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

Authors: LI, HONGLI - Shanghai University; XU, YUANZHONG - University Of Texas Health Science Center; JIANG, YANYAN - University Of Texas Health Science Center; JIANG, ZHIYING - University Of Texas Health Science Center; OTIZ-GUZMAN, JOSHUA - Baylor College Of Medicine; MORRILL, JESSIE - University Of Texas Health Science Center; CAI, JING - University Of Texas Health Science Center; MAO, ZHENGMEI - University Of Texas Health Science Center; XU, YONG - Children'S Nutrition Research Center (CNRC); ARENKIEL, BENJAMIN - Children'S Nutrition Research Center (CNRC); HUANG, CHENG - Shanghai University; TONG, QINGCHUN - University Of Texas Health Science Center

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/5/2023
Publication Date: 4/17/2023
Citation: Li, H., Xu, Y., Jiang, Y., Jiang, Z., Otiz-Guzman, J., Morrill, J., Cai, J., Mao, Z., Xu, Y., Arenkiel, B., Huang, C., Tong, Q. 2023. The melanocortin action is biased toward protection from weight loss in mice. Nature Communications. 14. Article 2200. https://doi.org/10.1038/s41467-023-37912-z.
DOI: https://doi.org/10.1038/s41467-023-37912-z

Interpretive Summary: The way our body regulates weight is controlled by a process called melanocortin action. It's a system that helps us gain or lose weight. But even though we know it can help us lose weight, it has been hard to figure out how to use it to treat obesity. Scientists conducted experiments and found that changes in the melanocortin action only make us gain weight, not lose it. This was done by blocking certain neurons that control weight gain and found that the mice they studied became obese. But when they tried to activate those cells to help the mice lose weight, it didn't work. They also tried overexpressing certain genes, but that didn't really help either. This informs researchers that the melanocortin system is better at protecting us from losing weight, rather than helping us lose weight. This might be why it's been difficult to use it to treat obesity.

Technical 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.