Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutritional science and public health initiatives, sustained weight management success rates and prevention in obesity remain limited, underscoring its recognition as a multifactorial disease influenced by genetic, environmental, and behavioral determinants. Notably, the escalating prevalence of obesity and its earlier onset in younger populations have intensified the urgency to develop novel therapeutic agents that simultaneously ensure efficacy and safety. This review aims to elucidate the pathophysiological mechanisms underlying obesity, analyze its major complications—including type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), non-alcoholic fatty liver disease (NAFLD), obesity-related respiratory disorders, obesity-related nephropathy (ORN), musculoskeletal impairments, malignancies, and psychological comorbidities—and critically evaluate current anti-obesity strategies. Particular emphasis is placed on emerging pharmacological interventions, exemplified by plant-derived natural compounds such as berberine (BBR), with a focus on their molecular mechanisms, clinical efficacy, and therapeutic advantages. By integrating mechanistic insights with clinical evidence, this review seeks to provide innovative perspectives for developing safe, accessible, and effective obesity treatments.

Obesity, clinically defined by pathological adipose tissue accumulation disrupting metabolic homeostasis, has reached pandemic proportions. The World Obesity Atlas 2024 reports over 1.5 billion projected cases by 2035, highlighting its growing threat among pediatric and adult populations globally. While newly approved pharmacotherapies such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) show efficacy, their clinical utility remains constrained by dose-dependent gastrointestinal complications, underscoring the urgent need for safer alternatives. This therapeutic gap has revitalized interest in natural bioactive compounds, particularly berberine (BBR)—a benzodioxoloquinolizine alkaloid derived from Coptis chinensis and related medicinal plants. Preclinical and clinical studies demonstrate BBR’s multimodal anti-obesity mechanisms: (i) adenosine monophosphate-activated protein kinase (AMPK) activation enhancing lipolysis and β-oxidation, (ii) peroxisome proliferator-activated receptor γ (PPAR-γ) suppression inhibiting adipogenesis, (iii) gut microbiota modulation improving metabolic endotoxemia, and (iv) uncoupling protein 1 (UCP1) upregulation promoting adipose browning. Notably, BBR metabolites demonstrate pharmacological activity comparable to or exceeding that of the parent compound. However, BBR’s translational applications face biopharmaceutical challenges, including poor intestinal absorption (< 1% bioavailability) due to P-glycoprotein efflux and first-pass metabolism. This comprehensive review critically evaluates recent advances in BBR’s anti-obesity pharmacology through three lenses: (1) preclinical and clinical evidence from randomized controlled trials, (2) molecular mechanisms underlying metabolic regulation, and (3) innovative strategies for pharmacokinetic optimization. Given its multi-target efficacy and botanical safety profile, BBR represents a cost-effective adjuvant for obesity management, particularly in resource-limited settings. Future research should prioritize standardized clinical protocols and pharmacogenomic studies to optimize therapeutic outcomes.

GLP-1 receptor agonists (GLP-1 RA) are presently used as the first-line drugs for the clinical treatment of type 2 diabetes mellitus (T2DM). It can regulate blood glucose by stimulating insulin secretion and lowering glucagon levels. We used 16S rRNA amplicon sequencing to detect structural changes in the composition of the intestinal flora of newly diagnosed T2DM after 1 and 48 weeks of dulaglutide administration. Our research found no significant changes in the intestinal flora after the administration of dulaglutide for 1 week to subjects with newly diagnosed T2DM. Nevertheless, after 48 weeks of dulaglutide administration, the composition of the intestinal flora changed significantly, with a significant reduction in the abundance of intestinal flora. Furthermore, we found that fasting glucose levels, fasting c-peptide levels, HbA1c levels, and BMI are also closely associated with intestinal flora. This reveals that intestinal flora may be one of the mechanisms by which dulaglutide treats T2DM.

Background: Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of medications used to treat type 2 diabetes, including metformin, which is considered first-line therapy for type 2 diabetes. In recent years, GLP-1 receptor agonists (GLP-1 RAs) have been found to alter the composition and structure of gut flora and also promote the production of gut probiotics. However, there have been few clinical studies regarding the effects of GLP-1 RAs on gut flora. In this study, we investigated changes in the abundance of Lactobacillus delbrueckii (L delbrueckii) and Faecalibacterium prausnitzii (F prausnitzii) 1 week after administration of a GLP-1 RA in the clinical treatment of type 2 diabetes. The association with glycemic and body mass index (BMI) correlations was also explored. Methods: Twelve newly diagnosed patients with type 2 diabetes were examined for changes in the abundance of L delbrueckii and F prausnitzii by Fluorescence in Situ Hybridization 1 week after administration of GLP-1 RAs. Subjects BMI was measured and fasting glucose changes were detected using the glucose oxidase method, and Spearman correlation analysis was performed to explore their relevance. Results: There was no significant change in the abundance of L delbrueckii in the intestine (P = .695) and no significant correlation with BMI and fasting glucose levels (R = 0.134, P = .534) after the use of GLP-1 RA (R = −0.098, P = .647); F prausnitzii on the other hand had a significantly higher abundance (P = .002) and a significant negative correlation with fasting glucose level (R = −0.689, P < .001), but no significant correlation with BMI (R = −0.056, P = .796). Conclusion: F prausnitzii may be one of the pathways through which glucose is regulated in the treatment of type 2 diabetes by GLP-1 RAs.

Objective: 1) To investigate the effect of FOXC2 on the differentiation of adipose-derived mesenchymal stem cells. 2) To analyze the mechanism between FOXC2 expression regulation in adipose differentiation and insulin resistance (IR). Methods: We first amplified the FOXC2 promoter region-512 and cloned it into the luciferase expression vector. The reporter gene system was transfected into the adipose tissue-derived mesenchymal stem cell to study insulin-mediated FOXC2 expression. We also manipulated FOXC2 protein expression by either siRNA or overexpression and studied the differentiation capability of adipose tissue-derived mesenchymal stem cell into adipocytes, as well as the influence on several IR-related genes: GLUT4, PPARγ, UCP1 and PAI-1. Results: 1) Insulin effectively induced the expression of FOXC2 protein in adipose tissue-derived mesenchymal stem cells under differentiation (P< 0.01). Insulin also induced FOXC2-pro-512T promoter activity significantly (P< 0.01). 2) The stem cell adipose differentiation decreased in the FOXC2 overexpression group. 3) When FOXC2 was overexpressed, the expression of GLUT4, PAI-1 and UCP1 was higher than control groups (p< 0.001). When FOXC2 was down-regulated by siRNA, both GLUT4 and PAI-1’s protein expression were decreased (p< 0.001), and the protein expression of PPARγ was increased (p< 0.001). In the presence of insulin induction, overexpression of FOXC2 led to significantly higher UCP-1 expression (p< 0.001) and lower PAI-1 expression (p< 0.001). The protein expression of GLUT4, PAI-1 (p< 0.001) and UCP-1 (p< 0.05) was decreased in cells transfected with FOXC2 siRNA. Conclusion: Insulin effectively induced the expression of FOXC2 protein in adipose tissue-derived mesenchymal stem cells under differentiation, possibly through the regulation of the FOXC2-pro-512T promoter activity. The different protein expression of FOXC2 has regulatory effects on several genes related to insulin resistance. FOXC2 is an important regulatory factor in adipocyte differentiation and insulin resistance.