Improved Glucose Tolerance Research Articles

Berberine Metabolites Stimulate GLP-1 Secretion by Alleviating Oxidative Stress and Mitochondrial Dysfunction.

Berberine (BBR) is a principal component of Rhizoma coptidis known for its therapeutic potential in treating diseases such as type 2 diabetes mellitus (T2DM) and obesity. Despite the trace levels of BBR in plasma, it's believed that its metabolites play a pivotal role in its biological activities. While BBR is recognized to promote GLP-1 production in intestinal L cells, the cytoprotective effects of its metabolites on these cells are yet to be explored. The present study investigates the effects of BBR metabolites on GLP-1 secretion and the underlying mechanisms. Our results revealed that, out of six BBR metabolites, berberrubine (BBB) and palmatine (PMT) significantly increased the production and glucose-stimulated secretion of GLP-1 in GLUTag cells. Notably, both BBB and PMT could facilitate GLP-1 and insulin secretion and enhance glucose tolerance in standard mice. Moreover, a single dose of PMT could markedly increase plasma GLP-1 and improve glucose tolerance in mice with obesity induced by a high-fat diet. In palmitic acid or TNF[Formula: see text]-treated GLUTag cells, BBB and PMT alleviated cell death, oxidative stress, and mitochondrial dysfunction. Furthermore, they could effectively reverse inflammation-induced inhibition of the Akt signaling pathway. In general, these insights suggest that the beneficial effects of orally administered BBR on GLP-1 secretion are largely attributed to the pharmacological activity of BBB and PMT by their above cytoprotective effects on L cells, which provide important ideas for stimulating GLP-1 secretion and the treatment of T2DM.

Empagliflozin alters lipid metabolism in the myocardium and liver in a prediabetes model with severe dyslipidemia.

Recent studies suggest that empagliflozin reduces total and cardiovascular mortality in both diabetic and nondiabetic subjects. Although the exact mechanism is unclear, it is understood to positively affect myocardial energetics, including the metabolism of ketone bodies, lipids, and fatty acids. In this study, we compared empagliflozin effects on lipid metabolism in the heart and liver in a prediabetic rat model with severe dyslipidemia. Wistar rats served as the control group, while hereditary hypertriglyceridemic (HHTg) rats were used as a nonobese, prediabetic model. Rats were treated with or without empagliflozin at a dose of 10mg/kg body weight (BW) for 8weeks. In HHTg rats, empagliflozin decreased body weight and adiposity, improved glucose tolerance, and decreased serum triacylglycerols (TAGs) (p < 0.001). Empagliflozin decreased the activity and gene expression of the lipogenic enzyme SCD-1 (p < 0.001) in the myocardium, which may have led to a decrease in the ectopic accumulation of TAGs and lipotoxic diacylglycerols and lysophosphatidylcholines (p < 0.001). Changes in the myocardial phosphatidylcholine/phosphatidylethanolamine ratio (p < 0.01) and in the fatty acid profile of myocardial phospholipids may have contributed to the antifibrotic effects of empagliflozin. The anti-inflammatory effects of empagliflozin were evidenced by an increased IL-10/TNFα ratio (p < 0.001), a marked decrease in arachidonic acid metabolites (20-HETE, p < 0.001), and an increase in PUFA metabolites (14,15-EETs, p < 0.001) in the myocardium. However, empagliflozin did not significantly affect either the concentration or utilization of ketone bodies. In the liver, empagliflozin decreased lipogenesis and the accumulation of TAGs and lipotoxic intermediates. Its effect on arachidonic acid metabolites and alterations in n-3 PUFA metabolism was less pronounced than in the myocardium. Our findings suggest that empagliflozin treatment in the heart and liver reduced the accumulation of neutral lipids and lipotoxic intermediates and altered the metabolism of n-3 PUFA. In the heart, empagliflozin altered arachidonic acid metabolism, which is likely associated with the anti-inflammatory and antifibrotic effects of the drug. We assume that these alterations in lipid metabolism contribute to the cardioprotective effects of empagliflozin in prediabetic states with severe dyslipidemia.

Encapsulation of telmisartan inside insulinoma-cell-derived extracellular vesicles outperformed biomimetic nanovesicles in modulating the pancreatic inflammatory microenvironment.

Diabetes mellitus (DM) is a chronic metabolic condition, characterized by hyperglycaemia, oxidative imbalance, pancreatic β-cell death, and insulin insufficiency. Angiotensin II (Ang II) increases oxidative stress, inflammation, and apoptosis, and Ang II type 1 receptor (AT1R) blockers (ARBs) can ameliorate inflammatory response and oxidative stress. However, like other small-molecule drugs, free ARBs show poor in vivo efficacy and dose-limiting toxicities. Hence, in this study, we developed nano-formulations of telmisartan (TEL), an ARB, by encapsulating it inside a murine insulinoma cell-derived extracellular vesicle (nanoTEL) and a bio-mimetic lipid nanovesicle (lipoTEL). Both nano-formulations showed spherical morphology and sustained release of TEL. In vitro, nanoTEL restored oxidative equilibrium, attenuated reactive oxygen species levels, enhanced the uptake of glucose analogue, and increased the expression of glucose transporter protein 4 better than lipoTEL. In a streptozotocin-induced murine model of diabetes, nanoTEL lowered blood glucose levels, improved glucose tolerance, and promoted insulin synthesis and secretion significantly better than lipoTEL. Moreover, nanoTEL was found superior in ameliorating the pancreatic inflammatory microenvironment by regulating NF-κBp65, HIF-1α, and PPAR-γ expression; modulating IL-1β, IL-6, tumor necrosis factor-α, IL-10, and IL-4 levels and inducing the polarization of macrophage from M1 to M2. Further, nanoTEL administration induced angiogenesis and promoted the proliferation of pancreatic cells to restore the structural integrity of the islets of Langerhans more efficiently than lipoTEL. These findings collectively suggest that nanoTEL outperforms lipoTEL in restoring the function of pancreatic β-cells by modulating the pancreatic inflammatory microenvironment and show potential for the treatment of DM.

Lactobacillus plantarum alleviates high-fat diet-induced obesity by altering the structure of mice intestinal microbial communities and serum metabolic profiles.

Obesity, which is always accompanied by disorders of lipid metabolism and dysbiosis of the gut microbiota, has become a global epidemic recognised by the World Health Organisation, necessitating innovative strategies and a globally accepted agreement on treating obesity and its related complications. Probiotics, as major active ingredients in many foods, offer potential as biological treatments for obesity prevention and management. Lactobacillus plantarum (L. plantarum) possesses a wide range of biological activities and is widely used to alleviate and ameliorate various diseases. This research demonstrated that Lactobacillus plantarum reduces the weight increase and fat build-up caused by a high-fat diet (HFD) in mice, while also improving glucose tolerance and insulin sensitivity in obese mice. Results indicated that L. plantarum effectively controlled the intestinal microbial community's structure, counteracted disruptions in gut flora caused by HFD, normalized the Firmicutes to Bacteroidota ratio (F/B), and decreased the prevalence of detrimental bacteria Desulfovibrio and Clostridia. Serum metabolomics findings indicate notable alterations in serum metabolites across various groups, notably the increased levels of Isoprothiolane and Inosine, key regulators of lipid metabolism disorders and enhancers of fat burning. These differential metabolites were mainly enriched in unsaturated fatty acid biosynthesis, sulfur metabolism, fatty acid biosynthesis, and purine metabolism. Consequently, we propose that L. plantarum has the potential to alter the gut microbial community's composition, positioning it as a promising option for obesity therapy.

Egg white-derived peptides reduced blood glucose in high-fat-diet and low-dose streptozotocin-induced type 2 diabetic mice via regulating the hepatic gluconeogenic signaling and metabolic profile.

Food proteins are considered an ideal source for the identification of bioactive peptides with the potential to intervene in nutrition-related chronic diseases such as cardiovascular disease, obesity, and diabetes. Egg white-derived peptides (EWPs) have been shown to improve glucose tolerance in insulin-resistant rats. However, underlying mechanisms are to be elucidated. Therefore, we hypothesized that EWP exerts a hypoglycemic effect by regulating hepatic glucose homeostasis. Our results showed that 7 weeks of EWP treatment reduced the fasting blood glucose in T2DM mice and the inhibition of the liver gluconeogenic pathway was involved in the mechanisms of actions. Using the untargeted metabolomics technique, we found that EWP treatment also altered the hepatic metabolic profile in T2DM mice, in which, the role of fatty acid esters of hydroxy fatty acids in mediating the hypoglycemic effect of EWPs might be pivotal.

Dietary supplementation with capsaicinoids alleviates obesity in mice fed a high-fat-high-fructose diet.

Capsaicinoids are the pungent compounds in chili peppers. The present study investigated the effect of capsaicinoids on obesity in mice induced by a high-fat-high-fructose diet. Thirty-two male C57BL/6J mice were randomly divided into four groups (n = 8) and fed one of the following diets, namely, a low-fat diet (LFD), a high-fat-high-fructose diet (HFF), an HFF + 0.015% capsaicinoids (LCP), and an HFF + 0.045% capsaicinoids (HCP), for 12 weeks. Results showed that capsaicinoids significantly reversed HFF-induced obesity. Supplementation with capsaicinoids improved glucose tolerance, reduced plasma lipids, and attenuated inflammation. Capsaicinoids also reduced hepatic lipid accumulation by upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In addition, capsaicinoids enhanced the production of fecal short-chain fatty acids (SCFAs) and increased the fecal excretion of lipids. Gut microbiota analysis revealed that capsaicinoids decreased the Firmicutes/Bacteroidetes ratio and beneficially reconstructed the microbial community. However, the effects of capsaicinoids on intestinal villus length and lipid tolerance were negligible. In conclusion, capsaicinoids effectively attenuated HFF-induced obesity and metabolic syndrome by favorably modulating lipid metabolism, improving SCFA production, and reshaping gut microbial structure.

Effects of Statin and Annatto-extracted Tocotrienol Supplementation on Glucose Homeostasis, Bone Microstructure, and Gut Microbiota Composition in Obese Mice.

This study examined the effects of tocotrienols (TT) in conjunction with statin on glucose homeostasis, bone microstructure, gut microbiome, and systemic and liver inflammatory markers in obese C57BL/6J mice. Forty male C57BL/6J mice were fed a high-fat diet (HFD) and assigned into four groups in a 2 (no statin vs. 120 mg statin/kg diet)×2 (no TT vs. 400 mg TT/kg diet) factorial design for 14 weeks. Statin and TT improved glucose tolerance only when each was given alone, and only statin supplementation decreased insulin resistance. Consistently, only statin supplementation decreased serum insulin levels and HOMA-IR. Pancreatic insulin was also increased with statin treatment. Statin and TT, alone or in combination, reduced the levels of serum IL-6, but only TT attenuated the increased serum leptin levels induced by a HFD. Statin supplementation increased bone area/total area and connectivity density at LV-4, while TT supplementation increased bone area/total area and trabecular number, but decreased trabecular separation at the distal femur. Statin supplementation, but not TT, reduced hepatic inflammatory cytokine gene expression. Neither TT supplementation nor statin supplementation statistically altered microbiome species evenness or richness. However, they altered the relative abundance of certain microbiome species. Most notably, both TT and statin supplementation increased the relative abundance of Lachnospiraceae UCG-006. TT and statin collectively benefit bone microstructure, glucose homeostasis, and microbial ecology in obese mice. Such changes may be, in part, associated with suppression of inflammation in the host.

Ethanolic Extract of Moringa oleifera Leaves Improves Glucose Tolerance, Glycogen Levels, and Liver Health in Alloxan-Induced Diabetic Rats

Ethanolic Extract of Moringa oleifera Leaves Improves Glucose Tolerance, Glycogen Levels, and Liver Health in Alloxan-Induced Diabetic Rats

Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring

ObjectiveMaternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. MethodsC57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses. ResultsMaternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFβ2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFβ2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFβ receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss. ConclusionsOur study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way.

Carotid body denervation improves hyperglycemia in obese mice.

The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPRb) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of Leprb, Trpm7, and Insr gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of Leprb, Trpm7, or Insr gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB Leprb, Trpm7, and Insr had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB Leprb, Trpm7, and Insr.NEW & NOTEWORTHY This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.

Integrating transcriptomics and network pharmacology to reveal the mechanisms of total Rhizoma Coptidis alkaloids against nonalcoholic steatohepatitis

Ethnopharmacological relevanceNon-alcoholic steatohepatitis (NASH) has emerged as a major cause of cirrhosis and hepatocellular carcinoma, posing a significant threat to public health. Rhizoma Coptidis, a traditional Chinese medicinal herb has been shown to have significant curative effects on liver diseases. Total Rhizoma Coptidis Alkaloids (TRCA) is a primarily alkaloid mixture extracted from Rhizoma Coptidis, and its constituents are widely accepted to have hepatoprotective effects. Aim of the studyThis work aimed to investigate the efficacy and potential mechanisms of TRCA in ameliorating NASH through both in vitro experiments and in vivo mouse models. Materials and methodsThe study employed a mice model induced by a high-fat diet (HFD) to evaluate the effectiveness and pharmacological mechanisms of TRCA in alleviating NASH. Transcriptomic sequencing and network pharmacology were used to explore the possible targets and mechanisms of TRCA to ameliorate NASH. Further validation was performed in free fatty acid (FFA)-induced human hepatocytes (LO2) and human hepatocellular carcinoma cells (HepG2). ResultsTRCA effectively ameliorated the main features of NASH such as lipid accumulation, hepatitis and hepatic fibrosis in the liver tissue of mice induced by HFD, as well as improved glucose tolerance and insulin resistance in mice. Combined with transcriptomic and network pharmacological analyses, 68 core targets associated with the improvement of NASH by TRCA were obtained. According to the KEGG results, the core targets were significantly enriched in the PI3K-AKT signaling pathway whereas TRCA ameliorated the aberrant down-regulation of the PI3K-AKT signaling pathway induced by HFD. Furthermore, the five highest-ranked genes were obtained by PPI network analysis. Moreover, our findings suggest that TRCA may impede the progression of HFD-induced NASH by regulating the expression of PPARG, MMP9, ALB, CCL2, and EGFR. ConclusionsTRCA can ameliorate HFD-induced liver injury by modulating aberrant downregulation of the PI3K-AKT signaling pathway. Key proteins such as PPARG, MMP9, ALB, CCL2, and EGFR may be critical targets for TRCA to ameliorate NASH. This finding supports using Rhizoma Coptidis, a well-known herbal medicine, as a potential therapeutic agent for NASH.

Pea protein hydrolysate reduces blood glucose in high-fat diet and streptozotocin-induced diabetic mice.

Food proteins have been recognized as an ideal source to release bioactive peptides with the potential to intervene nutrition related chronic diseases, such as cardiovascular diseases, obesity and diabetes. Our previous studies showed that pea protein hydrolysate (PPH) could suppress hepatic glucose production in hepatic cells via inhibiting the gluconeogenic signaling. Thus, we hypothesized that PPH could play the hypoglycemic role in vivo. In the present study, the mice model with type 2 diabetic mellitus (T2DM) was developed by high-fat diet and low dose of streptozotocin injections. PPH was administered orally with a dosage of 1000 mg/kg body weight for 9 weeks, followed by the downstream biomedical analyses. The results showed that the 9-week treatment of PPH could reduce fasting blood glucose by 29.6% and improve glucose tolerance in the T2DM mice. The associated mechanisms included suppression of the gluconeogenic pathway, activation of the insulin signaling and modulation of the renin angiotensin system in the liver of the diabetic mice. In addition, the levels of pro-inflammatory markers in both liver and serum were reduced by the PPH treatment. The hypoglycemic effect of PPH in T2DM mice was demonstrated in the present study. Findings from this study could provide rationale to incorporate PPH into functional foods or nutraceuticals for glycemic control.

The Antiobesity Effects and Potential Mechanisms of Theaflavins.

Theaflavins are the characteristic polyphenols in black tea which can be enzymatically synthesized. In this review, the effects and molecular mechanisms of theaflavins on obesity and its comorbidities, including dyslipidemia, insulin resistance, hepatic steatosis, and atherosclerosis, were summarized. Theaflavins ameliorate obesity potentially via reducing food intake, inhibiting pancreatic lipase to reduce lipid absorption, activating the adenosine monophosphate-activated protein kinase (AMPK), and regulating the gut microbiota. As to the comorbidities, theaflavins ameliorate hypercholesterolemia by inhibiting micelle formation to reduce cholesterol absorption. Theaflavins improve insulin sensitivity by increasing the signaling of protein kinase B, eliminating glucose toxicity, and inhibiting inflammation. Theaflavins ameliorate hepatic steatosis via activating AMPK. Theaflavins reduce atherosclerosis by upregulating nuclear factor erythropoietin-2-related factor 2 signaling and inhibiting plasminogen activator inhibitor 1. In randomized controlled trails, black tea extracts containing theaflavins reduced body weight in overweight people and improved glucose tolerance in healthy adults. The amelioration on the hyperlipidemia and the prevention of coronary artery disease by black tea extracts were supported by meta-analysis.

Effect of metformin nanoemulsion through AMP-activated protein kinase (AMPK)-mediated autophagy on diabetic neuropathy

Metformin (MET) is the preferred first-line treatment for patients with type 2 diabetes. However, the mechanism of diabetic peripheral neuropathy (DPN) is still unclear. To improve the oral utilization of metformin, a metformin nanoemulsion (MET-NE) was prepared to investigate its effects on DPN and its underlying mechanism. In this study, a DPN model was established in Wistar rats induced by streptozotocin (STZ). The diabetic rats were randomly divided into four groups: the diabetic model group (DM group), the metformin tablet-treated group (MET group), the metformin nanoemulsion-treated group (MET-NE group), and a normal control group consisting of five normal Wistar rats. All groups were administered the treatment orally for a period of 10 weeks. The findings of the study demonstrated that both MET and MET-NE significantly reduced blood glucose levels, glycated serum protein levels, food intake, and water intake in DM rats. It was also observed that MET-NE was more effective than MET in reducing blood glucose levels. Additionally, both MET and MET-NE treatments significantly increased the motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), and sensory nerve action potential (SNAP) amplitude in DM rats. Furthermore, these treatments improved mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), resulting in a reduced sensitivity to pain stimuli. Moreover, both MET and MET-NE treatments promoted the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) proteins, as well as increased the activity of autophagic proteins in the sciatic nerve. However, no significant differences were observed between MET and MET-NE treatments in terms of these effects. In conclusion, the MET-NE demonstrated a rapid decrease in blood glucose levels and improved glucose tolerance and metabolism, which was found to be superior to MET. Furthermore, MET-NE significantly improved the neurophysiological function and sciatic nerve pain threshold in DPN rats. These beneficial effects may be attributed to the regulation of AMPK-mediated autophagy by MET-NE.

Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.

Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age-related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell-specific deletion of mTOR reduced protein expression by 60-70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium-dependent dilation (EDD) in old mice, indicating an improvement in age-related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial-rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development.

Ferulic acid combined with different dietary fibers improve glucose metabolism and intestinal barrier function by regulating gut microbiota in high-fat diet-fed mice

Consuming whole grains contributes to the preservation of glucose homeostasis and supports intestinal health, primarily attributed to the presence of functional components like polyphenols and dietary fiber. However, it is not well understood how the combined influence of cereal polyphenols and dietary fiber could benefit the glucose metabolism and alter the gut microbiota. Our results showed that compared to ferulic acid alone, ferulic acid combined with arabinoxylan or β-glucan could significantly improve glucose tolerance and maintain intestinal homeostasis in high-fat diet-fed mice. Ferulic acid combined with β-glucan significantly increased serum GLP-1 level and tight junction proteins expression in colon. Ferulic acid combined arabinoxylan increased the abundance of Bifidobacterium and Faecalibaculum. Ferulic acid combined with β-glucan increased the abundance of Akkermansia and norank_f_Muribaculaceae, which were negatively correlated with impaired glucose tolerance. Therefore, ferulic acid combined with arabinoxylan or β-glucan ameliorates glucose metabolism and protects intestinal barrier integrity by regulating gut microbiota.

Parental cardiorespiratory fitness influences early life energetics and metabolic health.

High cardiorespiratory fitness (CRF) is associated with a reduced risk of metabolic disease and is linked to superior mitochondrial respiratory function. This study investigated how intrinsic CRF affects bioenergetics and metabolic health in adulthood and early life. Adult rats selectively bred for low and high running capacity [low capacity runners (LCR) and high capacity runners (HCR), respectively] underwent metabolic phenotyping before mating. Weanlings were evaluated at 4-6 wk of age, and whole body energetics and behavior were assessed using metabolic cages. Mitochondrial respiratory function was assessed in permeabilized tissues through high-resolution respirometry. Proteomic signatures of adult and weanling tissues were determined using mass spectrometry. The adult HCR group exhibited lower body mass, improved glucose tolerance, and greater physical activity compared with the LCR group. The adult HCR group demonstrated higher mitochondrial respiratory capacities in the soleus and heart compared with the adult LCR group, which coincided with a greater abundance of proteins involved in lipid catabolism. HCR and LCR weanlings had similar body mass, but HCR weanlings displayed reduced adiposity. In addition, HCR weanlings exhibited better glucose tolerance and higher physical activity levels than LCR weanlings. Higher respiratory capacities were observed in the soleus, heart, and liver tissues of HCR weanlings compared with LCR weanlings, which were not owed to greater mitochondrial content. Proteomic analyses indicated a greater potential for lipid oxidation in the contractile muscles of HCR weanlings. In conclusion, offspring born to parents with high CRF possess an enhanced capacity for lipid catabolism and oxidative phosphorylation, thereby influencing metabolic health. These findings highlight that intrinsic CRF shapes the bioenergetic phenotype with implications for metabolic resilience in early life.NEW & NOTEWORTHY Inherited cardiorespiratory fitness (CRF) influences early life bioenergetics and metabolic health. Higher intrinsic CRF was associated with reduced adiposity and improved glucose tolerance in early life. This metabolic phenotype was accompanied by greater mitochondrial respiratory capacity in skeletal muscle, heart, and liver tissue. Proteomic profiling of these three tissues further revealed potential mechanisms linking inherited CRF to early life metabolism.

The secreted peptide BATSP1 promotes thermogenesis in adipocytes

Although brown adipose tissue (BAT) has historically been viewed as a major site for energy dissipation through thermogenesis, its endocrine function has been increasingly recognized. However, the circulating factors in BAT that play a key role in controlling systemic energy homeostasis remain largely unexplored. Here, we performed a peptidomic analysis to profile the extracellular peptides released from human brown adipocytes upon exposure to thermogenic stimuli. Specifically, we identified a secreted peptide that modulates adipocyte thermogenesis in a cell-autonomous manner, and we named it BATSP1. BATSP1 promoted BAT thermogenesis and induced browning of white adipose tissue in vivo, leading to increased energy expenditure under cold stress. BATSP1 treatment in mice prevented high-fat diet-induced obesity and improved glucose tolerance and insulin resistance. Mechanistically, BATSP1 facilitated the nucleocytoplasmic shuttling of forkhead transcription factor 1 (FOXO1) and released its transcriptional inhibition of uncoupling protein 1 (UCP1). Overall, we provide a comprehensive analysis of the human brown adipocyte extracellular peptidome following acute forskolin (FSK) stimulation and identify BATSP1 as a novel regulator of thermogenesis that may offer a potential approach for obesity treatment.

Skeletal Muscle Gene Expression Signatures of Obese High and Low Responders to Endurance Exercise Training.

Exercise training is known to improve glucose tolerance and reverse insulin resistance in people with obesity. However, some individuals fail to improve or even decline in their clinical traits following exercise intervention. This study focused on gene expression and DNA methylation signatures in skeletal muscle of low (LRE) and high responders (RES) to 8 weeks of supervised endurance training. We performed skeletal muscle gene expression and DNA methylation analyses in LRE and RES before and after exercise intervention. Additionally, we applied the least absolute shrinkage and selection operator (LASSO) approach to identify predictive marker genes of exercise outcome. We show that the two groups differ markedly already before the intervention. RES were characterized by lower expression of genes involved in DNA replication and repair, and higher expression of extracellular matrix (ECM) components. The LASSO approach identified several novel candidates (eg, ZCWPW2, FOXRED1, STK40) that have not been previously described in the context of obesity and exercise response. Following the intervention, LRE reacted with expression changes of genes related to inflammation and apoptosis, RES with genes related to mitochondrial function. LRE exhibited significantly higher expression of ECM components compared to RES, suggesting improper remodeling and potential negative effects on insulin sensitivity. Between 45% and 70% of differences in gene expression could be linked to differences in DNA methylation. Together, our data offer an insight into molecular mechanisms underlying differences in response to exercise and provide potential novel markers for the success of intervention.

Thrombospondin1 antagonist peptide treatment attenuates obesity-associated chronic inflammation and metabolic disorders in a diet-induced obese mouse model

Thrombospondin1 (TSP1) is a multifunctional matricellular protein. Previously, we demonstrated that TSP1 plays a pivotal role in obesity-related inflammation and insulin resistance (IR) by modulating macrophage accumulation and activation in adipose tissue. Moreover, in our in vitro studies, a CD36-derived peptide, functioning as a TSP1 antagonist, effectively inhibited TSP1-induced proinflammatory macrophage activation. However, whether this CD36 peptide can inhibit obesity-induced inflammation and IR in vivo is unknown and determined in this study in a high fat diet-induced obese mouse model (DIO). CD36 peptide or control peptide was intraperitoneally administered into the established obese mice triweekly for 6 weeks. We found that CD36 peptide treatment didn’t affect obesity or weight gain but significantly reduced proinflammatory cytokine production systemically and in visceral fat tissue. Adipose tissue exhibited fewer crown-like structures and reduced macrophage infiltration. CD36 peptide treatment also attenuated the proinflammatory phenotype of bone marrow derived macrophages from obese mice. Furthermore, CD36 peptide treatment improved glucose tolerance and insulin sensitivity, and mitigated obesity-related fatty liver disease and kidney damage. Collectively, this study suggests that the CD36 peptide, as a TSP1 antagonist, shows promise as a novel therapeutic approach for managing obesity-related metabolic disorders.