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 neurones expressing the melanocortin-4 receptor (MC4R). Even a 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 GαS , and this signalling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R 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 MC4R neurones produced resistance to melanocortin peptide-induced depolarisation of MC4R 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 MC4R-mediated phenotypes appeared intact, including Agouti-related peptide-induced stimulation of food intake and MC4R-mediated induction of peptide YY release from intestinal L cells. Thus, a subset of the consequences of MC4R signalling in vivo appears to be dependent on expression of the Kir7.1 channel in MC4R cells.

• Authors: Erica J P Anderson, Masoud Ghamari-Langroudi, Isin Cakir, Michael J Litt, Valerie Chen, Roman E Reggiardo, Glenn L Millhauser, Roger D Cone
• Journal: Journal of neuroendocrinology (J Neuroendocrinol) Vol. 31 Issue 1 Pg. e12670 (01 2019) ISSN: 1365-2826 [Electronic] United States
• PMID: 30561082 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 British Society for Neuroendocrinology.

Chemical References

• Kir7.1 channel
• Potassium Channels, Inwardly Rectifying
• Receptor, Melanocortin, Type 4

Topics

• Animals
• Feeding Behavior (physiology)
• Female
• Hypothalamus (physiopathology)
• Male
• Membrane Potentials
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (physiology)
• Obesity (physiopathology)
• Potassium Channels, Inwardly Rectifying (genetics, physiology)
• Receptor, Melanocortin, Type 4 (physiology)