Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin‐4 receptor

Abstract

Energy stores in fat tissue are determined in part by the activity of hypothalamic neurons expressing the melanocortin‐4 receptor (MC4R). Even partial reduction in MC4R expression levels in mice, rats, or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein‐coupled receptor that signals efficiently through Gα_S, and this signaling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R depolarized neurons through G protein‐independent regulation of the ion channel Kir7.1. We showed here that deletion of Kcnj13, the gene encoding Kir7.1, specifically from MC4R neurons produced resistance to melanocortin peptide‐induced depolarization of MC4R PVN neurons in brain slices, resistance to the sustained anorexic effect of exogenously administered melanocortin peptides, late onset obesity, increased linear growth, and glucose intolerance. Some MC4R‐mediated phenotypes appeared intact, including AgRP‐induced stimulation of food intake, and MC4R‐mediated induction of PYY release from intestinal L cells. Thus, a subset of the consequences of MC4R signaling in vivo appear dependent on expression of the Kir7.1 channel in MC4R cells.

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