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.
