Vascular sympathetic neurons in brown adipose tissue and systemic metabolism

PROJECT SUMMARY Cold exposure increases thermogenesis in brown adipose tissue (BAT) and improves systemic glucose and lipid metabolism. Thermogenesis is an energy-demanding process that relies on enhanced blood flow as well as uptake of fuels, processes that are triggered by sympathetic nervous system signaling. Thus, these parameters are often considered interchangeably when assessing the potential metabolic benefits of stimulating BAT in humans. And yet, there are conditions like diabetes where BAT thermogenic activity and glucose uptake are dissociated. A critical gap in the field stems from the consideration of sympathetic inputs to BAT as homogeneous, when it is well-established that perivascular sympathetic neurons (PVSNBAT) that project along blood vessels to innervate the organ parenchyma are molecularly and electrophysiologically distinct from vascular sympathetic neurons (VSNBAT) that innervate the vasculature. We developed a toolkit that includes novel mouse genetic and chemogenetic tools, improved imaging techniques and in vivo assays to parse the functions of projections from distinct subpopulations of sympathetic neurons to BAT. Chemogenetic stimulation of PVSNsBAT increases blood flow and thermogenesis, while activating VSNsBAT influences systemic glucose metabolism without altering blood flow. This was unexpected, as VSNs elsewhere in the body regulate vasoconstriction and vasodilation. The proposed studies utilize our new tools to explore the hypothesis that VSNBAT signals confer protection from obesity-induced metabolic dysfunction and to uncover the mechanisms regulating these effects. Experiments in Aim 1 use complementary chronic gain- and loss-of-function approaches to evaluate the contribution of VSNBAT to systemic glucose metabolism in the lean and obese condition. Subsequent Aims leverage our discovery that most of the molecular markers for VSNBAT are either ligands or receptors that have been implicated in glycemic regulation in humans. Experiments in Aim 2 evaluate contributions of co-transmitted ligands to VSNBAT actions. Experiments in Aim 3 explore whether signaling through specific receptors modulates the firing properties and functions of VSNBAT. This knowledge could lead to the identification of a new class of therapeutic compounds that target VSNBAT to improve glucose metabolism and insulin sensitivity independent of adrenergic agonists.