Targeting Adipose Tissue Neurovasculature to Improve Metabolism

Obesity affects 19% of children and 42% of adults in the US and increases the risk for the leading causes of death in the US and worldwide, including diabetes, heart disease, stroke, and some types of cancer. Brown adipose tissue (BAT) is a specialized type of adipose that is primarily responsible for regulating body temperature. Once activated by cold, BAT dissipates the chemical energy as heat in a process called adaptive thermogenesis. BAT is functionally distinct from white adipose tissue (WAT) which is the primary site of energy storage. Due to their high metabolic activity, thermogenic adipocytes act as a metabolic sink to improve glucose and lipid metabolism and thus exhibit anti-diabetic and lipid-lowering effects. The major challenge in targeting BAT thermogenesis as an anti-diabetes and anti-obesity therapy is the limited amount of active BAT in most adult humans. A critical barrier to harnessing the potential of BAT to enhance cardiometabolic health in humans is the lack of understanding of the full range of pathways involved in the activation of BAT thermogenesis. We have recently identified the axon guidance ligand Slit3 as an essential regulator of BAT thermogenesis. We showed that loss of Slit3 dramatically reduces angiogenesis and sympathetic innervation in BAT and impairs cold-induced BAT thermogenesis. However, the role of Slit3 in the establishment of the neurovascular network in developing adipose tissue and in response to obesogenic challenges is unknown. In this proposal, we will use a series of innovative strategies to determine the role of Slit3 in the early development of adipose tissue neurovasculature (Aim 1) and obesity-induced expansion and remodeling of adipose tissue (Aim 2). Since enhanced angiogenesis and sympathetic innervation in adipose tissue is linked to improved metabolic health, we will address the potential of Slit3 to ameliorate the detrimental effects of diet-induced and genetic obesity by promoting angiogenesis and sympathetic innervation in BAT and WAT. Successful completion of the proposed studies will identify a new potential node of intervention for obesity and metabolic diseases by stimulating the healthy expansion of adipose tissue.