Pathophysiology
Clinical meaning
Obesity is a chronic, relapsing neuroendocrine disease characterized by dysregulation of the hypothalamic appetite-satiety axis, leading to excessive energy storage as adipose tissue. The hypothalamus integrates peripheral signals from adipose tissue (leptin, adiponectin), the gastrointestinal tract (ghrelin from the stomach, GLP-1 and PYY from the ileum, cholecystokinin from the duodenum), the pancreas (insulin), and the brainstem to regulate energy balance through orexigenic (appetite-stimulating: NPY/AgRP neurons) and anorexigenic (appetite-suppressing: POMC/CART neurons) pathways. In obesity, leptin resistance develops despite high circulating leptin levels, reducing the hypothalamic satiety signal. Adipose tissue functions as an endocrine organ, producing pro-inflammatory cytokines (TNF-alpha, IL-6, resistin) that drive insulin resistance, endothelial dysfunction, and systemic chronic low-grade inflammation. Visceral adipose tissue is metabolically more active and pathogenic than subcutaneous fat. Anti-obesity pharmacotherapy targets multiple pathways: GLP-1 receptor agonists (semaglutide, liraglutide) activate central satiety pathways and delay gastric emptying; phentermine/topiramate combines norepinephrine release with GABAergic appetite suppression; naltrexone/bupropion blocks opioid-mediated reward eating while enhancing POMC neuron activity; and orlistat inhibits pancreatic lipase reducing dietary fat absorption by 30%. Metabolic surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) produces weight loss through...