The melanocortin action is biased toward protection from weight loss in mice

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 () and Qingchun Tong ()
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Hongli Li: Shanghai University of Traditional Chinese Medicine
Yuanzhong Xu: University of Texas Health Science Center at Houston
Yanyan Jiang: University of Texas Health Science Center at Houston
Zhiying Jiang: University of Texas Health Science Center at Houston
Joshua Otiz-Guzman: Texas Children’s Hospital
Jessie C. Morrill: University of Texas Health Science Center at Houston
Jing Cai: University of Texas Health Science Center at Houston
Zhengmei Mao: University of Texas Health Science Center at Houston
Yong Xu: Baylor College of Medicine, One Baylor Plaza
Benjamin R. Arenkiel: Texas Children’s Hospital
Cheng Huang: Shanghai University of Traditional Chinese Medicine
Qingchun Tong: University of Texas Health Science Center at Houston

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37912-z

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