Adipose ATGL-dependent lipolysis is required for Calorie Restriction–induced Adipocyte heterogeneity and Metabolic health

Calorie restriction (CR) is a robust non-pharmacological intervention with well-documented lifespan and health span benefits in a range of species from flies to non-human primates. A major hallmark of CR is the metabolic reprogramming of white adipose tissue (WAT) marked by increased lipid mobilization and utilization. Prior studies from our lab show that CR induces both intra- and inter-adipose heterogeneity reflected by the presence of functionally distinct adipocyte sub-populations within the subcutaneous WAT (Sc-WAT) - a catabolic (medium chain acyl-CoA dehydrogenase (MCAD)high and fatty acid synthase (FASN)low expression cells) and anabolic phenotype (FASNhigh and MCADlow cells). Notably, this heterogeneity is absent in visceral WAT (Vis-WAT). Evidence from previous studies suggests that lipolysis and the transcriptional program activated by free fatty acids as key upstream regulators of adipocyte heterogeneity during CR. Based on these findings, we hypothesize that lipolysis is a key driver of adipocyte heterogeneity and, in turn, mediates the metabolic benefits of CR. To test this, we subjected wild-type (WT) and inducible adipose-specific ATGL knockout (iAAKO) mice (both sexes, 3–4 months old) to either ad libitum feeding or a 30% CR regimen for 16 weeks. Body composition was assessed, and indirect calorimetry was performed to evaluate whole-body energy metabolism. Glucose homeostasis was measured by oral glucose tolerance test and HOMA-IR, and adipose heterogeneity was evaluated using immunohistochemistry. Our results show that CR-induced reductions in body weight and fat mass were abolished in iAAKO compared to WT controls. In addition, CR-mediated improvements in glucose tolerance and insulin sensitivity were blunted in the iAAKO mice. Further, the loss of adipose ATGL diminished the beneficial effects of CR on metabolic rate and energy expenditure in iAAKO mice. Ongoing analyses are evaluating additional metabolic parameters, including adipose heterogeneity and mitochondrial function, circulating adipokines and metabolites, and inflammation. Collectively, our findings suggest that adipose ATGL-dependent lipolysis is required for the metabolic benefits of CR and likely regulates CR-induced adipocyte heterogeneity, including distinct populations specializing in de novo lipogenesis or lipid oxidation. This work is supported by NIH K01AG073613 and R03AG095868, AHA CDA1048544, AFAR Junior Faculty award and HHDC Novel pilot grant. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.