Treatment Of Metabolic Diseases Research Articles

Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease.

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease.

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Ramadan Fasting in Individuals with Metabolic Dysfunction-Associated Steatotic Liver Disease, Liver Transplant, and Bariatric Surgery: A Narrative Review.

Metabolic dysfunction-associated steatotic liver disease is a growing worldwide pandemic. A limited number of studies have investigated the potential effect of Ramadan fasting on metabolic dysfunction-associated steatotic liver disease (MASLD). There is no single medication for the treatment of MASLD. There is a growing interest in dietary intervention as potential treatment for metabolic diseases including MASLD. The aim of this study was to discuss the epidemiology, pathogenesis, and risk factors of MASLD and the potential effects of Ramadan fasting on MASLD, liver transplant, and bariatric surgery. We searched PubMed and SCOPUS databases using different search terms. The literature search was based on research studies published in English from the year 2000 to the 2024. Thirty-two studies were included in this review. Ramadan fasting reduced body weight and improved lipid profile, anthropometric indices, fasting plasma glucose, plasma insulin, and inflammatory cytokines. Ramadan fasting improved risk factors of nonalcoholic fatty liver disease and might improve MASLD through weight reduction. However, further studies are needed to assess the safety and effectiveness of Ramadan fasting in liver transplant recipients and bariatric surgery.

Identification of an alternative ligand-binding pocket in peroxisome proliferator-activated receptor gamma and its correlated selective agonist for promoting beige adipocyte differentiation.

The pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARγ) is a convenient and promising strategy for promoting beige adipocyte biogenesis to combat obesity-related metabolic disorders. However, thiazolidinediones (TZDs), the full agonists of PPARγ exhibit severe side effects in animal models and in clinical settings. Therefore, the development of efficient and safe PPARγ modulators for the treatment of metabolic diseases is emerging. In this study, using comprehensive methods, we report a previously unidentified ligand-binding pocket (LBP) in PPARγ and link it to beige adipocyte differentiation. Further virtual screening of 4097 natural compounds based on this novel LBP revealed that saikosaponin A (NJT-2), a terpenoid compound, can bind to PPARγ to induce coactivator recruitment and effectively activate PPARγ-mediated transcription of the beige adipocyte program. In a mouse model, NJT-2 administration efficiently promoted beige adipocyte biogenesis and improved obesity-associated metabolic dysfunction, with significantly fewer adverse effects than those observed with TZD. Our results not only provide an advanced molecular insight into the structural ligand-binding details in PPARγ, but also develop a linked selective and safe agonist for obesity treatment.

CETP and SGLT2 inhibitor combination therapy increases glycemic control: a 2x2 factorial Mendelian randomization analysis.

Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin. We conducted a 2x2 factorial Mendelian Randomization analysis involving 233,765 participants from the UK Biobank. This study aimed to evaluate whether simultaneous genetic inhibition of CETP and SGLT2 enhances glycemic control compared to inhibiting each separately. Our findings indicate that dual genetic inhibition of CETP and SGLT2 significantly reduces glycated hemoglobin levels compared to controls and single-agent inhibition. Additionally, the combined inhibition is linked to a lower incidence of diabetes compared to both the control group and SGLT2 inhibition alone. These results suggest that combining CETP and SGLT2 inhibitor therapies may offer superior glycemic control over SGLT2 inhibitors alone. Future clinical trials should investigate the potential of repurposing CETP inhibitors for metabolic disease treatment, providing an oral therapeutic option that could benefit high-risk patients before they require injectable therapies like insulin or glucagon-like peptide-1 (GLP-1) receptor agonists.

Anti-adipogenesis and anti-obesity potential of alliin mediated by modulating glycolipid metabolism via activating PPARγ signaling.

Garlic exhibits hypolipidemic, hypoglycemic, and cardiovascular benefits. The inconsistent results of garlic preparations on adipogenesis have caused more confusion in the public and academia. The compounds responsible for the anti-adipogenesis effect of garlic remain unknown. The present study aimed to verify the real anti-adipogenesis and anti-obesity component in garlic and explored its possible effects in metabolic syndrome. We verified the real anti-adipogenesis and anti-obesity components of garlic in 3T3-L1 preadipocytes and a 10-week-high fat diet (HFD)-induced obese mice. In vitro, two water-soluble and four typical lipid-soluble compounds of garlic were tested for their anti-adipogenesis. Then, the water-soluble compound, alliin, and two processing methods produced garlic oils, were evaluated in vivo study. Mice received oral administration of alliin (25mg/kg) and garlic oils (15mg/kg) daily for 8weeks. Serum lipids, parameters of obesity, and indicators involved in regulating glycolipid metabolism were examined. Our findings confirmed that both water-soluble and lipid-soluble organosulfur compounds of garlic contributed to garlic's anti-adipogenesis effect, in which water-soluble sulfides, especially alliin, exhibited greater potency. Alliin possessed potent effects of anti-obesity and improvement in glucose and lipid metabolism in HFD-induced obese mice. Alliin mediated these effects partly attributed to its modulation of enzymatic activities within glycolipid metabolism and activating PPARγ signaling pathway. In contrast to odorous lipid-soluble sulfides, alliin is odorless, stable, and safe, and is an ideal nutraceutical or even medicinal candidates for the treatment of metabolic diseases. Alliin could be used to standardize the quality of garlic products.

The use of systems biology in treatment of metabolic diseases

The use of systems biology in treatment of metabolic diseases

Phospholipid Acyltransferases: Characterization and Involvement of the Enzymes in Metabolic and Cancer Diseases.

This review delves into the enzymatic processes governing the initial stages of glycerophospholipid (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) and triacylglycerol synthesis. The key enzymes under scrutiny include GPAT and AGPAT. Additionally, as most AGPATs exhibit LPLAT activity, enzymes participating in the Lands cycle with similar functions are also covered. The review begins by discussing the properties of these enzymes, emphasizing their specificity in enzymatic reactions, notably the incorporation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid and docosahexaenoic acid (DHA) into phospholipids. The paper sheds light on the intricate involvement of these enzymes in various diseases, including obesity, insulin resistance, and cancer. To underscore the relevance of these enzymes in cancer processes, a bioinformatics analysis was conducted. The expression levels of the described enzymes were correlated with the overall survival of patients across 33 different types of cancer using the GEPIA portal. This review further explores the potential therapeutic implications of inhibiting these enzymes in the treatment of metabolic diseases and cancer. By elucidating the intricate enzymatic pathways involved in lipid synthesis and their impact on various pathological conditions, this paper contributes to a comprehensive understanding of these processes and their potential as therapeutic targets.

Network-targeted transcranial direct current stimulation of the hypothalamus appetite-control network: a feasibility study.

The hypothalamus is the key regulator for energy homeostasis and is functionally connected to striatal and cortical regions vital for the inhibitory control of appetite. Hence, the ability to non-invasively modulate the hypothalamus network could open new ways for the treatment of metabolic diseases. Here, we tested a novel method for network-targeted transcranial direct current stimulation (net-tDCS) to influence the excitability of brain regions involved in the control of appetite. Based on the resting-state functional connectivity map of the hypothalamus, a 12-channel net-tDCS protocol was generated (Neuroelectrics Starstim system), which included anodal, cathodal and sham stimulation. Ten participants with overweight or obesity were enrolled in a sham-controlled, crossover study. During stimulation or sham control, participants completed a stop-signal task to measure inhibitory control. Overall, stimulation was well tolerated. Anodal net-tDCS resulted in faster stop signal reaction time (SSRT) compared to sham (p = 0.039) and cathodal net-tDCS (p = 0.042). Baseline functional connectivity of the target network correlated with SSRT after anodal compared to sham stimulation (p = 0.016). These preliminary data indicate that modulating hypothalamus functional network connectivity via net-tDCS may result in improved inhibitory control. Further studies need to evaluate the effects on eating behavior and metabolism.

The Role of Exerkines in Obesity-Induced Disruption of Mitochondrial Homeostasis in Thermogenic Fat.

There is a notable correlation between mitochondrial homeostasis and metabolic disruption. In this review, we report that obesity-induced disruption of mitochondrial homeostasis adversely affects lipid metabolism, adipocyte differentiation, oxidative capacity, inflammation, insulin sensitivity, and thermogenesis in thermogenic fat. Elevating mitochondrial homeostasis in thermogenic fat emerges as a promising avenue for developing treatments for metabolic diseases, including enhanced mitochondrial function, mitophagy, mitochondrial uncoupling, and mitochondrial biogenesis. The exerkines (e.g., myokines, adipokines, batokines) released during exercise have the potential to ameliorate mitochondrial homeostasis, improve glucose and lipid metabolism, and stimulate fat browning and thermogenesis as a defense against obesity-associated metabolic diseases. This comprehensive review focuses on the manifold benefits of exercise-induced exerkines, particularly emphasizing their influence on mitochondrial homeostasis and fat thermogenesis in the context of metabolic disorders associated with obesity.

Association of serum total IgE and allergen-specific IgE with insulin resistance in adolescents: an analysis of the NHANES database

BackgroundRecent studies have found that total immunoglobulin E (IgE) and allergen-specific IgE were associated with some metabolic diseases. However, the role of IgE in metabolism among adolescents is still unclear. Herein, this study aims to investigate the associations of serum total IgE and allergen-specific IgE with insulin resistance (IR) in adolescents, in order to provide some reference for the prevention and treatment of metabolic diseases in a young age.MethodsData of 870 adolescents were extracted from the National Health and Nutrition Examination Survey (NHANES) database in 2005–2006 in this cross-sectional study. Weighted univariate and multivariate logistic regression analyses were utilized to screen covariates and explore the relationships of serum total IgE and allergen-specific IgE with IR. The evaluation indexes were odds ratios (ORs) and 95% confidence intervals (CIs). In addition, these relationships were also assessed in subgroups of allergy history, asthma history, and number of allergens.ResultsAmong eligible adolescents, 168 had IR. No significant association between serum total IgE level and IR was found. However, adolescents with higher level of allergen-specific IgE to rye grass [OR = 0.47, 95%CI: (0.25–0.91)], white oak [OR = 0.57, 95%CI: (0.37–0.88)], or peanut [OR = 0.38, 95%CI: (0.15–0.97)] seemed to have lower odds of IR, whereas those had higher level of shrimp-specific IgE [OR = 2.65, 95%CI: (1.21–5.84)] have increased odds of IR. In addition, these associations between allergen-specific IgE and IR were also discovered in adolescents who had allergy history or asthma history, or had different numbers of allergens.ConclusionPaying attention to different allergens in adolescents may be important in the early identification of IR among this high-risk population. The study results relatively provided some reference for further exploration on IR prevention.

The Pharmacological Effects and Potential Applications of Limonene From Citrus Plants: A Review

The citrus plant is the general term for Citrus, Fortunella, and Poncirus, which includes oranges, tangerines, lemons, grapefruits, and citrons. Not only does it contain a variety of delicious fruits, but it is also an important part of traditional Chinese medicine. Citrus plant peels are rich in essential oils, the primary active component of which is limonene. Modern pharmacological research has revealed that limonene has many pharmacological effects, including antibacterial, anticancer, analgesic, immune regulation, neuroprotection, antioxidant, anti-inflammatory properties, and the treatment of metabolic diseases. It finds widespread application in a variety of industries, including cosmetics, food, personal care, medicine, pesticides, and others. This article reviews the pharmacological effects of limonene from citrus plants to build a scientific basis for future limonene research and application and also to lay the groundwork for developing functional foods for the prevention and management of linked disorders.

Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance

Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.

Analysis of the Correlation Between Visceral Fat Area and Insulin Resistance in Patients with Type 2 Diabetes and Abdominal Obesity

Objective: To analyze the correlation between visceral fat area and insulin resistance index (HOMA-IR) in patients with type 2 diabetes mellitus (T2DM) and abdominal obesity and to provide a reference for screening and related research of such patients. Methods: Two hundred patients with T2DM admitted to Guandu People’s Hospital of Kunming were included. The study was carried out from October 2022 to December 2023. The patients were divided into three groups according to different abdominal visceral fat areas (VFA): Group A (n = 65) was less than 75cm2, Group B (n = 75) was 75–100 cm2, and Group C (n = 60) was greater than 100 cm2. The subjects in the three groups were all tested for glycated hemoglobin (HbA1c), fasting insulin (FINS), and fasting blood glucose (FPG). Height and weight were measured to calculate body mass index (BMI). The HOMA-IR and TYG (fasting triglyceride and glycemic index) were also calculated. Changes in the BMI, VFA, HOMA-IR, and TYG levels were observed in the three groups. Results: The VFA, BMI, HbA1c, FPG, FINS, HOMA-IR, and TYG of the patients all increased, with a more significant increase in the BMI, FINS, HOMA-IR, and TYG levels (P < 0.01). Multiple linear stepwise regression analyses used visceral fat area (VFA) as the dependent variable. The results showed that VFA was closely related to BMI, FINS, HOMA-IR, and TYG. Conclusion: Early reduction of VFA to reduce insulin resistance may be a better treatment and effective method for T2DM, providing powerful measures and new strategies for effective blood sugar control and early prevention in the treatment of metabolic diseases.

Prevención en el neonato de enfermedades que cursan con daño cerebral irreversible, derecho humano

Since the 1960s, my scientific activity has focused on the diagnosis and treatment of metabolic diseases, rare pathologies which, in some cases, cause irreversible brain damage. “Irreversible” is the word that should trigger all preventive efforts and ensure widespread screening. Its prevention implies early diagnosis and treatment. The fundamental objective was to detect avoidable hereditary diseases in newborns, which generally lead to irreversible mental retardation. In a short time, accompanied by the “luck of the bold”, we detected a first case of phenylketonuria and the pilot plan was set up, which led to its successive implementation throughout Spain and participation in specialised international meetings was initiated, as well as biochemical and genetic research, to contribute to scientific knowledge of such an important aspect of preventive medicine. As with any social, environmental or clinical phenomenon, it is necessary to apply treatment in time before the alteration that is to be avoided occurs, particularly when irreversible situations are involved. On several occasions I have referred to the need to act in a timely manner in order to stop the process at stages prior to the point of no return (ethics of time). Every day I feel more and more strongly, and I try to express it in this way, that the search for, dissemination and application of knowledge is the most beautiful task offered to man’s terrible perplexity, astonishment, doubt and fear. I remember that a few months after finishing my degree in Pharmacy, when I was starting to work in Prof. Santos Ruiz’s laboratory, I visited an institution for the mentally handicapped. There, on that day, many things in my life took root. Other things were erased by the force of that memory. And the feeling that it is necessary to contribute to alleviating and making the life of man, the only being aware of the great gift of life, more bearable, became more intense and urgent. In 2023, on the 75th anniversary of the Universal Declaration of Human Rights, I proposed to the United Nations, through its High Commissioner for Human Rights, Mr. Volker Turk, the recognition as a human right of the prevention of diseases that cause irreversible neurological damage and requested their help in the processing of this new human right. We then asked all governments, institutions and scientific societies to support the proposal to declare as a human right the prevention through neonatal screening of pathologies in which irreversible damage can be avoided through early treatment. It is now necessary to promote a conscious citizenship that is not a spectator of what is happening, but an actor for the progressive and urgent elimination of risks that affect humanity without further remedy. At last, human beings are gradually recognising that they are equal in dignity and can express themselves freely. Now we can. Now we must. The creative capacity that distinguishes the human species encourages us and gives us hope.

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes.

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut-brain communication can be leveraged to achieve sustained body weight loss without adverse effects.

Auditory Changes in Occupational Health Associated With Metabolic Diseases in Adult Workers

Introduction: The most common hearing losses in the population are associated with genetic conditions, use of ototoxic substances or medications, infectious diseases, metabolic diseases and chronic ear diseases and the association of exposure to occupational risks or the natural aging process. Objective: Verify the association between hearing loss in workers and metabolic diseases. Method: Retrospective cross-sectional study with analysis of secondary data of subjects exposed to occupational noise and undergoing drug treatment for metabolic disease, attended in two occupational health clinics (C1 and C2) from January 2020 to December 2022, considering the data of reference examinations from the year 2005. Results: Of the n = 97 subjects evaluated, 73.20% were male, exposed to occupational noise (64.90%), with medication use for treating cardiovascular diseases (89.70%). The most recurrent auditory complaint was tinnitus (28.90%), n = 53 subjects presented sensorineural hearing loss with a statistical association between the decline of hearing loss and medications used for metabolic and hormonal regulation. Conclusion: Here was a higher frequency in the use of medications for treating cardiovascular diseases with a risk of triggering or worsening hearing loss in these subjects and greater impairment and decline of hearing thresholds were observed in the results of C2.

Plicatin C: A New Cinnamate Derivative from Mangrove-derived Fungus Aspergillus terreus DM62

Background: Marine fungi have been proven to be a new arsenal for the discovery of valuable secondary metabolites. Method:: Fungus strain Aspergillus terreus DM62 was initially fermentated using solid corn medium and PDA liquid medium. Subsequently, extensive chromatographic methods were applied to isolate the fermentation cultures of DM62, and the chemical structures of isolate compounds were elucidated by pectroscopic analyses and optical rotations comparison. Additionally, α-glucosidase and ATPcitrate lyase (ACL) inhibitory activities of isolate compounds were assessed to investigate their hypoglycemic and lipid-lowering activities. Result:: A new cinnamate derivative, plicati n C (1), together with 18 known compounds, were isolated from the solid and liquid state fermentations of A. terreus DM62. Activity evaluation showed that compounds 3, 6, and 8-10 exhibited stronger α-glucosidase inhibitory activities than acarbose at 400 μM, and butenolide 3, with an IC50 value of 21.5 μM, was discovered with significant ACL inhibitory activity for the first time. Conclusion:: This study not only discovered a new cinnamate derivative but also found butenolides with potent ACL inhibitory activity, which is favorable to clarify their pharmacological mechanism in the treatment of metabolic disease.

Stellera chamaejasme L. extract inhibits adipocyte differentiation through activation of the extracellular signal-regulated kinase pathway.

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.

Xiasangju alleviate metabolic syndrome by enhancing noradrenaline biosynthesis and activating brown adipose tissue.

Metabolic syndrome (MetS) is a clinical condition associated with multiple metabolic risk factors leading to type 2 diabetes mellitus and other metabolic diseases. Recent evidence suggests that modulating adipose tissue to adaptive thermogenesis may offer therapeutic potential for MetS. Xiasangju (XSJ) is a marketed drug and dietary supplement used for the treatment of metabolic disease with anti-inflammatory activity. This study investigated the therapeutic effects of XSJ and the underlying mechanisms affecting the activation of brown adipose tissue (BAT) in MetS. The results revealed that XSJ ameliorated MetS by enhancing glucose and lipid metabolism, leading to reduced body weight and abdominal circumference, decreased adipose tissue and liver index, and improved blood glucose tolerance. XSJ administration stimulated catecholamine biosynthesis, increasing noradrenaline (NA) levels and activating NA-mediated proteins in BAT. Thus, BAT enhanced thermogenesis and oxidative phosphorylation (OXPHOS). Moreover, XSJ induced changes in gut microbiota composition, with an increase in Oscillibacter abundance and a decrease in Bilophila, Candidatus Stoquefichus, Holdemania, Parasutterella and Rothia. XSJ upregulated the proteins associated with intestinal tight junctions corresponding with lower serum lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6) levels to maintain NA signaling transport. In summary, XSJ may alleviate MetS by promoting thermogenesis in BAT to ultimately boost energy metabolism through increasing NA biosynthesis, strengthening intestinal barrier integrity and reducing low-grade inflammation. These findings suggest XSJ has potential as a natural therapeutic agent for the treatment of MetS.