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. Overall design: The goal was to use transcriptome analysis to determine differences in mRNA levels in the hypothalami of C57BL6/J mice (wild type, WT) and homozygous Kcnb1NULL KI mice (C57BL/6J-Kcnb1em2Sesf/J) here called NULL. The Kcnb1NULL allele bears a nonsense (stop) mutation in the exon coding for the S4 transmembrane domain of the KCNB1 protein. This results in a truncated protein (?37 kDa vs ? 110 kDa of the WT protein) that is not trafficked to the plasma membrane and is quickly degraded. Results from preclinical models of obesity have not underscored a clear sex-dependence. Therefore age-matched animals of either sexes were used. Specifically we used one WT and one NULL six month-old and two WT and two NULL one month-old animals (total 6 mice).