Leptin reduction as a required component for weight loss

Authors: ZHAO, SHANGANG - University Of Texas Southwestern Medical Center; LI, NA - University Of Texas Southwestern Medical Center; XIONG, WEI - University Of Texas Health Science Center; LI, GUANNAN - University Of Texas At San Antonio; HE, SIJIA - University Of Texas At San Antonio; ZHANG, ZHUZHEN - Wuhan University; ZHU, QINGZHANG - University Of Texas Southwestern Medical Center; JIANG, NISI - University Of Texas At San Antonio; IKEJIOFOR, CHRISTIAN - University Of Texas At San Antonio; ZHU, YI - Children'S Nutrition Research Center (CNRC); WANG, MAY-YUN - University Of Texas Southwestern Medical Center; HAN, XIANLIN - University Of Texas At San Antonio; ZHANG, NINGYANG - University Of Texas Health Science Center; SOLIS-HERRERA, CAROLINA - University Of Texas At San Antonio; KUSMINSKI, CHRISTINE - University Of Texas Southwestern Medical Center; AN, ZHIQIANG - University Of Texas Health Science Center; ELMQUIST, JOEL - University Of Texas Southwestern Medical Center; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/31/2023
Publication Date: 2/1/2024
Citation: Zhao, S., Li, N., Xiong, W., Li, G., He, S., Zhang, Z., Zhu, Q., Jiang, N., Ikejiofor, C., Zhu, Y., Wang, M., Han, X., Zhang, N., Solis-Herrera, C., Kusminski, C., An, Z., Elmquist, J.K., Scherer, P.E. 2024. Leptin reduction as a required component for weight loss. Diabetes. 73(2):197-210. https://doi.org/10.2337/db23-0571.
DOI: https://doi.org/10.2337/db23-0571

Interpretive Summary: Reducing leptin levels can lead to weight loss, and weight loss can in turn lower leptin levels. This paper found that certain drugs can quickly lower leptin levels, which contributes to their positive effects on metabolism. By lowering leptin even more using additional treatments, they saw even greater weight loss and improved glucose tolerance in obese mice, suggesting that reducing leptin may be a key step in treating obesity and insulin resistance.

Technical Abstract: 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 glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed 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 induced 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 was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced 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.