Improved Glucose Intolerance Research Articles

Loureirin B Ameliorates Glycolipid Metabolism Disorders in Ob/ob Mice by Regulating Bile Acid Levels and Modulating Gut Microbiota Composition.

Loureirin B (LB), an active component of Resina Draconis, exhibits hypoglycemic and hypolipidemic effects; however, its mode of action remains unclear. Here, ob/ob mice were utilized to investigate the effects of LB on the regulation of glucolipid metabolism disorders. Non-targeted metabolomics and 16S rDNA sequencing were performed to elucidate the potential mechanisms involved. Results indicated that LB treatment (45 mg/kg) significantly improved glucose intolerance and insulin resistance, reduced lipid levels, and alleviated hepatic steatosis. Non-targeted metabolomics analysis revealed that LB treatment regulated bile acid levels. Quantification of liver bile acids demonstrated that LB treatment significantly decreased the ratio of 12α-OH to non-12α-OH bile acids in the liver. 16S rDNA sequencing results showed that LB treatment increased the abundance of short-chain fatty acid-producing microbiota while decreasing the abundance of bile salt hydrolase (BSH) enzyme-producing microbiota. In conclusion, LB ameliorates glucolipid metabolism disorders by regulating liver bile acid levels and modulating the composition of the gut microbiota.

GR113808, a serotonin receptor 4 antagonist, prevents high-fat-diet-induced obesity, fatty liver formation, and insulin resistance in C57BL/6J mice

BackgroundThe burden of nonalcoholic fatty liver disease is increasing, and limited therapeutic drugs are available for its treatment. Serotonin binds to approximately 14 serotonin receptors (HTR) and plays diverse roles in obesity and metabolic complications. In this study, we focused on the function of HTR4 on nonalcoholic fatty liver disease using GR113808, a selective HTR4 antagonist.MethodsMale C57BL/6J mice were fed high-fat diet for 12 weeks with intraperitoneal GR113808 injection, and HTR expression, weight changes, glucose and lipid metabolism, hepatic fat accumulation, changes in adipose tissue, the changes in transcriptional factors of signaling pathways, and inflammations were assessed. Hep3B cells and 3T3-L1 cells were treated with siRNA targeting HTR4 to downregulate its expression and then cultured with palmitate to mimic a high-fat diet. The changes in transcriptional factors of signaling pathways, and inflammations were assessed in those cells.ResultsAfter feeding a high-fat diet to male C57BL/6J mice, HTR4 expression in the liver and adipose tissues decreased. GR113808 suppressed body weight gain and improved glucose intolerance. Furthermore, GR113808 not only decreased fatty liver formation but also reduced adipose tissue size. Additionally, GR113808 reduced inflammatory cytokine serum levels and inflammasome complex formation in both tissues. Palmitate treatment in HTR4-downregulated Hep3B cells, also reduced peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1 pathway induction as well as inflammasome complex formation, thus decreasing inflammatory cytokine levels. HTR4 downregulation in 3T3-L1 cells also reduced palmitate-induced inflammasome complex formation and inflammatory cytokine production. Palmitate-induced insulin resistance in Hep3B cells, but not in 3T3-L1 cells, was improved by HTR4 downregulation.ConclusionsIn summary, GR113808 protected against fatty liver formation and improved inflammation in the liver and adipose tissue. Downregulation of HTR4 ameliorated insulin resistance in the liver. These results suggest that HTR4 could serve as a promising therapeutic target for metabolic diseases.

An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice.

Protein folding in the endoplasmic reticulum (ER) requires a high ratio of oxidized to reduced glutathione (GSSG/rGSH). Since the GSSG/rGSH depends on total glutathione (tGSH = GSSG + rGSH) levels, we hypothesized that limiting GSH biosynthesis will ameliorate protein misfolding by enhancing the ER oxidative milieu. As a proof-of-concept, we used DL-buthionine-(S,R)-sulfoximine (BSO) to inhibit GSH biosynthesis in Akita mice, which are prone to proinsulin misfolding. We conducted a 2-week intervention to investigate if BSO was safe and a 6-week intervention to find its effect on glucose intolerance. In both cohorts, male heterozygous Akita (AK) and wild-type (WT) mice were continuously administered 15mM BSO. No adverse effects were observed on body weight, food intake, and water intake in either cohort. Unaltered levels of plasma aspartate and alanine aminotransferases, and cystatin-C, indicate that BSO was safe. BSO-induced decreases in tGSH were tissue-dependent with maximal effects in the kidneys, where it altered the expression of genes associated with GSH biosynthesis, redox status, and proteostasis. BSO treatment decreased random blood glucose levels to 80% and 67%of levels in untreated mice in short-term and long-term cohorts, respectively, and 6-h fasting blood glucose to 82% and 74%of levels in untreated mice, respectively. BSO also improved glucose tolerance by 37% in AK mice in the long-term cohort, without affecting insulin tolerance. Neither glucose tolerance nor insulin tolerance were affected in WT. Data indicate that BSO might treat misfolded proinsulin-induced glucose intolerance. Future studies should investigate the effect of BSO on proinsulin misfolding and if it improves glucose intolerance in individuals with Mutant Insulin Diabetes of Youth.

The microbiota-dependent tryptophan metabolite alleviates high-fat diet–induced insulin resistance through the hepatic AhR/TSC2/mTORC1 axis

Type 2 diabetes (T2D) is potentially linked to disordered tryptophan metabolism that attributes to the intricate interplay among diet, gut microbiota, and host physiology. However, underlying mechanisms are substantially unknown. Comparing the gut microbiome and metabolome differences in mice fed a normal diet (ND) and high-fat diet (HFD), we uncover that the gut microbiota-dependent tryptophan metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) is present at lower concentrations in mice with versus without insulin resistance. We further demonstrate that the microbial transformation of tryptophan into 5-HIAA is mediated by Burkholderia spp. Additionally, we show that the administration of 5-HIAA improves glucose intolerance and obesity in HFD-fed mice, while preserving hepatic insulin sensitivity. Mechanistically, 5-HIAA promotes hepatic insulin signaling by directly activating AhR, which stimulates TSC2 transcription and thus inhibits mTORC1 signaling. Moreover, T2D patients exhibit decreased fecal levels of 5-HIAA. Our findings identify a noncanonical pathway of microbially producing 5-HIAA from tryptophan and indicate that 5-HIAA might alleviate the pathogenesis of T2D.

Obesity-induced upregulation of miR-483-5p impairs the function and identity of pancreatic β-cells.

To assess the expression and function of miR-483-5p in diabetic β cells. The expression of miR-483-5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual-luciferase activity, and western blotting assays, were utilized for miR-483-5p target gene verification. Mice with β cell-specific miR-483-5p downregulation were studied under metabolic stress (i.e. a high-fat diet) condition. Lineage tracing was used to determine β-cell fate. miR-483-5p increased in the islets of obese mouse models. Expression levels of miR-483-5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR-483-5p in β cells results in impaired insulin secretion and β-cell identity. Cell lineage-specific analyses revealed that miR-483-5p overexpression deactivated β-cell identity genes (insulin, Pdx1 and MafA) and derepressed β-cell dedifferentiation (Ngn3) genes. miR-483-5p downregulation in β cells of high-fat diet-fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR-483-5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β-cell maturation. These findings indicate that the miR-483-5p-mediated reduction of mRNAs specifies β-cell identity as a contributor to β-cell dysfunction via the loss of cellular differentiation.

Cocoa extract induces browning of white adipocytes and improves glucose intolerance in mice fed a high-fat diet.

Cocoa extract (CE) offers several health benefits, such as anti-obesity and improved glucose intolerance. However, the mechanisms remain unclear. Adipose tissue includes white adipose tissue (WAT) and brown adipose tissue. Brown adipose tissue leads to body fat reduction by metabolizing lipids to heat via uncoupling protein 1 (UCP1). The conversion of white adipocytes into brown-like adipocytes (beige adipocytes) is called browning, and it contributes to the anti-obesity effect and improved glucose tolerance. This study aimed to evaluate the effect of CE on glucose tolerance in terms of browning. We found that dietary supplementation with CE improved glucose intolerance in mice fed a high-fat diet, and it increased the expression levels of Ucp1 and browning-associated gene in inguinal WAT. Furthermore, in primary adipocytes of mice, CE induced Ucp1 expression through β3-adrenergic receptor stimulation. These results suggest that dietary CE improves glucose intolerance by inducing browning in WAT.

Plasma Proteomics Identifies B2M as a Regulator of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction.

Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

CTRP9 alleviates diet induced obesity through increasing lipolysis mediated by enhancing autophagy-initiation complex formation.

Recently, emerging evidence has suggested that obesity become a prevalent health threat worldwide. Reportedly, CTRP9 can ameliorate HFD induced obesity. However, the molecular mechanism underlying the role of CTRP9 in obesity remains elusive. In this study, we reported its major function in the regulation of lipolysis. First, we found that the expression of CTRP9 was decreased in mature adipocytes and white adipose tissue of obese mice. Then, we showed that overexpression adipose tissue CTRP9 alleviated diet-induced obesity and adipocytes hypertrophy, improved glucose intolerance and raised energy expenditure. Moreover, CTRP9 increased the lipolysis in vitro and vivo. Additionally, we determined that CTRP9 enhanced autophagy flux in adipocytes. Intriguingly, knock down Beclin1 by SiRNA abolished the effect of CTRP9 on lipolysis. Mechanically, CTRP9 enhanced the expression of SNX26. We demonstrated that SNX26 was a component of the ATG14L-Beclin1-VPS34 complex and enhanced the assembly of the autophagy-initiation complex. Collectively, our results suggested that CTRP9 alleviated diet induced obesity through enhancing lipolysis mediated by autophagy-initiation complex formation.

Chrysanthemum morifolium Ramat extract and probiotics combination ameliorates metabolic disorders through regulating gut microbiota and PPARα subcellular localization

BackgroundChrysanthemum morifolium Ramat, a traditional Chinese medicine, has the effects on liver clearing, vision improving, and anti-inflammation. C. morifolium and probiotics have been individually studied for their beneficial effects on metabolic diseases. However, the underlying molecular mechanisms were not completely elucidated. This study aims to elucidate the potential molecular mechanisms of C. morifolium and probiotics combination (CP) on alleviating nonalcoholic fatty liver disease (NAFLD) and the dysregulation of glucose metabolism in high-fat diet (HFD)-fed mice.MethodsThe therapeutic effect of CP on metabolism was evaluated by liver histology and serum biochemical analysis, as well as glucose tolerance test. The impact of CP on gut microbiota was analyzed by 16S rRNA sequencing and fecal microbiota transplantation. Hepatic transcriptomic analysis was performed with the key genes and proteins validated by RT-qPCR and western blotting. In addition, whole body Pparα knockout (Pparα−/−) mice were used to confirm the CP-mediated pathway.ResultsCP supplementation ameliorated metabolic disorders by reducing body weight and hepatic steatosis, and improving glucose intolerance and insulin resistance in HFD fed mice. CP intervention mitigated the HFD-induced gut microbiota dysbiosis, which contributed at least in part, to the beneficial effect of improving glucose metabolism. In addition, hepatic transcriptomic analysis showed that CP modulated the expression of genes associated with lipid metabolism. CP downregulated the mRNA level of lipid droplet-binding proteins, such as Cidea and Cidec in the liver, leading to more substrates for fatty acid oxidation (FAO). Meanwhile, the expression of CPT1α, the rate-limiting enzyme of FAO, was significantly increased upon CP treatment. Mechanistically, though CP didn’t affect the total PPARα level, it promoted the nuclear localization of PPARα, which contributed to the reduced expression of Cidea and Cidec, and increased expression of CPT1α, leading to activated FAO. Moreover, whole body PPARα deficiency abolished the anti-NAFLD effect of CP, suggesting the importance of PPARα in CP-mediated beneficial effect.ConclusionThis study revealed the hypoglycemic and hepatoprotective effect of CP by regulating gut microbiota composition and PPARα subcellular localization, highlighting its potential for therapeutic candidate for metabolic disorders.

Knockdown of LAP2α inhibits adipogenesis of human adipose-derived stem cells and ameliorates high-fat diet-induced obesity.

Adipogenesis, a pivotal cellular process involving the differentiation of mesenchymal stem cells (MSCs) to mature adipocytes, plays a significant role in various physiological functions. Dysregulation of adipogenesis is implicated in conditions such as obesity. However, the complete molecular understanding of adipogenesis remains elusive. This study aimed to uncover the novel role of lamina-associated polypeptide 2 alpha (LAP2α) in human adipose-derived stem cells (hASCs) adipogenesis and its impact on high-fat diet (HFD)-induced obesity and associated metabolic disturbances. LAP2α expression was assessed during the adipogenic differentiation of hASCs using RT-qPCR and western blotting. The functional role of LAP2α in adipogenesis was explored both invitro and invivo through loss- and gain-of-function studies. Moreover, mice with HFD-induced obesity received lentivirus injection to assess the effect of LAP2α knockdown on fat accumulation. Molecular mechanisms underlying LAP2α in adipogenic differentiation were investigated using RT-qPCR, Western blotting, immunofluorescence staining, and Oil Red O staining. LAP2α expression was upregulated during hASCs adipogenic differentiation. LAP2α knockdown hindered adipogenesis, while LAP2α overexpression promoted adipogenic differentiation. Notably, LAP2α deficiency resisted HFD-induced obesity, improved glucose intolerance, mitigated insulin resistance, and prevented fatty liver development. Mechanistically, LAP2α knockdown attenuated signal transducer and activator of transcription 3 (STAT3) activation by reducing the protein level of phosphorylated STAT3. A STAT3 activator (Colivelin) counteracted the negative impact of LAP2α deficiency on hASCs adipogenic differentiation. Taken together, our current study established LAP2α as a crucial regulator of hASCs adipogenic differentiation, unveiling a new therapeutic target for obesity prevention.

Reactive Oxygen Species-Responsive Delivery of a Notch Inhibitor to Alleviate Nonalcoholic Steatohepatitis by Inhibiting Hepatic de Novo Lipogenesis and Inflammation.

With the increased prevalence of nonalcoholic steatohepatitis (NASH) in the world, effective pharmacotherapy in clinical practice is still lacking. Previous studies have shown that dibenzazepine (DBZ), a Notch inhibitor, could alleviate NASH development in a mouse model. However, low bioavailability, poor water solubility, and extrahepatic side effects restrict its clinical application. To overcome these barriers, we developed a reactive oxygen species (ROS)-sensitive nanoparticle based on the conjugation of bilirubin to poly(ethylene glycol) (PEG) chains, taking into account the overaccumulation of hepatic ROS in the pathologic state of nonalcoholic steatohepatitis (NASH). The PEGylated bilirubin can self-assemble into nanoparticles in an aqueous solution and encapsulate insoluble DBZ into its hydrophobic cavity. DBZ nanoparticles (DBZ Nps) had good stability, rapidly released DBZ in response to H2O2, and effectively scavenged intracellular ROS of hepatocytes. After systemic administration, DBZ Nps could accumulate in the liver of the NASH mice, extend persistence in circulation, and improve the bioavailability of DBZ. Furthermore, DBZ Nps significantly improved glucose intolerance, relieved hepatic lipid accumulation and inflammation, and ameliorated NASH-induced liver fibrosis. Additionally, DBZ Nps had no significant extrahepatic side effects. Taken together, our results highlight the potential of the ROS-sensitive DBZ nanoparticle as a promising therapeutic strategy for NASH.

The combination of berberine and isoliquiritigenin synergistically improved adipose inflammation and obesity-induced insulin resistance.

White adipose tissue accumulation and inflammation contribute to obesity by inducing insulin resistance. Herein, we aimed to screen the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for the treatment of insulin resistance and explore the potential synergistic mechanisms. Enzyme-linked immunosorbent assay and quantitative PCR were used to detect expression levels of inflammatory genes in vitro and in vivo. Western blotting and immunohistochemistry were performed to detect protein levels of the insulin signaling pathway and macrophage markers. The effects on obesity-induced insulin resistance were verified using a diet-induced obesity (DIO) mouse model. Interactions between macrophage and adipocyte were assessed using a cellular supernatant transfer assay. Berberine (BBR) and isoliquiritigenin (ISL) alleviated mRNA levels and secretion of inflammatory genes in vitro and in vivo. Furthermore, BBR acted synergistically with ISL to ameliorate obesity and dyslipidemia in DIO mice. Meanwhile, the combination treatment significantly improved glucose intolerance and insulin resistance and decreased M1-macrophage accumulation and infiltration in the adipose tissue. Mechanistically, co-treatment with BBR and ISL upregulated the protein expression of the IRS1-PI3K-Akt insulin signaling pathway, enhanced glucose uptake in adipocyte, and suppressed the interaction between macrophage and adipocyte. BBR and ISL were identified as the synergistic components of the herbal pair Coptidis Rhizoma-Glycyrrhizae Radix et Rhizoma for treating insulin resistance. The synergistic combination of BBR with ISL can be a promising and effective strategy for improving obesity-induced adipose inflammation and insulin resistance.

Fructooligosaccharides Intake during Pregnancy Improves Metabolic Phenotype of Offspring in High Fat Diet-Induced Obese Mice.

Obesity and metabolic diseases are closely associated, and individuals who become obese are also prone to type 2 diabetes and cardiovascular disorders. Gut microbiota is mediated by diet and can influence host metabolism and the incidence of metabolic disorders. Recent studies have suggested that improving gut microbiota through a fructooligosaccharide (FOS)-supplemented diet may ameliorate obesity and other metabolic disorders. Although accumulating evidence supports the notion of the developmental origins of health and disease, the underlying mechanisms remain obscure. ICR mice are fed AIN-93G formula-based cellulose -, FOS-, acetate-, or propionate-supplemented diets during pregnancy. Offspring are reared by conventional ICR foster mothers for 4 weeks; weaned mice are fed high fat diet for 12 weeks and housed individually. The FOS and propionate offspring contribute to suppressing obesity and improving glucose intolerance. Gut microbial compositions in FOS-fed mothers and their offspring are markedly changed. However, the beneficial effect of FOS diet on the offspring is abolished when antibiotics are administered to pregnant mice. The findings highlight the link between the maternal gut environment and the developmental origin of metabolic syndrome in offspring. These results open novel research avenues into preemptive therapies for metabolic disorders by targeting the maternal gut microbiota.

Epigallocatechin gallate suppresses mitotic clonal expansion and adipogenic differentiation of preadipocytes through impeding JAK2/STAT3-mediated transcriptional cascades

BackgroundMitotic clonal expansion (MCE) is a prerequisite for preadipocyte differentiation and adipogenesis. Epigallocatechin gallate (EGCG) has been shown to inhibit preadipocyte differentiation. However, the exact molecular mechanisms are still elusive. PurposeThis study investigated whether EGCG could inhibit adipogenesis and lipid accumulation by regulating the cell cycle in the MCE phase of adipogenesis and its underlying molecular mechanisms. Method3T3-L1 preadipocytes were induced to differentiate by a differentiation cocktail (DMI) and were treated with EGCG (25–100 μM) for 9, 18, and 24 h to examine the effect on MCE, or eight days to examine the effect on terminal differentiation. C57BL/6 mice were fed a high-fat diet (HFD) for three months to induce obesity and were given EGCG (50 or 100 mg/kg) daily by gavage. ResultsWe showed that EGCG significantly inhibited terminal adipogenesis and lipid accumulation in 3T3-L1 cells and decreased expressions of PPARγ, C/EBPα, and FASN. Notably, at the MCE phase, EGCG regulated the cell cycle in sequential order, induced G0/G1 arrest at 18 h, and inhibited the G2/M phase at 24 h upon DMI treatment. Meanwhile, EGCG regulated the expressions of cell cycle regulators (cyclin D1, cyclin E1, CDK4, CDK6, cyclin B1, cyclin B2, p16, and p27), and decreased C/EBPβ, PPARγ, and C/EBPα expressions at MCE. Mechanistic studies using STAT3 agonist Colivelin and antagonist C188–9 revealed that EGCG-induced cell cycle arrest in the MCE phase and terminal adipocyte differentiation was mediated by the inhibition of JAK2/STAT3 signaling cascades and STAT3 (Tyr705) nuclear translocation. Furthermore, EGCG significantly protected mice from HFD-induced obesity, reduced body weight and lipid accumulations in adipose tissues, reduced hyperlipidemia and leptin levels, and improved glucose intolerance and insulin sensitivity. Moreover, RNA sequencing (RNA-seq) analysis showed that the cell cycle changes in epididymal white adipose tissue (eWAT) were significantly enriched upon EGCG treatment. We further verified that EGCG treatment significantly reduced expressions of adipogenic factors, cell cycle regulators, and p-STAT3 in eWAT. ConclusionEGCG inhibits MCE, resulting in the inhibition of early and terminal adipocyte differentiation and lipid accumulation, which were mediated by inhibiting p-STAT3 nucleus translocation and activation.

Ectopic OR1A1 activation ameliorates hepatic lipid deposition through AMPK/SREBP-1/FASN pathway by three monoterpenes

Ectopic olfactory receptors, such as OR1A1, are involved in the regulation of lipid metabolism homeostasis. In this study, we investigated the effects of three monoterpenes, (+)-limonene, (−)-carvone and thymol, upon hepatic lipid deposition. Oral administration of (+)-limonene, (−)-carvone and thymol for 8 weeks in high-fat-diet (HFD)-fed mice significantly lowered the levels of fasting blood glucose, improved glucose intolerance, serum lipid parameters, adiposity, and hepatic steatosis. In LO2 cells, (+)-limonene, (−)-carvone and thymol increased the cyclic adenosine monophosphate (cAMP), induced protein kinase A (PKA) activity and phosphorylation of AMPK, downregulated the expression of SREBP-1 and FASN, and eventually led to a reduction in hepatic lipid deposition. Meanwhile, these beneficial effects in cultured LO2 cells were negated by OR1A1 knockdown and the adenylyl cyclase inhibitor SQ22536, respectively, indicating that they can ameliorate disorders of lipid metabolism through activating OR1A1 and subsequent AMPK/SREBP-1/FASN pathway, indicating OR1A1 as a potential target for counteracting hepatic steatosis.

Modulation of the gut microbiota alleviates insulin resistance in type 2 diabetic mice by daucosterol from Eleocharis dulcis peel

Daucosterol, a natural saponin from Eleocharis dulcis peel, exhibited anti-hyperglycemic properties. This study investigated daucosterol's effects on glycemic control, insulin resistance, and gut microbiota in type 2 diabetic mice. The results demonstrated that daucosterol treatment reduced fasting glucose, improved glucose intolerance and pancreatic islet damage. It decreased HOMA-IR and increased ISI, indicating enhanced insulin sensitivity. Daucosterol supplementation enriched gut microbiota diversity, including reducing Firmicutes and Desulfobacterota while increasing Bacteroidia. This involved an increase in Enterococcus, Akkermansia, Alistipes, Clostridium_sensu_stricto_1, and Odoribacter, coupled with decreased Aerococcus, Desulfovibrio, and Blautia, improved gut health. Uncultured_bacterium_g_Clostridium_sensu_stricto_1 and Bifidobacterium_pseudolongum were identified as major biomarkers. PICRUSt analysis revealed daucosterol improved the pathways of glycan biosynthesis and metabolism, lipid metabolism, carbohydrate metabolism, and some organismal systems. Therefore, daucosterol act as a potential anti-hyperglycemic agent, improving insulin resistance and optimizing gut microbiota to alleviate type 2 diabetes.

Oleanolic acid alleviates obesity-induced skeletal muscle atrophy via the PI3K/Akt signaling pathway.

Oleanolic acid (OA) is a pentacyclic triterpene with reported protective effects against various diseases, including diabetes, hepatitis, and different cancers. However, the effects of OA on obesity-induced muscle atrophy remain largely unknown. This study investigated the effects of OA on skeletal muscle production and proliferation of C2C12 cells. We report that OA significantly increased skeletal muscle mass and improved glucose intolerance and insulin resistance. OA inhibited dexamethasone (Dex)-induced muscle atrophy in C2C12 myoblasts by regulating the PI3K/Akt signaling pathway. In addition, it also inhibited expression of MuRF1 and Atrogin1 genes in skeletal muscle of obese mice suffering from muscle atrophy, and increased the activation of PI3K and Akt, thereby promoting protein synthesis, and eventually alleviating muscle atrophy. Taken together, these findings suggest OA may have potential for the prevention and treatment of muscle atrophy.

Maternal Phlorizin Intake Protects Offspring from Maternal Obesity-Induced Metabolic Disorders in Mice via Targeting Gut Microbiota to Activate the SCFA-GPR43 Pathway.

Maternal obesity increases the risk of obesity and metabolic disorders (MDs) in offspring, which can be mediated by the gut microbiota. Phlorizin (PHZ) can improve gut dysbiosis and positively affect host health; however, its transgenerational metabolic benefits remain largely unclear. This study aimed to investigate the potential of maternal PHZ intake in attenuating the adverse impacts of a maternal high-fat diet on obesity-related MDs in dams and offspring. The results showed that maternal PHZ reduced HFD-induced body weight gain and fat accumulation and improved glucose intolerance and abnormal lipid profiles in both dams and offspring. PHZ improved gut dysbiosis by promoting expansion of SCFA-producing bacteria, Akkermansia and Blautia, while inhibiting LPS-producing and pro-inflammatory bacteria, resulting in significantly increased fecal SCFAs, especially butyric acid, and reduced serum lipopolysaccharide levels and intestinal inflammation. PHZ also promoted intestinal GLP-1/2 secretion and intestinal development and enhanced gut barrier function by activating G protein-coupled receptor 43 (GPR43) in the offspring. Antibiotic-treated mice receiving FMT from PHZ-regulated offspring could attenuate MDs induced by receiving FMT from HFD offspring through the gut microbiota to activate the GPR43 pathway. It can be regarded as a promising functional food ingredient for preventing intergenerational transmission of MDs and breaking the obesity cycle.

Inhibitory effects of naringenin on estrogen deficiency-induced obesity via regulation of mitochondrial dynamics and AMPK activation associated with white adipose tissue browning

AimsPost-ovariectomy (OVX) changes in hormones induce obesity and white adipose tissue (WAT) inflammation. Increased energy expenditure via WAT browning is a novel therapeutic strategy for treating obesity. Naringenin (NAR) reduces inflammation and lipogenesis in obesity and attenuates estrogen deficiency-associated metabolic disorders; however, its role in WAT browning remains unclear. Materials and methodsWe investigated NAR ability to inhibit estrogen deficiency-associated obesity in vivo using a rat model and in vitro using 3T3-L1 adipocytes. Key findingsNAR significantly decreased the body weight and WAT mass of rats. O2 consumption, CO2 production, and energy expenditure were significantly lower in the OVX group than in the sham group, but NAR treatment reversed these effects of OVX. NAR treatment markedly improved glucose intolerance and lipid profiles as well as leptin, adiponectin, and irisin levels. NAR upregulated markers of browning and mitochondrial biogenesis in inguinal WAT. Moreover, it enhanced markers of mitochondrial fusion and inhibited fission via activating the AMP-activated protein kinase pathway. Similar results were observed in 3T3-L1 adipocytes. Moreover, NAR-induced mitochondrial biogenesis and fusion were suppressed by dorsomorphin (an AMP-activated protein kinase inhibitor). SignificanceNAR alleviates obesity and metabolic dysfunction through the induction of WAT browning achieved via the modulation of AMP-activated protein kinase-regulated mitochondrial dynamics in WATs. NAR supplementation may therefore represent a potential intervention for preventing postmenopausal adipose tissue dysregulation.

Genistein in combination with Chlorogenic acid ameliorates insulin resistance and oxidative stress in skeletal muscle of high-fat diet fed mice

Objectives: Increasing evidence has demonstrated that oxidative stress plays a significant role in the pathogenesis of muscle insulin resistance. The beneficial impacts of genistein (GEN) and chlorogenic acid (CGA) on insulin resistance have already been revealed. However, their combined effects on skeletal muscle oxidative stress and insulin resistance have not been completely understood. The aim of the present study was to determine the effect of GEN in combination with CGA on skeletal muscle insulin resistance in high-fat diet (HFD) fed C57BL/6 mice.
 Methods: C57BL/6 male mice were fed an HFD for 15 weeks. The mice were then divided into five groups: standard chow diet (SCD), HFD, HFD + GEN, HFD + CGA, and HFD + GEN + CGA for 10 weeks.
 Results: The findings indicated that single treatment with GEN or CGA, and with a stronger effect of GEN+CGA combined treatment, decreased body weight gain and improved glucose intolerance. Moreover, following treatment with GEN and CGA alone or in combination with further effect, the level of plasma and muscle triglyceride (TG) were reduced. Furthermore, the combination therapy of GEN and CGA with greater efficacy than the single treatments, could decrease several oxidative stress markers in the skeletal muscle. Treatment with GEN and CGA alone or in combination could increase the expression of NF-E2–related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P): Quinone Oxidoreductase 1 (NQO1).
 Conclusion: The data of this study suggest that the combination of GEN and CGA might ameliorate insulin resistance and reduce oxidative stress in the skeletal muscle of mice fed HFD.