From diet to hypothalamic dysfunction: Neuroanatomical and hormonal integration of the microbiota-hypothalamus-adipose tissue axis

Obesity is a chronic neurometabolic disorder characterized by low-grade systemic inflammation, adipose tissue dysfunction, and impaired central regulation of energy balance. This review summarizes mechanistic and translational evidence showing that diet-induced changes in the gut microbiota contribute to altered signaling along the gut-hypothalamus-adipose tissue axis. Obesogenic diets modify microbial metabolic activity by reducing short-chain fatty acid production, altering bile acid composition, and increasing endotoxin-related signaling, which together impair intestinal barrier function and promote metabolic endotoxemia. These signals reach the brain through endocrine (GLP-1, PYY), immune (cytokines, TLR4-dependent pathways), and neural (vagal/neuropod) routes, and are associated with hypothalamic microinflammation, impaired leptin and insulin signaling, and a persistent orexigenic drive. At the same time, adipose tissue undergoes hypertrophy and immunometabolic remodeling, reinforcing systemic inflammation and central dysregulation in a self-sustaining feedback loop. Incretin-based therapies, including GLP-1 and dual GIP/GLP-1 receptor agonists, act in part through modulation of this axis, including microbiota-related mechanisms. However, the frequent regain of weight after treatment discontinuation indicates that central and peripheral circuits are not fully reprogrammed. Viewing obesity as a disorder of disrupted inter-organ signaling highlights microbial metabolic pathways as relevant targets for more durable metabolic improvement.