31, and 39 and performed an insulin tolerance test at week 40. We further analyzed correlations between the gut microbiota and key metabolic parameters.Interestingly, alterations in glucose homeostasis and glucose clearance were temporally separated, while 16S ribosomal gene amplicon sequencing revealed that gut microbial alterations formed correlation clusters with fat mass and either glucose homeostasis or glucose clearance, but rarely both. Importantly, effective glucose clearance was maintained in FOD- and even increased in LFD-fed mice, whereas SOD-fed mice rapidly developed impaired glucose clearance followed by a gradual improvement from week 8 to week 39. All groups had similar responses to insulin 40 weeks post diet initiation despite severe nonalcoholic steatohepatitis in SOD-fed mice.We conclude that age-related alterations in glucose regulation may occur in both lean and obese mice and are modulated by dietary fat as indicated by the sustained metabolic homeostasis observed in mice fed ω3-polyunsaturated fatty acids.     

Effects of Dietary Eicosapentaenoic Acid (EPA) Supplementation in High-Fat Fed Mice on Lipid Metabolism and Apelin/APJ System in Skeletal Muscle

Various studies have shown that eicosapentaenoic acid (EPA) has beneficial effects on obesity and associated disorders. Apelin, the ligand of APJ receptor also exerts insulin-sensitizing effects especially by improving muscle metabolism. EPA has been shown to increase apelin production in adipose tissue but its effects in muscle have not been addressed. Thus, the effects of EPA supplementation (36 g/kg EPA) in high-fat diet (HFD) (45% fat, 20% protein, 35% carbohydrate) were studied in mice with focus on muscle lipid metabolism and apelin/APJ expression. Compared with HFD mice, HFD+EPA mice had significantly less weight gain, fat mass, lower blood glucose, insulinemia and hepatic steatosis after 10 weeks of diet. In addition, EPA prevented muscle metabolism alterations since intramuscular triglycerides were decreased and β-oxidation increased. In soleus muscles of HFD+EPA mice, apelin and APJ expression were significantly increased compared to HFD mice. However, plasma apelin concentrations in HFD and HFD+EPA mice were similar. EPA-induced apelin expression was confirmed in differentiated C2C12 myocytes but in this model, apelin secretion was also increased in response to EPA treatment. In conclusion, EPA supplementation in HFD prevents obesity and metabolic alterations in mice, especially in skeletal muscle. Since EPA increases apelin/APJ expression in muscle, apelin may act in a paracrine/autocrine manner to contribute to these benefical effects.     

Impaired Glucose Metabolism in Response to High Fat Diet in Female Mice Conceived by In Vitro Fertilization (IVF) or Ovarian Stimulation Alone

Individuals conceived by in vitro fertilization (IVF) may be at increased risk of cardio-metabolic disorders. We recently reported that IVF conceived male mice displayed impaired glucose metabolism at normal and high body weights. In this study, we examined glucose metabolism in mature female C57BL/6J mice that were conceived by natural conception (NC), by ovarian stimulation (OS) or by IVF following chow or high-fat diet (HFD) for 8 weeks. By design, litter size was comparable between groups, but interestingly the birth weight of IVF and OS females was lower than NC females (p≤0.001). Mature IVF female mice displayed increased fasting glucose as compared to NC and OS mice, irrespective of diet. Mature IVF and OS mice were also more susceptible to the metabolic consequences of high fat diet as compared with NC females, with impaired glucose tolerance (p≤0.01), whereas peripheral insulin resistance and increased hepatic expression of gluconeogenic genes Ppargc1α, Pck1 and G6pc was observed in IVF mice only (p<0.05). This study suggests that ovarian stimulation alone and IVF program distinct metabolic effects in females, but that high fat diet may be required to unmask these effects. This study adds to the growing body of literature that assisted reproduction procedures may increase the risk of developing type 2 diabetes in an obesity prone environment.     

The young göttingen minipig as a model of childhood and adolescent obesity: Influence of diet and gender

Objective:

Gender and sex hormones influence the development of obesity and metabolic syndrome in humans and Göttingen minipigs. The aim of this study was to investigate possible gender differences in the metabolic response to a high energy diet in young Göttingen minipigs as a model of childhood/adolescent obesity.

Design and Methods:

Nine‐week‐old male and female Göttingen minipigs were fed restrictedly on either a low energy diet (LED) or a high energy diet (HED) for 4 months (n = 5‐7). Parameters of interest were fat percentage, visceral fat mass, plasma lipids and glucose tolerance, insulin resistance, and β‐cell function measured by oral and intravenous glucose tolerance tests.

Results:

At 11 to 12 weeks of age, after 2 weeks diet feeding, both genders on HED had increased fat percentage, glucose intolerance, decreased insulin sensitivity, and increased plasma levels of cholesterol and triglycerides (TGs). There was no gender difference in body weight (BW) or fat percentage, but males had lower glucose tolerance than females. After 3.5 to 4 months on the diets, the pigs on HED had increased BW, fat percentage, and visceral fat mass and were more glucose intolerant and insulin resistant than pigs on LED. Also increases in plasma cholesterol and TG levels were observed in the pigs on HED. Females had higher fat percentage and more visceral fat, were more insulin resistant, and had a more unfavorable lipid profile compared with males independent of diet.

Conclusion:

In conclusion, the young Göttingen minipig, and especially the female gender, seems to be a potential model for diet induced childhood/adolescent obesity and metabolic syndrome.     

A high‐fat diet reverses metabolic disorders and premature aging by modulating insulin and IGF1 signaling in SIRT6 knockout mice

Mammalian sirtuin 6 (SIRT6) is involved in the regulation of many essential processes, especially metabolic homeostasis. SIRT6 knockout mice undergo premature aging and die at age ~4 weeks. Severe glycometabolic disorders have been found in SIRT6 knockout mice, and whether a dietary intervention can rescue SIRT6 knockout mice remains unknown. In our study, we found that at the same calorie intake, a high‐fat diet dramatically increased the lifespan of SIRT6 knockout mice to 26 weeks (males) and 37 weeks (females), reversed multi‐organ atrophy, and reduced body weight, hypoglycemia, and premature aging. Furthermore, the high‐fat diet partially but significantly normalized the global gene expression profile in SIRT6 knockout mice. Regarding the mechanism, excessive glucose uptake and glycolysis induced by the SIRT6 deficiency were attenuated in skeletal muscle through inhibition of insulin and IGF1 signaling by the high‐fat diet. Similarly, fatty acids but not ketone bodies inhibited glucose uptake, glycolysis, and senescence in SIRT6 knockout fibroblasts, whereas PI3K inhibition antagonized the effects of a high‐fatty‐acid medium in vitro. Overall, the high‐fat diet dramatically reverses numerous consequences of SIRT6 deficiency through modulation of insulin and IGF1 signaling, providing a new basis for elucidation of SIRT6 and fatty‐acid functions and supporting novel therapeutic approaches against metabolic disorders and aging‐related diseases.     

Stronger anti-obesity effect of white ginseng over red ginseng and the potential mechanisms involving chemically structural/compositional specificity to gut microbiota

BackgroundGinseng has therapeutic potential for treating obesity and the associated gut microbiota dysbiosis. However, whether white ginseng and red ginseng, the two kinds of commonly used processed ginseng, possess different anti-obesity effects remains unknown.PurposeAnti-obesity effects of water extracts of white ginseng and red ginseng (WEWG and WERG) were compared, and the potential mechanisms were discussed.MethodsChemical profiles of WEWG and WERG were characterized by ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS) and high performance liquid chromatography coupled with evaporative light scattering detector (HPLC-ELSD). Anti-obesity effects of WEWG/WERG were examined by determining fat accumulation, systemic inflammation, enteric metabolic disorders and gut microbiota dysbiosis in high-fat diet (HFD)-fed obese mice.ResultsBoth WEWG and WERG exerted anti-obesity effects, with WEWG stronger than WERG. Compared to WERG, WEWG contained less contents of carbohydrates (polysaccharides, oligosaccharides, free monosaccharides) and ginsenosides, but chemical structures or compositions of these components in WEWG were characteristic, i.e. narrower molecular weight distribution and higher molar ratios of glucose residues of polysaccharides; higher content ratios of oligosaccharides DP2–3 (di-/tri-saccharides)-to-oligosaccharides DP4–7 (tetra-/penta-/hexa-/hepta-saccharides), sucrose-to-melibiose, maltose-to-trehalose and high-polar-to-low-polar ginsenosides. WEWG better ameliorated fat accumulation, enteric metabolic disorders and gut microbiota dysbiosis in HFD-fed obese mice than WERG.ConclusionThe stronger anti-obesity effect of white ginseng appears to correlate with differences in its chemical profile as compared to red ginseng. The carbohydrates and ginsenosides in WEWG potentially present more structural and compositional specificity to the obesity-associated gut bacteria, allowing more beneficial effects of WEWG on the gut microbiota dysbiosis. This consequently better alleviates the enteric metabolic disorders and systemic inflammation, thereby contributing to the stronger anti-obesity effect of WEWG as compared to WERG.