Cytosolic Versus Lysosomal Lipolysis in Adipose Tissue: Opposing Roles in Cardiometabolic Disease

Adipose tissue lipid metabolism is a critical regulator of systemic energy balance, but its impact on cardiometabolic health is paradoxical. This review dissects the 2 primary lipolytic systems in adipocytes: the canonical cytosolic pathway driven by ATGL/PNPLA2 (adipose triglyceride lipase) and the lysosomal pathway governed by LAL/LIPA (lysosomal acid lipase). We present emerging evidence that these pathways exert opposing effects in the context of obesity. While excessive fatty acid efflux from dysregulated cytosolic lipolysis is a known driver of adiposopathic dyslipidemia, adipose inflammation, and direct cardiac lipotoxicity, which collectively impair cardiometabolic health, the activity of the lysosomal pathway is emerging as a protective counterbalance. Genetic and pharmacological studies demonstrate that inhibiting cytosolic ATGL is beneficial for metabolic health, whereas enhancing LAL-mediated lipolysis mitigates obesity-related dysfunction. This functional antagonism between cytosolic and lysosomal lipolysis presents a new paradigm in lipid metabolism, suggesting that therapeutic strategies must be pathway-specific. We conclude that selectively inhibiting pathogenic cytosolic lipid release while promoting beneficial lysosomal lipid processing offers a nuanced approach to treating metabolic disease.