Search Results (131)

Succinate, a tricarboxylic acid (TCA) cycle intermediate, is the essential signal molecule that links metabolic signals and inflammation. Dietary succinate supplementation has been reported to prevent obesity induced by a high-fat diet (HFD). However, the underlying mechanism remains elusive. Here, we found that dietary succinate elevated the serum succinate levels. Meanwhile, we found succinate increased methyltransferaselike 3 (METTL3) protein expression in brown adipocytes, thereby elevating N⁶-methyladenosine (m⁶A) levels in Hypoxia-inducible factor1-alpha (Hif1a) mRNA. Hif1a mRNA is recognized by the m⁶A-binding protein YTH domain-containing family protein 1 (YTHDF1), facilitating HIF1A protein expression. HIF1A activates the transcription of thermogenic genes, ultimately increasing brown adipose energy expenditure. Together, our research provided new insights into the effect of succinate on m⁶A modification in brown adipose tissue thermogenesis. Full article

Purpose: Obesity is a global public health issue, and natural products that promote white fat browning and enhance thermogenesis to consume energy represent promising strategy for addressing this problem. Forsythoside A (FTA) is key bioactive constituent isolated from the fruit of Forsythia suspensa. It has been reported that FTA can alleviate metabolic disorders such as hepatic lipid accumulation induced by high-fat diet (HFD). However, research on the role of FTA in alleviating obesity by promoting white fat browning remains scarce. Materials and Methods: We intervened in diet-induced obesity (DIO) mice and differentiated 3T3-L1 cells with FTA and detected thermogenic indices and the expression of thermogenesis-related genes under the guidance of network pharmacology. Mechanistically, molecular docking combined with molecular biology techniques was employed to verify the affinity of pathway-related proteins, and the AMPK inhibitor (BML-275) was used to intervene in 3T3-L1 cells to assist in demonstrating the main pathway through which FTA stimulates white fat browning. Results: FTA significantly attenuated lipid accumulation in both in vivo and in vitro models. Gene Ontology (GO) enrichment analysis revealed that FTA may promote white adipocyte browning and mitochondrial thermogenesis. Consistent with improved energy metabolism, FTA treatment increased oxygen consumption and carbon dioxide production in mice, while maintaining the respiratory exchange ratio (RER) at approximately 0.7. In vitro, FTA enhanced cellular oxygen consumption rate (OCR) and mitochondrial density. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis combined with molecular docking identified the AMPK signaling cascade as a key potential pathway mediating FTA action. Molecular biology assays further confirmed that FTA promotes AMPK phosphorylation and activates the canonical thermogenic downstream PGC-1α/UCP1 pathway. Consistently, inhibition of AMPK with BML-275 abolished the beneficial effects of FTA in 3T3-L1 adipocytes. Conclusions: This study reveals that FTA enhances white fat browning via the AMPK pathway while increasing thermogenesis in adipose tissue. Full article

GLP-1 receptor agonists and dual GLP-1/GIP agonists have significantly transformed the treatment of obesity, enabling clinically meaningful weight reduction and improvements in cardiometabolic parameters. However, clinical trial data indicate that cessation of therapy is associated with biologically driven weight regain and a partial loss of metabolic benefits. This phenomenon underscores the chronic nature of obesity and the limited durability of effects achieved through pharmacotherapy alone. Nevertheless, structured clinical frameworks describing how to maintain satiety and metabolic stability after GLP-1/GIP dose reduction or discontinuation remain limited. The aim of this narrative review is to discuss the mechanisms underlying weight regain following dose reduction or discontinuation of GLP-1/GIP pharmacotherapy and to present strategies supporting long-term metabolic stabilisation. Weight regain is driven in part by persistent metabolic adaptations, including a reduction in resting energy expenditure (adaptive thermogenesis), alterations in the hunger–satiety axis (increased ghrelin, reduced leptin signalling), and potentially incomplete restoration of adipose tissue and liver-related metabolic function, although direct evidence in this specific setting remains limited. Weight loss is often accompanied by a reduction in fat-free mass, which further lowers energy expenditure and increases susceptibility to a positive energy balance after treatment cessation. It remains unclear whether pharmacological suppression of appetite results in sustained normalisation of endogenous satiety regulation after treatment cessation, and its effects on gut microbiota function remain uncertain. In clinical practice, key priorities include preserving muscle mass (adequate protein intake, resistance training), maintaining dietary nutrient density, stabilising postprandial glycaemia, and ensuring sufficient intake of fermentable fibre to support short-chain fatty acid production and gut–brain signalling. GLP-1/GIP pharmacotherapy should be viewed as a component of an integrated model of obesity treatment. We propose that long-term weight stabilisation may require a transition from pharmacologically induced satiety to satiety supported by diet quality, preserved fat-free mass, and metabolic stability. Further research is needed to define optimal post-treatment strategies and to identify patients in whom therapy can be safely reduced or discontinued. This transition should be regarded as a conceptual framework and forward-looking hypothesis requiring validation in prospective studies. Full article

Adipose tissues (ATs) are dynamic and heterogeneous organs divided into three distinct categories, including white, beige, and brown ATs. Collectively, they contribute to systemic energy homeostasis in various ways. White adipocytes primarily store excess energy, whereas brown and beige adipocytes dissipate energy as heat through non-shivering thermogenesis. Recent advances in multi-omics technologies have transformed our understanding of adipocyte biology, enabling comprehensive interrogation of transcriptional, epigenetic, proteomic, and metabolomic networks that define adipocyte identity and function. Transcriptomic studies reveal distinct gene signatures underlying thermogenic activation and lineage commitment, while epigenomic profiling highlights regulatory elements that orchestrate adipocyte plasticity, particularly the inducible browning of white fat. Proteomic and metabolomic analyses further uncover mitochondrial remodeling, lipid turnover pathways, and metabolite, hormone interactions that regulate thermogenic capacity and metabolic health. Integrating these multi-layered datasets provides systems-level insights into the roles of environmental cues, such as diet and temperature, and endogenous factors, including hormonal signaling, circadian rhythms, and genetic background, in reshaping adipocyte phenotypes and influencing whole-body metabolism. Multi-omics approaches are increasingly identifying potential novel biomarkers and therapeutic targets aiming to enhance the activity of brown and beige adipocyte to combat obesity and metabolic disorders. Overall, these technologies provide a powerful framework for elucidating the complexity of ATs and advancing precision strategies for metabolic disease management and prevention. Full article

Obesity, driven by chronic energy imbalance, has become a major global health burden and is strongly associated with metabolic disorders, including diabetes, hypertension, and cardiovascular disease. Conventional pharmacotherapies often exhibit limited long-term efficacy and are accompanied by undesirable side effects, highlighting the urgent need for safer and more sustainable strategies. Browning of White adipose tissue (WAT)—a process in which white adipocytes acquire brown fat-like thermogenic characteristics—has emerged as a promising approach to enhance energy expenditure and counteract obesity. Increasing evidence demonstrates that various diets and naturally occurring dietary bioactive compounds can effectively induce WAT browning through diverse molecular pathways. Among these, AMPK-, PPAR-, SIRT-, TRP channel-, β3-adrenergic-, and FGF21-related signaling cascades represent the major regulatory hubs linked to mitochondrial biogenesis, lipid metabolism, and thermogenesis. This review summarizes recent advances in diet-induced WAT browning, with particular emphasis on key dietary ingredients, their molecular targets, mechanistic pathways, and metabolic benefits. By integrating findings from in vitro studies, animal models, and emerging translational research, we provide updated insights that may guide the development of novel nutritional interventions, functional foods, and therapeutic strategies for obesity prevention and management. Full article

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. We have reported that local administration of the sEH inhibitor, t-TUCB, to the endogenous interscapular BAT (iBAT) of diet-induced obese mice decreased serum triglycerides and enhanced the expression of essential genes associated with lipid metabolism. Here, the effects of sEH inhibition by t-AUCB were assessed on human brown adipocyte (HuBr) differentiation and in nude mice transplanted with t-AUCB-treated HuBr. HuBr cells were differentiated with t-AUCB (1–10 µM) or the vehicle (0.1% DMSO). HuBr differentiated with t-AUCB at 5 μM (AUCB 5) or DMSO was mixed with matrix gel and transplanted into the nude mice. The mice were then fed a high-fat diet for eight weeks. The mice receiving AUCB 5-treated HuBr exhibited markedly reduced lipid accumulation in the iBAT compared with DMSO or matrix-only controls, along with increased protein expression of thermogenic PGC1α and UCP1, fatty acid transporter CD36, and CPT1A in the iBAT, while the NFκB inflammatory pathways were suppressed in both the AUCB 5 and DMSO groups. Moreover, the PGC1α and CPT1A protein levels were elevated, and the adipocyte sizes were decreased in the epididymal white adipose tissue of the AUCB 5 group. Our findings indicate that the transplantation of HuBr treated with AUCB 5 may stimulate thermogenesis, enhance lipid metabolism, and reduce inflammation in iBAT. Full article

Obesity is a major global health concern, being associated with insulin resistance and multiple metabolic disorders. Gremlin 1 (GREM1), a bone morphogenetic protein (BMP) antagonist, is increasingly recognized as a key regulator of adipose tissue dysfunction and impaired thermogenesis in obesity. Orlistat, a lipase inhibitor that reduces dietary fat absorption, is one of the most commonly used pharmacological agents for obesity management. White tea has demonstrated antioxidant and anti-obesity properties in experimental models. The aim of this study was to evaluate the effects of white tea on metabolic parameters (HOMA-IR, BMP4, Gremlin1) and GREM1 expression in rats made obese by a high-fat diet (HFD). A total of 40 male Sprague-Dawley rats were randomized into five groups: a standard diet group (STD); a high-fat diet group (HFD); an HFD + orlistat group (ORL); an HFD + 50 mg/kg white tea group (WT50); and an HFD + 150 mg/kg white tea group (WT150). Obesity was induced by feeding the rats a 45% high-fat diet for 3 weeks. Serum insulin, glucose and HOMA-IR levels were measured. Levels of GREM1 and BMP4 in serum and retroperitoneal adipose tissue were assessed. White tea supplementation significantly reduced weight gain and HOMA-IR compared to the HFD group. GREM1 mRNA expression in visceral adipose tissue decreased markedly in the WT50 and WT150 groups (p = 0.002 and p = 0.017, respectively). Serum GREM1 levels were significantly lower in the white tea-treated groups than in the HFD group (p = 0.011). Tissue BMP4 levels were only significantly reduced in the WT50 group (p = 0.005), indicating a non-linear dose–response pattern. There was a negative correlation between serum BMP4 levels and weight gain (rho = −0.440, p = 0.015). White tea was associated with improvements in metabolic parameters in an HFD-induced obesity model. These observations suggest a potential association between white tea bioactives and adipose tissue-related molecular pathways implicated in obesity. Given the short intervention duration and the exploratory design of this animal study, the findings should be interpreted with caution. Full article

Background: The browning of white adipose tissue for thermogenesis is an effective strategy for combating obesity. The formation of beige adipocytes is reversible, making their maintenance a key therapeutic target. Rutin has been shown to promote the transition from white to beige adipocytes. It remains unclear whether rutin can prevent the reversion of beige adipocytes to white adipocytes and what mechanisms underlie this process. Objectives: This study aims to determine whether rutin can sustain the thermogenic phenotype of beige adipocytes and to elucidate its mechanism. Methods: We established a beige adipocyte model with CL-316, 243(CL) in vitro. A white adipocyte model was created by CL withdrawal after 3 days. Then, we conducted a co-intervention with CL and rutin, as well as sustained rutin intervention on beige adipocytes following CL withdrawal. In vivo, we utilized a C57BL/6 mouse model, including ND, high-fat diet (HFD), and HFD + Rutin groups. The mice were further divided into Cold and −Cold groups, with the former undergoing 7 days of exposure to 4 °C and the latter experiencing 10 days of 22–24 °C. Rutin was administered continuously until the conclusion of the experiment. Results: Rutin consistently ameliorates metabolic disorders and prevents the expansion of adipose tissue. It concomitantly suppresses mitochondrial autophagy during beige induction, upregulates thermogenic markers in brown adipocytes, and safeguards the mitochondrial-related functional indicators. Conclusions: In summary, rutin obstructs the transformation of beige adipocytes into white adipocytes and concomitantly suppresses mitochondrial autophagy, thereby continuously improving obesity induced by a high-fat diet. Full article

Background/Objectives: The increase in the global prevalence of obesity has created a need for safe and effective preventive strategies. Probiotics have gained attention for their potential to modulate the gut microbiota and improve metabolic health. In this study, we examined the anti-obesity effects of Lactiplantibacillus plantarum strain 06CC2 (LP06CC2) in a mouse model of mild diet-induced obesity that mimics early-stage metabolic imbalance without significant body weight gain. Methods: Mice were fed a high-fat diet for 8 weeks, with or without LP06CC2 supplementation. Biochemical assays were used to determine the metabolic effects of LP06CC2, and 16S rRNA sequencing was performed to analyze the gut microbiota. Results: LP06CC2 attenuated epididymal fat accumulation and adipocyte hypertrophy, improved the gene expression profiles related to lipid metabolism and inflammation in adipose tissue, and reduced early hepatic steatosis. 16S rRNA sequencing revealed that LP06CC2 modulated the diversity and composition of the gut microbiota, notably suppressing HFD-induced increases in Mucispirillum schaedleri and other taxa associated with inflammation. LP06CC2-treated mice exhibited higher alpha diversity and partial restoration of their microbial profiles toward those of the normal diet-fed animals. LP06CC2 also downregulated pro-inflammatory cytokines and genes related to lipid uptake while modulating markers of thermogenesis and lipolysis. Conclusions: These findings indicate that LP06CC2 can prevent fat accumulation and gut dysbiosis in the pre-obese state, supporting its potential as a functional food ingredient for early intervention in obesity. Further human trials and studies using advanced obesity models are warranted to confirm its efficacy and elucidate its underlying mechanisms of action. Full article

Background: Korean red ginseng marc (KRGM), a by-product of Korean red ginseng (KRG) processing, retains numerous bioactive compounds with potential health benefits. Among them, KRGM-derived gintonin (KRGM-gintonin) is particularly rich in lysophosphatidic acid (LPA) and phospholipids, which have been linked to favorable metabolic effects. This study investigated the anti-obesity potential of KRGM-gintonin in high-fat diet (HFD)–induced obese mice, focusing on its impact on weight regulation, liver health, and energy metabolism. Methods: Obese mice (C57BL/6N, 4 weeks, male) were administered KRGM-gintonin either orally for 25 weeks or through intracerebroventricular (ICV) injection for 14 weeks. Throughout the study, body weight, food intake, metabolic parameters, liver tissue morphology, behavioral performance, and thermogenic gene expression were carefully monitored to evaluate treatment effects. Results: Both oral and ICV administration of KRGM-gintonin significantly reduced body weight gain in HFD-fed obese mice without altering food intake, suggesting enhanced energy expenditure. Treatment through both routes improved physical performance and increased metabolic rate. Oral KRGM-gintonin also alleviated fatty liver, reduced plasma triacylglycerol and cholesterol levels, and promoted the expression of thermogenesis-related genes, including uncoupling protein-1 (UCP1) and hormone-sensitive lipase (HSL), specifically in brown adipose tissue. Additionally, oral administration lowered tumor necrosis factor-α (TNF-α) expression, indicating anti-inflammatory activity and further supporting metabolic health. Conclusions: KRGM-gintonin exerts strong anti-obesity effects, primarily through oral administration, with supportive evidence from central ICV action. These findings highlight its potential as a functional therapeutic agent for obesity prevention and management, offering dual benefits in metabolic regulation and inflammation control. Full article

Polyphenols have been widely recognized for their potential anti-obesity effects. This study aimed to evaluate the impact of a polyphenol compound-epigallocatechin-3-gallate, quercetin, and rutin (EQR) on obesity-related parameters and gut microbiota composition. After four weeks of high-fat diet (HFD) induction, the obese Wistar male rats received EQR treatment for an additional four weeks. EQR supplementation significantly reduced body weight gain, feed efficiency, adipose tissue accumulation, and liver lipid content in obese rats. Additionally, it enhanced fecal short-chain fatty acid (SCFA) levels and modulated gut microbiota composition. Specifically, EQR treatment significantly induced Fusobacteria, Fusobacteriaceae, Christensenellaceae, Christensenellaceae R-7 group, Lachnoclostridium, Enterorhabdus, and Parvibacter levels and reduced Deferribacteres and Mucispirillum levels. Gene expression analysis in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) revealed that EQR upregulated the expression of liver PPAR-α, WAT SIRT-1, and BAT PGC-1α, while downregulating liver PPAR-γ, liver FATP-1, and WAT FAS, indicating its role in promoting fatty acid oxidation and thermogenesis, as well as suppressing lipid synthesis and transport. In conclusion, EQR demonstrated significant anti-obesity effects by modulating gut microbiota and lipid metabolism, suggesting its potential as a functional ingredient for obesity management. Full article

The kallikrein–kinin system and its B1 and B2 receptors are key regulators in metabolic disorders such as obesity, diabetes, and insulin resistance. Obesity, a chronic and multifactorial condition often associated with comorbidities like type 2 diabetes and dyslipidemia, remains poorly understood at the metabolic level. The kinin B2 receptor (B2R) is involved in blood pressure regulation and glucose metabolism, promoting glucose uptake in skeletal muscle via bradykinin. Studies in B2R-KO mice demonstrate that the absence of this receptor predisposes animals to glucose intolerance under a high-fat diet and impairs adaptive thermogenesis, indicating a protective role for B2R in metabolic homeostasis and insulin sensitivity. In contrast, the kinin B1 receptor (B1R) is inducible under pathological conditions and is activated by kinin metabolites. Mouse models lacking B1R exhibit improved metabolic profiles, including protection against high-fat diet-induced obesity and insulin resistance, enhanced energy expenditure, and increased leptin sensitivity. B1R inactivation in adipocytes enhances insulin responsiveness and glucose tolerance, supporting its role in the development of insulin resistance. Moreover, B1R deficiency improves energy metabolism and thermogenic responses to adrenergic and cold stimuli, promoting the activation of brown adipose tissue and the browning of white adipose tissue. Collectively, these findings suggest that B1R and B2R represent promising therapeutic targets for the treatment of metabolic disorders. Full article

This study aims to evaluate the anti-obesity effects of Ashwagandha (Withania somnifera, AS), Chrysanthemum zawadskii Herbich var. latilobum (Maxim.) Kitamura (C), and their combination (AS:C = 3:1, ASC) in high-fat-diet (HFD)-induced obese animal models. Key metabolic parameters, including body weight, lipid metabolism, adipogenesis, energy expenditure, and glucose homeostasis, were assessed. HFD-fed mice were supplemented with AS25, C25, or ASC at different concentrations (ASC25, ASC50, and ASC100). Body weight, food efficiency ratio (FER), organ and adipose tissue weights were measured. Serum biochemical markers, including lipid profiles, glucose, insulin, and liver enzymes, were analyzed. Western blot analysis was conducted to assess the expression of key proteins involved in adipogenesis, lipogenesis, lipolysis, and energy metabolism. ASC complex supplementation, particularly at higher doses (ASC100), significantly reduced body weight gain, liver weight, and total white adipose tissue (WAT) accumulation. ASC complex groups exhibited improved lipid profiles, with reductions in triglycerides, total cholesterol, and low-density lipoprotein (LDL). Serum glucose, insulin, and HbA1c levels were significantly reduced, suggesting improved insulin sensitivity. Western blot analysis revealed that ASC complex supplementation downregulated key adipogenic markers, including PPARγ, C/EBPα, and SREBP1c, while enhancing adiponectin levels. ASC complex also promoted energy metabolism by increasing the phosphorylation of AMPK and UCP1 expression, indicative of enhanced thermogenesis and lipid oxidation. ASC complex supplementation demonstrates a potent anti-obesity effect by modulating adipogenesis, lipid metabolism, and energy expenditure. The findings suggest that ASC complex could serve as a promising natural therapeutic strategy for obesity and metabolic disorders. Further research, including clinical trials, is warranted to validate its efficacy and safety in human populations. Full article

Obesity, marked by excessive white adipose tissue (WAT) accumulation, worsens metabolic disorders, and inducing WAT browning is a promising therapy. This study examined the synergistic effects of moderate-intensity aerobic training and resveratrol (RES) on WAT browning and its underlying mechanisms in obese male rats. Methods: Male Sprague Dawley rats were divided into a normal diet control group (n = 8) and a high-fat-diet modeling group (n = 32), with the rats in the latter group being further divided randomly in groups of eight into a high-fat group; a high-fat, exercise group; a high-fat, RES group; and a high-fat, exercise-combined-with-RES group. The rats in the exercise intervention groups underwent moderate-intensity aerobic treadmill exercise for one hour daily, six days a week, while those in the RES groups received a 50 mg/kg/d RES solution via gavage before exercise, once daily, six days a week. Both interventions lasted eight weeks. Results: The combined intervention synergistically suppressed weight gain and visceral fat accumulation. WAT browning was enhanced, evidenced by upregulated UCP1 and CIDEA expression. Mitochondrial biogenesis was activated via the SIRT1-PGC-1α-NRF-1-TFAM pathway, accompanied by elevated mitochondrial enzyme activity and improved lipid mobilization (reduced serum free fatty acids and triglycerides). Conclusions: The combination of aerobic exercise and RES promotes WAT browning and lipolysis by enhancing mitochondrial biogenesis and stimulating mitochondrial thermogenesis through the modulation of the SIRT1-PGC-1α-NRF-1-TFAM pathway. Full article

Background: Whether intestinal epithelial cells can regulate distant adipose tissue remains a mystery. Methods: Cold-stimulated intestinal epithelial cell-derived exosomes (Cold IEC-Exo) play a pivotal role in enhancing adipose thermogenesis and metabolic homeostasis, as demonstrated in this study. Results: IEC-Exo can accumulate in adipose tissue. Compared with IEC-Exo derived from room temperature mice (RT IEC-Exo), Cold IEC-Exo significantly enhanced the thermogenesis of adipose. In vitro, Cold IEC-Exo directly stimulated thermogenesis in primary adipocytes by elevating oxygen consumption rate, proton leak, and fatty acid uptake, with no effect on glucose uptake. Small RNA sequencing identified miR-674-3p as a key mediator enriched in Cold IEC-Exo. miR-674-3p mimicry replicated Cold IEC-Exo effects, augmenting Ucp1 expression, mitochondrial uncoupling, and fatty acid utilization in adipocytes. Local overexpression of miR-674-3p in BAT and sWAT via AAV in vivo enhanced thermogenesis and attenuated diet-induced glucose intolerance. Conclusions: These findings establish that Cold IEC-Exo, via miR-674-3p transfer, drive adipose thermogenic activation and mitigate metabolic dysfunction, highlighting their therapeutic potential in obesity-related disorders. Full article