KCNB1-Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus

The neurons of the melanocortin system regulate feeding and energy homeostasis through a combination of electrical and endocrine mechanisms. However, the molecular basis for this functional heterogeneity are poorly understood. Here, a voltage-gated potassium (K+) channel named KCNB1 (alias Kv2.1), formed stable complexes with the leptin receptor (LepR) in proopiomelanocortin (POMC) expressing neurons of the Arcuate nucleus of the hypothalamus (ARCPOMC). Mice lacking functional KCNB1 channels (NULL mice), exhibited constitutive depolarization of ARCPOMC neurons along with aberrant POMC production. In NULL neurons, canonical LepR-STAT3 signaling--which underlies POMC production--was impaired, whereas non-canonical insulin receptor substrate PI3K/Akt/FOXO1 and ERK signaling were significantly upregulated. Accordingly, the NULL animals were insensitive to anorexic stimuli induced by leptin administration and produced less adipose tissue and circulating leptin than WT animals. Taken together, these findings unveil an exquisite mechanism of metabolic regulation whereby synergistic control of neuronal excitability and endocrine function is achieved through the partnership between a K+ channel and a hormone receptor. As aberrant KCNB1 channels cause developmental and epileptic encephalopathies, these results further establish a K+ channel as a causative link between epileptic and metabolic disorders.