237-LB: Regulation of Brown Adipose Tissue Neurovasculature by Slit3 Fragments

Abstract

The ability of brown adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a target against obesity. Chronic cold exposure increases brown adipose tissue (BAT) mass by de novo recruitment of brown adipocytes, as well as expanding the number of blood vessels and sympathetic nerves in the tissue. This coordinated expansion of the BAT neurovasculature is essential for enhanced thermogenesis. However, how these distinct processes are coordinated remains unclear. We have recently identified Slit guidance ligand 3 (Slit3) as a new niche factor that mediates crosstalk between preadipocytes, sympathetic neurons, and endothelial cells. We showed that Slit3 is essential for cold-induced angiogenesis and sympathetic innervation in BAT and that loss of Slit3 impairs cold-induced BAT thermogenesis in vivo. However, how Slit3 regulates the expansion of angiogenesis and sympathetic innervation is not known. Members of the Slit family are proteolytically cleaved into a large N-terminal fragment and a shorter C-terminal fragment. We observed that Slit3 undergoes proteolytic cleavage in adipocyte progenitors, generating Slit3 N-terminal (Slit3-N) and C-terminal (Slit3-C) fragments. Overexpression of Slit3-N and Slit3-C in BAT revealed distinct and overlapping functions of Slit3 fragments in the regulation of angiogenesis and sympathetic innervation. Collectively, this study provides important mechanistic insights into the role of Slit3 in regulating angiogenesis and sympathetic innervation in BAT. These findings could lead to the development of new approaches to enhance thermogenesis and combat obesity and related metabolic disorders. Disclosure F. M. Neto: None. H. E. Cervantes: None. T. Duarte afonso serdan: None. F. Shamsi: None. Funding National Institutes of Health (K01DK125608)