Metabolic Syndrome: From Mechanisms to Therapeutic Interventions

FIGURE 1. Metabolic syndrome in different metabolic organs and diseases. Metabolic syndrome involves multiple organs and is associated with several diseases, including Type 2 diabetes, cardiovascular disease, neurological disorders, gastrointestinal diseases, liver diseases, muscle‐related diseases, and renal disease.

FIGURE 2. The potential pathogenesis of metabolic syndrome. The intricate mechanisms include insulin resistance, chronic low‐grade inflammation, oxidative stress, epigenetic modifications, intestinal disorder, and adipose tissue dysfunction. Importantly, there are bidirectional communication pathways between the gut and adipose tissue.

FIGURE 3. The molecular mechanisms of the gut–adipose tissue axis in the progression of metabolic syndrome. Human adipose tissue comprises distinct anatomical depots: subcutaneous WAT (abdominal and hip/thigh regions), visceral AT (surrounding abdominal organs), and thermogenic BAT and inducible beige adipocytes (primarily supraclavicular). Adipocytes secrete adipokines (leptin, adiponectin, adipsin, visfatin, vaspin, apelin, IL‐6, PAI‐1, FABP‐4) and ADEVs that modulate gut microbial composition. Reciprocally, gut microbiota‐derived factors regulate adipose tissue function: LPS activates TLR signaling to drive WAT inflammation, hypoxia, and fibrosis; SCFAs signal through GPR41/43 to modulate insulin sensitivity and lipolysis; and succinate signals through SUCNR1/GPR91, whereas TMAO‐related pathways may involve ER stress signaling, thereby influencing adipose remodeling and thermogenic regulation.

FIGURE 4. Molecular mechanisms in gut–adipose tissue crosstalk. Microbial components (LPS, PAMPs) and metabolites (SCFAs, bile acids, endocannabinoids, tryptophan derivatives) activate distinct receptor signaling in colonocytes (TLR‐MyD88, CB1/CB2, AhR, PPARα/γ) and enteroendocrine cells (GPR119, TGR5, GPR43/41), modulating intestinal barrier function and hormone secretion (GLP‐1, PYY, insulin). These molecules enter circulation to regulate white and brown adipocyte metabolism: TLR4/CD14 signaling controls adipokine production and adipogenesis; GPR91, AhR, and cannabinoid receptors govern energy sensing and adipogenesis; while TGR5 and GPR43/41 activation promotes WAT browning, mitochondrial uncoupling, and thermogenesis. Conversely, adipose‐derived factors (extracellular vesicles, adiponectin, leptin, cathelicidins) feedback to reshape gut microbial composition and immune homeostasis.

FIGURE 5. The potential therapies for the gut–adipose tissue axis in the progression of metabolic syndrome. Strategies targeting gut–AT axis range from lifestyle modifications (caloric restriction and intermittent fasting) to microbial manipulation such as targeting BAs and LPS metabolism, prebiotics, probiotics, and synbiotics, CB1R antagonist, FMT, bariatric surgery, and intestinal mucosa secretions.