Alpha2/delta1- thrombospondin-3 signaling in the central control of metabolic function - Project Summary Brain-derived neurotrophic factor (BDNF) and its receptor TrkB play essential roles in the central regulation of energy and glucose homeostasis. BDNF signaling greatly influences many aspects of neuronal function, including survival, differentiation and synaptic plasticity and transmission. Deficits in BDNF function have been linked to over feeding and severe obesity in humans and mice. Accordingly, we showed that mice with BDNF depletion in the brain (BDNF2L/2LCk-cre) exhibit increased food intake, obesity, insulin resistance and dyslipidemia. Diminished a2d-1 (Cacna2d1) function in ventromedial hypothalamus (VMH) of BDNF2L/2LCk-cre mice contributes to the metabolic alterations that they exhibit. In support, viral-mediated rescue of deficient a2d-1 expression in the VMH of BDNF2L/2LCk-cre mice mitigated their hyperphagia and obesity. Importantly, it dramatically improved hepatic lipid accumulation and normalized deficits in glycemic control even though rescued mutants remained significantly heavier than wild type controls. Furthermore, a2d-1 knock down in the adult VMH resulted in susceptibility to diet-induced obesity (DIO). a2d-1 serves as a receptor for astrocyte- derived thrombospondins (TSP) to mediate excitatory synapse assembly. Electrophysiological analysis indicates that the metabolic effects of a2d-1 are related changes in the excitatory tone onto VMH neurons, implicating thrombospondin signaling. This project will test the hypothesis that TSP/a2d-1 signaling in the VMH facilitates synaptic remodeling during conditions of positive energy balance to increase the excitatory drive onto neurons mediating energy, glucose and lipid homeostasis. Aim 1 will determine how gain or loss of a2d-1 function in the adult VMH affects metabolic function and mechanisms activated by a2d-1 that prevent hepatic steatosis and glucose intolerance during obesogenic conditions. Aim 2 will examine the effects of gain or loss of astrocytic TSP function in the adult VMH in the regulation of metabolic function and whether these effects are a2d-1-dependent. Aim 3 will determine whether a2d-1 and TSP mediates the effects of caloric status on the excitatory synaptic physiology and activity of VMH neurons. Finally, Aim 4 will map the connectivity of VMH a2d-1+ neurons, examine their responses to caloric signals in vivo and the effects of stimulating or inhibiting these cells on metabolic function. Findings from this project will inform novel mechanisms facilitating metabolic health in individuals who are persistently overweight and new targets for the treatment of metabolic dysfunction. Importantly, they have the potential to inform pathological mechanisms underlying metabolic disturbances in individuals administered the anti-epileptic and anti- nociceptive drugs gabapentin and pregabalin, which bind and inhibit a2d-1.
