Current Obesity Reports | The Emerging Role of Autophagy and Lysosomal Dysfunction in Obesity-Related Metabolic Inflammation

This article systematically reviews the mechanistic links between obesity-induced metabolic inflammation and autophagy-lysosomal dysfunction, comprehensively analyzes pathological changes across multiple metabolic tissues, and evaluates potential therapeutic interventions, providing theoretical foundations for developing novel treatments for metabolic disorders.

 

Literature Overview
This paper published in Current Obesity Reports synthesizes the core roles of autophagy and lysosomal acidification dysfunction in obesity-associated systemic inflammation. The study systematically examines how obesity disrupts autophagy processes, leading to accumulation of damaged organelles and toxic aggregates, thereby exacerbating insulin resistance, lipotoxicity, and chronic inflammation. It further explores strategies like AMPK activation, dietary interventions, and lysosome-targeted therapies for restoring autophagy function, offering new therapeutic perspectives for obesity-related diseases.

Background Knowledge
Obesity has emerged as a global health crisis, strongly associated with metabolic diseases including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular disorders, and neurodegenerative conditions. Recent studies highlight autophagy's critical role in maintaining cellular homeostasis, while lysosomal acidification impairment intensifies obesity-induced systemic inflammation. Lysosomal V-ATPase serves as a central regulator of lysosomal acidity, and its dysfunction prevents proteases and lipases from operating effectively, leading to toxic accumulation and cellular stress. Autophagy dysregulation has been observed in adipose tissue, skeletal muscle, liver, pancreas, kidney, heart, and brain, correlating with obesity-related pathologies. Although interventions like exercise, nutritional supplementation, and pharmacological autophagy activation show promise in restoring cellular homeostasis, coordinated regulation of autophagy-lysosomal function across multiple organs remains a key challenge for future research.

 

 

Research Methods and Experiments
The study integrated in vivo and in vitro experiments to analyze autophagy and lysosomal dysfunction in obesity models. Using high-fat diet (HFD)-induced animal models, researchers evaluated autophagy markers (e.g., LC3-II, p62), lysosomal acidification levels, and protease release in various metabolic tissues. Pharmacological and nutritional interventions—including AMPK activators, fatty acid supplementation, and lysosome-targeted nanoparticles—were employed to assess their regulatory effects on autophagy flux and metabolic inflammation. Transgenic and gene-editing models further investigated the roles of specific genes (e.g., TFEB, CD36, TM4SF19) in lysosomal function regulation.

Key Conclusions and Perspectives

• Obesity impairs autophagy across multiple metabolic tissues, characterized by autophagosome accumulation and defective lysosomal acidification.
• Reduced lysosomal V-ATPase activity is a critical mechanism underlying obesity-associated autophagy defects, compromising cellular degradation efficiency.
• Lipotoxic mediators like palmitic acid induce lysosomal membrane permeabilization, releasing cathepsins (e.g., CTSB, CTSD) to trigger inflammation and apoptosis.
• Exercise, calorie restriction, and fatty acid supplementation (e.g., DHA, EPA) effectively restore autophagy flux and lysosomal function.
• Nanoparticle therapeutics (e.g., TFSA, PEFSU NPs) improve metabolic dysregulation in liver, pancreas, and myocardium by restoring lysosomal acidification.
• Gut microbiota dysbiosis and lysosomal dysfunction exhibit cross-regulation; enhancing autophagy improves intestinal barrier integrity.
• In neural tissues, autophagy impairment correlates with neuroinflammation and neurodegeneration, suggesting its role in obesity-linked neurological disorders.

Research Significance and Prospects
The study reveals the widespread impact of autophagy and lysosomal dysfunction in obesity-related metabolic diseases, establishing new intervention targets for multi-system disorders. Future research should focus on tissue-specific strategies to synergistically restore autophagy-lysosomal function and optimize clinical translation. Developing tissue-targeted nanotherapeutics or gene therapies for autophagy modulation may enable personalized treatment for obesity-associated conditions.

 

 

Conclusion
Obesity-induced autophagy and lysosomal dysfunction are widely observed across metabolic tissues, with strong correlations to chronic inflammation, insulin resistance, lipotoxicity, and neurodegenerative diseases. The study systematically summarizes core mechanisms including autophagy suppression, lysosomal acidification impairment, cathepsin release, and mitochondrial dysfunction, while assessing therapeutic potential of exercise, dietary modifications, AMPK activators, and lysosome-targeted nanoparticles. Although animal and cell models demonstrate improved metabolic homeostasis through interventions, safety and efficacy in human applications require further validation. Future research integrating multi-omics approaches, tissue-specific interventions, and nano-drug delivery systems may enable precision medicine for obesity and related disorders.

 

Lenny Yi Tong Cheong, Eka Norfaishanty Saipuljumri, Gavin Wen Zhao Loi, Jialiu Zeng, and Chih Hung Lo. Autolysosomal Dysfunction in Obesity-induced Metabolic Inflammation and Related Disorders. Current Obesity Reports.