High-fat Diet-induced Weight Gain Research Articles

A negative feedback loop between TET2 and leptin in adipocyte regulates body weight

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Tipepidine activates AMPK and improves adipose tissue fibrosis and glucose intolerance in high-fat diet-induced obese mice.

Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) (TP) is a non-narcotic antitussive used in Japan. Recently, the potential application of TP in the treatment of neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder, has been suggested; however, its functions in energy metabolism are unknown. Here, we demonstrate that TP exhibits a metabolism-improving action. The administration of TP reduced high-fat diet-induced body weight gain in mice and lipid accumulation in the liver and increased the weight of epididymal white adipose tissue (eWAT) in diet-induced obese (DIO) mice. Furthermore, TP inhibited obesity-induced fibrosis in the eWAT. We also found that TP induced AMP-activated protein kinase (AMPK) activation in the eWAT of DIO mice and 3T3-L1 cells. TP-induced AMPK activation was abrogated by the transfection of liver kinase B1 siRNA in 3T3-L1 cells. The metabolic effects of TP were almost equivalent to those of metformin, an AMPK activator that is used as a first-line antidiabetic drug. In summary, TP is a potent AMPK activator, suggesting its novel role as an antidiabetic drug owing to its antifibrotic effect on adipose tissues.

A macrophage-collagen fragment axis mediates subcutaneous adipose tissue remodeling in mice

Efficient removal of fibrillar collagen is essential for adaptive subcutaneous adipose tissue (SAT) expansion that protects against ectopic lipid deposition during weight gain. Here, we used mice to further define the mechanism for this collagenolytic process. We show that loss of collagen type-1 (CT1) and increased CT1-fragment levels in expanding SAT are associated with proliferation of resident M2-like macrophages that display increased CD206-mediated engagement in collagen endocytosis compared to chow-fed controls. Blockage of CD206 during acute high-fat diet-induced weight gain leads to SAT CT1-fragment accumulation associated with elevated inflammation and fibrosis markers. Moreover, these SAT macrophages' engagement in collagen endocytosis is diminished in obesity associated with elevated levels collagen fragments that are too short to assemble into triple helices. We show that such short fragments provoke M2-macrophage proliferation and fibroinflammatory changes in fibroblasts. In conclusion, our data delineate the importance of a macrophage-collagen fragment axis in physiological SAT expansion. Therapeutic targeting of this process may be a means to prevent pathological adipose tissue remodeling, which in turn may reduce the risk for obesity-related metabolic disorders.

The gastrointestinal tract is a major source of the acute metformin-stimulated rise in GDF15

The hormone GDF15 is secreted in response to cellular stressors. Metformin elevates circulating levels of GDF15, an action important for the drug’s beneficial effects on body weight. Metformin can also inhibit mammalian respiratory complex I, leading to decreases in ATP:AMP ratio, activation of AMP Kinase (AMPK), and increased GDF15 production. We undertook studies using a range of mice with tissue-specific loss of Gdf15 (namely gut, liver and global deletion) to determine the relative contributions of two classical metformin target tissues, the gut and liver, to the elevation of GDF15 seen with metformin. In addition, we performed comparative studies with another pharmacological agent, the AMP kinase pan-activator, MK-8722. Deletion of Gdf15 from the intestinal epithelium significantly reduced the circulating GDF15 response to oral metformin, whereas deletion of Gdf15 from the liver had no effect. In contrast, deletion of Gdf15 from the liver, but not the gut, markedly reduced circulating GDF15 responses to MK-8722. Further, our data show that, while GDF15 restricts high-fat diet-induced weight gain, the intestinal production of GDF15 is not necessary for this effect. These findings add to the body of evidence implicating the intestinal epithelium in key aspects of the pharmacology of metformin action.

Imeglimin improves systemic metabolism by targeting brown adipose tissue and gut microbiota in obese model mice

Imeglimin is a recently developed anti-diabetic drug that could concurrently promote insulin secretion and insulin sensitivity, while its mechanisms of action are not fully understood. Here we show that imeglimin administration could protect mice from high fat diet-induced weight gain with enhanced energy expenditure and attenuated whitening of brown adipose tissue. Imeglimin administration led to significant alteration of gut microbiota, which included an increase of Akkermansia genus, with attenuation of obesity-associated gut pathologies. Ablation of microbiota by antibiotic treatment partially abrogated the insulin sensitizing effects of imeglimin, while not affecting its actions on body weight gain or brown adipose tissue. Collectively, our results characterize imeglimin as a potential agent promoting energy expenditure and gut integrity, providing new insights into its mechanisms of action.

Intestinal Trefoil Factor 3: a new biological factor mediating gut-kidney crosstalk in diabetic kidney disease.

To investigate the effect of TFF3 in the pathogenesis of Diabetic Kidney Disease (DKD), and explore the dynamic changes of TFF3 expression pattern in renal injury process. DKD animal model was established by streptozotocin (STZ) (40 mg/kg/d, ip, for 5 days, consecutively) combined with the high fat diet (HFD) for 12 weeks. While animals were sacrificed at different time stages in DKD process (4 weeks, 8 weeks and 12 weeks, respectively). STZ combined with high-fat diet induced weight gain, increased blood glucose and decreased glucose tolerance in DKD mice. Compared to the control group, the DKD group exhibits extracellular matrix (ECM) accumulation and the renal injury was aggravated in a time-dependent manner. The TFF3 expression level was decreased in kidney, and increased in colon tissue. TFF3 is not only expressed in colon, but also expressed in renal medulla and cortex. TFF3 might be play a pivotal role in renal mucosal repair by gut-kidney crosstalk, and protect renal from high glucose microenvironment damage.

A mixture of Nordic berries improves cognitive function, metabolic function and alters the gut microbiota in C57Bl/6J male mice.

Our diets greatly influence our health. Multiple lines of research highlight the beneficial properties of eating berries and fruits. In this study, a berry mixture of Nordic berries previously identified as having the potential to improve memory was supplemented to young C57Bl/6J male mice to investigate effects on cognition function, metabolic health, markers of neuroinflammation, and gut microbiota composition. C57Bl/6J male mice at the age of 8 weeks were given standard chow, a high-fat diet (HF, 60%E fat), or a high-fat diet supplemented with freeze-dried powder (20% dwb) of a mixture of Nordic berries and red grape juice (HF + Berry) for 18 weeks (n = 12 animals/diet group). The results show that supplementation with the berry mixture may have beneficial effects on spatial memory, as seen by enhanced performance in the T-maze and Barnes maze compared to the mice receiving the high-fat diet without berries. Additionally, berry intake may aid in counteracting high-fat diet induced weight gain and could influence neuroinflammatory status as suggested by the increased levels of the inflammation modifying IL-10 cytokine in hippocampal extracts from berry supplemented mice. Furthermore, the 4.5-month feeding with diet containing berries resulted in significant changes in cecal microbiota composition. Analysis of cecal bacterial 16S rRNA revealed that the chow group had significantly higher microbial diversity, as measured by the Shannon diversity index and total operational taxonomic unit richness, than the HF group. The HF diet supplemented with berries resulted in a strong trend of higher total OTU richness and significantly increased the relative abundance of Akkermansia muciniphila, which has been linked to protective effects on cognitive decline. In conclusion, the results of this study suggest that intake of a Nordic berry mixture is a valuable strategy for maintaining and improving cognitive function, to be further evaluated in clinical trials.

Rice Bran Extract Suppresses High-Fat Diet-Induced Hyperlipidemia and Hepatosteatosis through Targeting AMPK and STAT3 Signaling.

Rice bran, a by-product of rice milling, is abundant in bioactive molecules and is highly recognized for its health-promoting properties, particularly in improving metabolic conditions. Building on this knowledge, we aimed to optimize the extraction conditions to maximize the functional efficacy of rice bran extract (RBE) and further validate its impact on lipid metabolism. We found that the optimized RBE (ORBE) significantly suppressed high-fat diet-induced weight gain, hyperlipidemia, and hepatosteatosis in mouse models. ORBE treatment not only suppressed lipid uptake in vivo, but also reduced lipid accumulation in HepG2 cells. Importantly, we discovered that ORBE administration resulted in activation of AMPK and inhibition of STAT3, which are both crucial players in lipid metabolism in the liver. Collectively, ORBE potentially offers promise as a dietary intervention strategy against hyperlipidemia and hepatosteatosis. This study underlines the value of optimized extraction conditions in enhancing the functional efficacy of rice bran.

A novel polyphenol-rich combination of 5 plant extracts prevents high-fat diet-induced body weight gain by regulating intestinal macronutrient absorption in mice

Global prevalence of obesity and type 2 diabetes are rapidly increasing to pandemic proportions. A novel supplement composed of 5 plant extracts from olive leaf, bilberry, artichoke, chrysanthellum, and black pepper was designed to prevent type 2 diabetes development in people at risk. It was previously shown to improve body weight and glucose control in preclinical rodent models, with these effects being accompanied by increased fecal energy excretion and in vitro inhibition of several digestive enzymes. Thus, we hypothesized that, in mice fed a high-fat diet (HFD), a single dose of this botanical supplementation would decrease the responses to oral fat and carbohydrate tolerance tests, and that chronic supplementation would result in increased fecal triglyceride content. We showed that acute administration in HFD-fed mice (1.452 g/kg body weight) markedly reduced circulating triglycerides following an oral lipid gavage, whereas glycemic responses to various carbohydrate tests were only mildly affected. When incorporated into the food (2.5%) of HFD-fed mice, chronic supplementation prevented body weight gain and improved glucose homeostasis and lipid tolerance. Fecal free fatty acid content, but not triglyceride, was significantly increased in supplemented animals, suggesting reduced lipid absorption in the digestive tract. Congruently, this botanical supplementation downregulated several genes associated with fatty acid transport whose expression was increased by HFD, principally in the jejunum. This study provides novel insights as for the mode of action behind the antiobesity effect of this plant-based supplementation, in HFD-fed mice.

Kappa opioid receptor activation increases thermogenic energy expenditure which drives increased feeding

Opioid receptors, including the kappa opioid receptor (KOR), exert control over thermoregulation and feeding behavior. Notably, activation of KOR stimulates food intake, leading to postulation that KOR signaling plays a central role in managing energy intake. KOR has also been proposed as a target for treating obesity. Herein, we report studies examining how roles for KOR signaling in regulating thermogenesis, feeding, and energy balance may be interrelated using pharmacological interventions, genetic tools, quantitative thermal imaging, and metabolic profiling. Our findings demonstrate that activation of KOR in the central nervous system causes increased energy expenditure via brown adipose tissue activation. Importantly, pharmacologic, or genetic inhibition of brown adipose tissue thermogenesis prevented the elevated food intake triggered by KOR activation. Furthermore, our data reveal that KOR-mediated thermogenesis elevation is reversibly disrupted by chronic high-fat diet, implicating KOR signaling as a potential mediator in high-fat diet-induced weight gain.

NMP4, an Arbiter of Bone Cell Secretory Capacity and Regulator of Skeletal Response to PTH Therapy.

The skeleton is a secretory organ, and the goal of some osteoporosis therapies is to maximize bone matrix output. Nmp4 encodes a novel transcription factor that regulates bone cell secretion as part of its functional repertoire. Loss of Nmp4 enhances bone response to osteoanabolic therapy, in part, by increasing the production and delivery of bone matrix. Nmp4 shares traits with scaling factors, which are transcription factors that influence the expression of hundreds of genes to govern proteome allocation for establishing secretory cell infrastructure and capacity. Nmp4 is expressed in all tissues and while global loss of this gene leads to no overt baseline phenotype, deletion of Nmp4 has broad tissue effects in mice challenged with certain stressors. In addition to an enhanced response to osteoporosis therapies, Nmp4-deficient mice are less sensitive to high fat diet-induced weight gain and insulin resistance, exhibit a reduced disease severity in response to influenza A virus (IAV) infection, and resist the development of some forms of rheumatoid arthritis. In this review, we present the current understanding of the mechanisms underlying Nmp4 regulation of the skeletal response to osteoanabolics, and we discuss how this unique gene contributes to the diverse phenotypes among different tissues and stresses. An emerging theme is that Nmp4 is important for the infrastructure and capacity of secretory cells that are critical for health and disease.

Central nervous system IL-17R expression influences weight gain by altering food-intake and fat-mass accumulation

Abstract Cytokines influence innate behaviors in mice and IL-17a may function within the hypothalamus to reduce food-intake. We examine contributions of nervous system IL-17R expression on mouse feeding behavior following obesogenic diet exposure. We crossed IL-17Ra f/fand Synapsin1-Cre or Na v1.8-Cre mice to generate pan-neuronal (Syn-Cre IL-17Ra f/f) or peripheral neuronal- (Na-v1.8-Cre IL17Ra f/f) IL-17R knockout mice, respectively. Body weights of male and female mice were measured over 10-weeks of 60% high-fat diet (HFD) feeding. 60% HFD fed male Syn-Cre IL-17Ra f/fand IL-17Ra f/fmice underwent metabolic phenotyping and body composition analyses. Syn-Cre IL-17Ra f/fand IL-17Ra f/fmice received CNS penetrant Nrf2 activator Dimethyl-Fumarate (DMF) to assess whether pharmacological inhibition of IL-17a secretion alters HFD induced weight gain. Male and female Syn-Cre IL-17Ra f/fbut not Na-v1.8-Cre IL17Ra f/fmice displayed a 15–20% reduction in bodyweight after 10-weeks of HFD feeding (male p=0.00046, female p=0.0061). DMF treatment did not impact body weight. Syn-Cre IL-17Ra f/ftrended towards a reduction in food-intake and meal numbers when compared to IL-17Ra f/fmice. Syn-Cre IL-17Ra f/fhad a significant reduction in fat mass (total p=0.01, %total p=0.04) and lean mass (total p=0.03 and %total p=0.04). In sum, loss of central but not peripheral nervous system expression of IL-17R robustly and significantly blunts weight gain following chronic exposure to an obesogenic diet. This decrease in body weight was associated with a decrease in total fat mass. Our data suggest that a population of IL-17R expressing neurons within the brain influence food-intake by modulating feeding behaviors associated with meal frequency. NIH funding sources include F31-DK127728 and T32-DK07563

Hepatic IDH2 regulates glycolysis and gluconeogenesis

Background and aimsThe liver plays a central role in controlling glucose and lipid metabolism. IDH2, a mitochondrial protein, controls TCA cycle flux. However, its role in regulating metabolism in obesity is still unclear. This study intends to investigate the impact of hepatic IDH2 expression on overnutrition-regulated glucose and lipid metabolism. MethodsHepatic IDH2 was knocked-out in mice by the approach of CRISPR-Cas9. Mice were subjected to starvation and refeeding for hepatic glucose and lipid studies in vivo. Primary hepatocytes and mouse normal liver cell line, AML12 cells were used for experiments in vitro. ResultsThis study found that IDH2 protein levels were elevated in the livers of obese people and mice with high-fat diet consumption or hepatic steatosis. Liver IDH2-deletion mice (IDH2LKO) were resistant to high-fat diet-induced body weight gain, with lower serum glucose and TG levels, increased insulin sensitivity, and higher FGF21 secretion, despite the higher TG content in the liver. Consistently, overexpression of IDH2 in hepatocytes promoted gluconeogenesis and enhanced glycogenesis. By performing mass spectrometry and proteomics analyses, we further demonstrated that IDH2-deficiency in hepatocytes accelerated ATP production by increasing forward TCA cycle flux, thus promoting glycolysis pathway and decreasing glycogen synthesis at refeeding state, and inhibiting hepatic gluconeogenesis, increasing β-oxidation during starvation. Moreover, experiments in vivo demonstrated that IDH2-knockout might not exacerbate hepatic inflammatory responses in the NASH model. ConclusionsElevated hepatic IDH2 under over-nutrition state contributes to elevated gluconeogenesis and glycogen synthesis. Inhibition of IDH2 in the liver could be a potential therapeutic target for obesity and diabetes.

Combined treatment with teneligliptin and canagliflozin additively suppresses high-fat diet-induced body weight gain in mice with modulation of lipid metabolism-related gene expression

In the treatment of type 2 diabetes mellitus (T2DM), comprehensive management of multiple risk factors, such as blood glucose, body weight, and lipids, is important to prevent disease progression. Although the combination of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor is often used clinically, the effects of this combination, other than glucose metabolism, have yet to be thoroughly investigated. In this study, we evaluated the effects of combined treatment with a DPP-4 inhibitor, teneligliptin, and an SGLT2 inhibitor, canagliflozin, on the body weight and lipid metabolism in high-fat diet (HFD)-induced obese mice. We found that monotherapy with teneligliptin or canagliflozin showed suppressive effects on high-fat diet-induced body weight gain and reduced inguinal white adipose tissue (iWAT) mass, and combined treatment additively reduced body weight gain and iWAT mass. Teneligliptin significantly increased oxygen consumption during the light phase, and this effect was preserved in the combined treatment. The combined treatment did not alter the mRNA expression levels of thermogenesis-related genes in adipose tissue but showed the tendency to additively induce mRNA of fatty acid oxidation-related genes in brown adipose tissue and tended to additively decrease mRNA of fatty acid synthesis-related genes in iWAT and liver tissues. These results suggest that combined treatment with teneligliptin and canagliflozin additively suppresses HFD-induced body weight gain with increasing oxygen consumption and modulating the expression of lipid metabolism-related genes. This combination therapy may provide effective body weight management for patients with T2DM and obesity.

Dietary butyrate ameliorates metabolic health associated with selective proliferation of gut Lachnospiraceae bacterium 28-4.

Short-chain fatty acids, including butyrate, have multiple metabolic benefits in individuals who are lean but not in individuals with metabolic syndrome, with the underlying mechanisms still being unclear. We aimed to investigate the role of gut microbiota in the induction of metabolic benefits of dietary butyrate. We performed antibiotic-induced microbiota depletion of the gut and fecal microbiota transplantation (FMT) in APOE*3-Leiden.CETP mice, a well-established translational model for developing human-like metabolic syndrome, and revealed that dietary butyrate reduced appetite and ameliorated high-fat diet-induced (HFD-induced) weight gain dependent on the presence of gut microbiota. FMT from butyrate-treated lean donor mice, but not butyrate-treated obese donor mice, into gut microbiota-depleted recipient mice reduced food intake, attenuated HFD-induced weight gain, and improved insulin resistance. 16S rRNA and metagenomic sequencing on cecal bacterial DNA of recipient mice implied that these effects were accompanied by the selective proliferation of Lachnospiraceae bacterium 28-4 in the gut as induced by butyrate. Collectively, our findings reveal a crucial role of gut microbiota in the beneficial metabolic effects of dietary butyrate as strongly associated with the abundance of Lachnospiraceae bacterium 28-4.

CD47 antisense oligonucleotide treatment attenuates obesity and its-associated metabolic dysfunction

Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.

High fat diet is protective against kidney injury in hypertensive-diabetic mice, but leads to liver injury.

Chronic kidney disease (CKD) is a worldwide health burden with increases risk of end-stage renal function if left untreated. CKD induced in the context of metabolic syndrome (MS) increases risks of hypertension, hyperglycemia, excess body fat and dyslipidemia. To test if combining a high-fat diet (HFD) regimen onto the hypertensive/ diabetic phenotype would mimic features of MS induced-CKD in mice, hyperglycemia was induced in genetically hypertensive mice (Lin), followed by HFD regimen. For that, 8-week-old male were subjected to streptozotocin (STZ) intraperitoneal (i.p.) injections (50 mg/kg, 5 days consecutive). LinSTZ were fed a 60% kCal HFD for 8 weeks. Lin mice treated with STZ developed polydipsia, became hypertensive and hyperglycemic. HFD induced weight gain, protected against glomerular hypertrophy, scarring, and albuminuria at endpoint compared to regular diet fed LinSTZ. On the other hand, HFD induced steatosis, liver fibrosis, inflammation, and increase in AST/ALT ratio, characteristics of non-alcoholic liver disease. Taken together, our results show that LinSTZ mice fed a HFD did not lead to a more robust model of MS-induced CKD, protected against kidney injury, but inducing liver damage. More studies are necessary to understand the kidney protective mechanisms of HFD when superimposed with hypertension and type 1 diabetes.

Therapeutic impact of stachyose on hyperlipidaemia caused by a high-fat diet in mice as revealed by gut microbiota and metabolomics

Hyperlipidaemia, which is characterized by an excess of lipids or fats in the bloodstream, is a high-risk factor and critical indicator of many metabolic diseases. This study used 16 S rRNA gene sequencing and metabolomics to determine that stachyose (ST) has a therapeutic effect and is a mechanism of hyperlipidaemia. These results show that ST significantly attenuated high-fat diet-induced weight gain and fat deposition while also adjusting the gut microbial composition. Untargeted serum metabolomics identified 12 biomarkers, which suggests that ST may function by regulating metabolic pathways. These results highlight the potential of ST in treating hyperlipidaemia and provides directions for future research including an in-depth investigation of the bioactive components, dosage, and treatment strategies of ST.

Characterization of Hypolipidemic Phenol Analogues from Fermented Tea by Eurotium cristatum

Fuzhuan brick tea (FBT), a type of black tea, is a traditional beverage in China, especially popular among frontier ethnic groups. FBT is well-known for its health benefits, such as hypoglycemic, anti-hypertensive, anti-inflammatory, diuretic, and detoxification effects. Nevertheless, the underlying mechanisms on the molecular level are still elusive and the key compounds responsible for the health benefits are unidentified. Previous studies have mainly focused on functional studies of the water extract. However, FBT is typically cooked with butter or milk. Therefore, we hypothesized that some lipophilic components in FBT, which can be absorbed through the co-consumption of butter or milk, may play an important role in the health benefits. The present study aimed to investigate whether the liposoluble extract of FBT alleviates symptoms related to metabolic diseases and to identify the active compounds involved. By comparing the high-performance liquid chromatography (HPLC) profiles of water, milk and hexane extract, some low polarity peaks were observed in the milk and hexane extracts. Furthermore, the hexane extract treatment alleviated body weight gain, serum total cholesterol and triglyceride levels, and inhibited the accumulation of hepatic fat granules in a high-fat diet (HFD)-induced C57BL/6N mouse model. In order to identify the key functional lipophilic compounds in FBT, the hexane extract of FBT was subjected to chemical characterization. Four phenol analogs were characterized, namely, isodihydroauroglaucin (1), dihydroauroglaucin (2), tetrahydroauroglaucin (3), and flavoglaucin (4). Compounds 1 and 4 reduced the levels of total cholesterol and triglyceride in vivo. Both compounds also inhibited the high-fat diet-induced body weight gain and accumulation of fat granules in the liver of C57BL/6N mice. Isodihydroauroglaucin and flavoglaucin have therefore been identified as bioactive ingredients that contribute to the health benefits of FBT.

Tremella fuciformis polysaccharide reduces obesity in high-fat diet-fed mice by modulation of gut microbiota.

Obesity is a metabolic disease associated with gut microbiota and low-grade chronic inflammation. Tremella fuciformis is a medicinal and edible fungus; polysaccharide (TP) is the main active component, which has a variety of biological activities, such as hypoglycemic and hypolipidemic. However, the anti-obesity effects and potential mechanisms of TP have never been reported. This study was conducted to elucidate the inhibitory effect of TP on high-fat diet (HFD)-induced obesity in mice. Mice were split into five groups: normal chow diet (NCD) group, NCD_TP_H group, HFD group, HFD_TP_L group and HFD_TP_H group. Our study showed that TP inhibited high-fat diet-induced weight gain and fat accumulation in mice and reduced blood glucose, hyperlipidemia and inflammation. TP also improved gut microbiota disorders by reducing the Firmicutes/Bacteroidetes ratio and modulating the relative abundance of specific gut microbiota. We also found that the anti-obesity and gut microbiota-modulating effects of TP could be transferred to HFD-fed mice via faecal microbiota transplantation (FMT), confirming that the gut microbiota was one of the targets of TP for obesity inhibition. Further studies showed that TP increased the production of short-chain fatty acids and the secretion of intestinal hormones. Our studies showed that TP inhibited obesity by modulating inflammation and the microbe-gut-brain axis, providing a rationale for developing TP to treat obesity and its complications.