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Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin‐4 receptor
Author(s) -
Anderson Erica J. P.,
GhamariLangroudi Masoud,
Cakir Isin,
Litt Michael J.,
Chen Valerie,
Reggiardo Roman E.,
Millhauser Glenn L.,
Cone Roger D.
Publication year - 2019
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12670
Subject(s) - melanocortin , medicine , endocrinology , melanocortin 4 receptor , receptor , melanocortin receptor , stimulation , potassium channel , inward rectifier potassium ion channel , biology , melanocortin 3 receptor , chemistry , ion channel
Energy stores in fat tissue are determined in part by the activity of hypothalamic neurones expressing the melanocortin‐4 receptor ( MC 4R). Even a partial reduction in MC 4R 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 MC 4R. The MC 4R is a G protein‐coupled receptor that signals efficiently through Gα S , and this signalling pathway is essential for normal MC 4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC 4R depolarised neurones via G protein‐independent regulation of the ion channel Kir7.1. In the present study, we show that deletion of Kcnj13 (ie, the gene encoding Kir7.1) specifically from MC 4R neurones produced resistance to melanocortin peptide‐induced depolarisation of MC 4R paraventricular nucleus neurones in brain slices, resistance to the sustained anorexic effect of exogenously administered melanocortin peptides, late onset obesity, increased linear growth and glucose intolerance. Some MC 4R‐mediated phenotypes appeared intact, including Agouti‐related peptide‐induced stimulation of food intake and MC 4R‐mediated induction of peptide YY release from intestinal L cells. Thus, a subset of the consequences of MC 4R signalling in vivo appears to be dependent on expression of the Kir7.1 channel in MC 4R cells.