Alpha2delta‐1 Identified as a novel effector underlying the action of brain‐derived neurotrophic factor in hypothalamic control of feeding in mice (641.21)

Abstract

Brain‐derived neurotrophic factor (BDNF), a protein that supports neuronal survival and synaptic plasticity, is essential for energy balance regulation. Genetic polymorphisms that impede BDNF function pose risk factors for obesity in humans. Similarly, blunted BDNF signaling in the rodent brain is associated with overeating (OV), body weight (BW) gain and metabolic dysfunction. Here we identified alpha2delta‐1 (α2δ‐1), a high voltage‐gated calcium channel subunit and thrombospondin receptor, as a novel appetite regulator underlying BDNF function in the ventromedial hypothalamus (VMH). α2δ‐1 is highly expressed in the VMH of wild‐type (WT) mice. Moreover, mice lacking central Bdnf (CM) have reduced cell surface α2δ‐1 expression in VMH cells. Selective inhibition of VMH α2δ‐1 in WT mice through chronic delivery of gabapentin resulted in a significant increase in food intake and BW gain after 7 days. Rescuing the α2δ‐1 deficit in VMH cells of CM, through targeted delivery of an adeno‐associated virus encoding α2δ‐1, mitigated the OV and BW gain and normalized glucose homeostasis. These data inform mechanisms underlying effects of BDNF in the VMH and identify a critical role for α2δ‐1 in feeding control.