1574-P: Loss of Slit3 in Adipocyte Progenitors Impairs Brown Adipose Tissue Function and Systemic Metabolism

Introduction and Objective: Obesity is a complex condition characterized by excessive body fat accumulation, influenced by genetic, environmental, and behavioral factors. White adipose tissue (WAT) stores excess energy in the form of triglycerides. Brown adipose tissue (BAT), however, is a specialized type of adipose that plays a distinct role in energy expenditure and adaptive thermogenesis through the conversion of metabolites such as glucose and lipids to heat rather than energy storage. Therefore, enhancing BAT activity is a promising strategy to combat obesity and its related metabolic disorders. Methods: To sustain its thermogenic capacity, BAT requires a dense network of sympathetic nerves and blood vessels. We have recently identified Slit guidance ligand 3 (Slit3) as a new adipokine that is essential for the development and cold-induced expansion of BAT neurovasculature. We found that Slit3 is primarily expressed in Platelet derived growth factor receptor alpha (Pdgfra)-expressing adipocyte progenitor cells (Pdgfra-creposAPCs). Given this, we developed two independent APC-specific Slit3 loss-of-function mouse models, Pdgfra-cre;Slit3flox and Pdgfra-creERT2;Slit3flox to investigate how the specific deletion of Slit3 in Pdgfra-crepos APCs affects WAT and BAT development and its effect on systemic metabolism. Results: Our findings show that specifically targeting these cells in vivo ablates Slit3 expression in WAT and BAT depots. Both our constitutive and inducible knockout models showed that the loss of Slit3 impairs cold-induced thermogenesis. Moreover, male Pdgfra-cre;Slit3flox mice exhibit impaired glucose tolerance and insulin resistance when fed a high-fat diet. Conclusion: In summary, these findings demonstrate that Slit3 is required for proper development and remodeling of adipose tissue and plays a critical role in regulating systemic metabolism. Disclosure H.E. Cervantes: None. T. Duarte Afonso Serdan: None. F. Shamsi: None. Funding NIH/NIDDK (R01DK136724)?(to F.S.)