Autophagy as a therapeutic linchpin in metabolic diseases and obesity-associated diabetes

Autophagy, a conserved lysosomal degradation pathway, is increasingly recognized as a central regulator of metabolic health. Its impairment contributes directly to obesity and type 2 diabetes by disrupting nutrient sensing, stress adaptation, and organelle quality control. Hyperactivation of MTORC1 with insufficient AMPK and SIRT1 signaling suppresses autophagic flux, driving lipid accumulation, insulin resistance, and mitochondrial dysfunction. Clinically relevant consequences include adipose inflammation and hypertrophy, hepatic steatosis with impaired β-oxidation, pancreatic β-cell failure from unresolved ER stress, and skeletal muscle atrophy due to loss of proteostasis. Moreover, defective autophagy across the gut - liver - brain axis exacerbates intestinal barrier dysfunction, endotoxemia, and neuroendocrine imbalance, amplifying systemic metabolic deterioration. Emerging interventions that restore autophagic capacity, including exercise-induced AMPK activation, dietary modulation of unsaturated fatty acids, pharmacological inducers, and nanotechnology-based lysosomal re-acidification show promise in preclinical models. However, the tissue-specific duality of autophagy, where suppression may be beneficial in some contexts but harmful in others, highlights the complexity of therapeutic targeting. This review highlights current mechanistic and translational insights to position autophagy as a therapeutic linchpin in obesity-associated metabolic disease. By aligning molecular pathways with clinical outcomes, we herein highlight opportunities to develop precision strategies that harness autophagy to combat the global burden of obesity and metabolic disorders.<b>Abbreviation</b>: AGEs: advanced glycation endproducts; ALR: autophagic lysosomal reformation; AMPK: AMP-activated protein kinase; AT: adipose tissue; BAT: brown adipose tissue; CMA: chaperone-mediated autophagy; CR: caloric reduction/restriction; DC: diabetic cardiomyopathy; DN: diabetic nephropathy; ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; FFAs: free fatty acids; HFD: high-fat diet; HOPS: homotypic fusion and vacuole protein sorting; KO: knockout; LAMs: Lipid-associated macrophages; LD: lipid droplet; MBH: mediobasal hypothalamus; Med diet: Mediterranean diet; MDBs: Mallory-Denk bodies; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; PI3K: phosphoinositide 3-kinase; PtdIns3K-CI: class III phosphatidylinositol 3-kinase complex I; T1D: type 1 diabetes; T2D: type 2 diabetes; TASCC: TOR-autophagy spatial coupling compartment; TRE: time-restricted eating; WAT: white adipose tissue.