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

Feb 24, 2026Autophagy

Autophagy as a key treatment target in metabolic diseases and obesity-related diabetes

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Impairment of autophagy is associated with obesity and type 2 diabetes through disruptions in nutrient sensing and stress adaptation.

Autophagy plays a crucial role in maintaining metabolic health by regulating nutrient sensing and organelle quality control.
Hyperactivation of MTORC1, coupled with insufficient AMPK and SIRT1 signaling, may suppress autophagy and lead to lipid accumulation and insulin resistance.
Consequences of impaired autophagy include inflammation and hypertrophy in adipose tissue, liver fat accumulation, pancreatic β-cell dysfunction, and skeletal muscle atrophy.
Defective autophagy across the gut-liver-brain axis could worsen intestinal barrier function and systemic metabolic health.
Interventions that aim to restore autophagic capacity, such as exercise and dietary changes, show promise in preliminary studies.
The complex duality of autophagy's effects in different tissues complicates the development of targeted therapies for metabolic diseases.

AI simplified

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.

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

Abstract

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief