Data from: 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 is 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 enhanced activity 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 may further identify a K+ channel as a
causative link between epileptic and metabolic disorders.