Autolysosomal Dysfunction in Obesity-induced Metabolic Inflammation and Related Disorders

Abstract

Purpose of review: 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.

Recent findings: 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.

Keywords: Autophagy function; Lysosomal acidification; Metabolic inflammation; Neurodegeneration; Neuroinflammation; Therapeutic strategies.

Fig. 1

Impact of obesity on various organ systems and tissues. In adipose tissue, obesity induces hypertrophy, immune cell infiltration, and the release of adipokines and inflammatory cytokines, which can propagate systemic inflammation. In skeletal muscle, obesity contributes to reduced muscle mass and strength. In the gut, obesity compromises intestinal barrier integrity and increased gut dysbiosis. In the liver and pancreas, excessive lipid accumulation leads to increased inflammation, impaired insulin signaling, and reduced insulin secretion in the pancreas. In the kidneys, obesity results in glomerular hypertrophy, macrophage infiltration, and heightened inflammation. In the heart, obesity is associated with contractile dysfunction and an increased risk of cardiomyopathy. In the brain, obesity promotes neuroinflammation and neuronal cell death. Furthermore, obesity-driven inflammation and cytokine release facilitate crosstalk between organs, exacerbating systemic metabolic dysfunction. Created with Biorender.com

Fig. 2

Key mechanisms by which obesity contributes to lysosomal acidification dysfunction. Under obesity-induced metabolic inflammation, excess free fatty acids (FFAs), cytokines, and adipokines disrupt lysosomal function by promoting the dissociation of lysosomal V-ATPase subunits, leading to increased lysosomal pH. Mitochondrial damage further exacerbates this dysfunction by reducing ATP production, limiting the energy supply required for lysosomal V-ATPase activity. Elevated lysosomal pH can induce lysosomal membrane permeabilization, resulting in the release of lysosomal cathepsins (e.g., CTSB) into the cytosol, triggering inflammation and cell death. Additionally, impaired autophagosome-lysosome fusion reduces autophagic flux. Excess lipids and cytokines also activate mTOR, which inhibits the ULK1, thereby suppressing autophagosome formation. Furthermore, mTOR activation suppresses TFEB activity, reducing lysosomal biogenesis and contributing to increased lysosomal pH. Created with Biorender.com

Fig. 3

Summary of therapeutic agents modulating autophagy initiation and lysosomal function. Therapeutic strategies targeting autophagy initiation primarily involve exercise, dietary supplementation (e.g., EPA, EGCG), and caloric restriction, which enhance AMPK activation. This, in turn, promotes ULK1 activation, leading to increased autophagosome formation while simultaneously inhibiting mTOR to further enhance autophagy. Pharmacological agents such as canagliflozin inhibit mTOR to induce autophagy. To restore lysosomal function, nanoparticles such as ceria-zirconia and salvianolic acid B NPs, as well as compounds like phillygenin, baicalein, and liraglutide, have been shown to upregulate TFEB, thereby enhancing lysosomal biogenesis. Additionally, nanoparticles that are designed to release acidic components (e.g., PLGA NPs, PEFSU NPs, TFSA NPs) to lower lysosomal pH can improve lysosomal acidification and function. It is important to note that while increasing autophagy initiation leads to greater autophagosome formation, this alone is insufficient if lysosomal function remains impaired. Without functional lysosomes, autophagosomes cannot fuse and degrade their contents effectively. Therefore, therapeutic approaches should target both autophagy initiation and lysosomal function to achieve optimal cellular restoration. Created with Biorender.com