American Diabetes Association
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Leptin Reduction as a Required Component for Weight Loss

posted on 2023-11-07, 21:42 authored by Shangang Zhao, Na Li, Wei Xiong, Guannan Li, Sijia He, Zhuzhen Zhang, Qingzhang Zhu, Nisi Jiang, Christian Ikejiofor, Yi Zhu, May-Yun Wang, Xianlin Han, Ningyang Zhang, Carolina Herrera-Solis, Christine Kusminski, Zhiqiang An, Joel K. Elmquist, Philipp E. Scherer


Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the GLP1R agonist liraglutide rapidly induce a reduction in leptin. This leptin reduction contributes to the beneficial effects of GLP1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtails the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induces greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain is observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slows down weight gain and preserves a better glucose tolerance. Mechanistically, a significant reduction in leptin induces a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.

Article Highlights

· Weight loss agents in the GLP1R and FGF21 group induce a rapid suppression of leptin immediately upon agonist exposure.

· This leptin suppression significantly contributes to the weightloss.

· Further leptin suppression with a leptin-neutralizing antibody enhances weight loss and further improves insulin sensitivity.

· Enhanced leptin reduction leads to further reduction in hepatic steatosis and fibrosis.


American Heart Association

U.S. Department of Health and Human Services > National Institutes of Health P01-AG051459 R00-AG068239 R00-DK114498 R01-DK088423 R01-DK099110 R01-DK118725 R01-DK127274 R01-DK131537 R01-DK136532 R01-DK55758 RC2-DK118620