Autolysosomal Dysfunction in Obesity-induced Metabolic Inflammation and Related Disorders

Obesity is a global health crisis affecting individuals across all age groups, significantly increasing the risk of metabolic disorders such as type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), and cardiovascular diseases. The World Health Organization reported in 2022 that 2.5 billion adults were overweight, with 890 million classified as obese, emphasizing the urgent need for effective interventions. A critical aspect of obesity's pathophysiology is meta-inflammation-a chronic, systemic low-grade inflammatory state driven by excess adipose tissue, which disrupts metabolic homeostasis. This review examines the role of autolysosomal dysfunction in obesity-related metabolic disorders, exploring its impact across multiple metabolic organs and evaluating potential therapeutic strategies that target autophagy and lysosomal function.

Emerging research highlights the importance of autophagy in maintaining cellular homeostasis and metabolic balance. Obesity-induced lysosomal dysfunction impairs the autophagic degradation process, contributing to the accumulation of damaged organelles and toxic aggregates, exacerbating insulin resistance, lipotoxicity, and chronic inflammation. Studies have identified autophagic defects in key metabolic tissues, including adipose tissue, skeletal muscle, liver, pancreas, kidney, heart, and brain, linking autophagy dysregulation to the progression of metabolic diseases. Preclinical investigations suggest that pharmacological and nutritional interventions-such as AMPK activation, caloric restriction mimetics, and lysosomal-targeting compounds-can restore autophagic function and improve metabolic outcomes in obesity models. Autolysosomal dysfunction is a pivotal contributor to obesity-associated metabolic disorders , influencing systemic inflammation and metabolic dysfunction. Restoring autophagy and lysosomal function holds promise as a therapeutic strategy to mitigate obesity-driven pathologies. Future research should focus on translating these findings into clinical applications, optimizing targeted interventions to improve metabolic health and reduce obesity-associated complications.