The Melanocortin Action Is Biased Toward Protection From Weight Loss in Mice

Authors

Hongli Li
Yuanzhong Xu
Yanyan Jiang
Zhiying Jiang
Joshua Otiz-Guzman
Jessie C Morrill
Jing Cai
Zhengmei Mao
Yong Xu
Benjamin R Arenkiel
Cheng Huang
Qingchun Tong

Publication Date

4-17-2023

Journal

Nature Communications

Abstract

The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. Furthermore, gain of function of the melanocortin action through overexpression of MC4R, POMC or its derived peptides had little effect on obesity prevention or reversal. These results reveal a bias of the melanocortin action towards protection of weight loss and provide a neural basis behind the well-known, but mechanistically ill-defined, predisposition to obesity development.

Keywords

Mice, Animals, Melanocortins, Pro-Opiomelanocortin, alpha-MSH, Obesity, Body Weight, Weight Loss, Receptor, Melanocortin, Type 4, Obesity, Hypothalamus, Obesity

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Associated Data

PMID: 37069175