Substrate-Selective Lipolysis Facilitates Unsaturated TAG Accumulation in Obesity

Obese adipose tissue is enriched in unsaturated triacylglycerol (TAG) species, yet the mechanisms driving this lipid remodeling remain incompletely understood. In this study, we conducted comprehensive lipidomic profiling of white adipose tissue from predominantly midlife obese individuals and consistently observed an enrichment of unsaturated TAG species. Acyl chain analysis of both TAGs and glycerophospholipids revealed a predominance of  C18 unsaturated fatty acids (FAs), particularly FA 18:1 and FA 18:2. To investigate the mechanistic basis of this selective enrichment, we performed integrated functional assays of lipogenesis and lipolysis in adipocytes under substrate-rich conditions. We found that adipose triglyceride lipase (ATGL), the rate-limiting enzyme in TAG hydrolysis, exhibits substrate selectivity: preferentially hydrolyzing saturated TAGs while displaying reduced activity toward unsaturated TAGs. This substrate-selective lipolysis impairs the mobilization of unsaturated TAGs, leading to their preferential retention and accumulation in obese adipose tissue. These findings reveal a previously underappreciated mechanism of lipid remodeling in obesity, whereby ATGL-mediated substrate specificity contributes to the disproportionate accumulation of unsaturated TAGs. This molecular insight highlights the importance of lipase selectivity in shaping adipose lipid composition and maintaining metabolic homeostasis.