瘦素
利拉鲁肽
减肥
内分泌学
内科学
小鼠苗条素受体
医学
肥胖
糖尿病
2型糖尿病
作者
Shangang Zhao,Na Li,Wei Xiong,Guannan Li,Sijia He,Zhuzhen Zhang,Qianzheng Zhu,Nisi Jiang,Christian Ikejiofor,Yi Zhu,May-Yun Wang,Xiao Han,Ningyang Zhang,Carolina Herrera-Solis,Christine M. Kusminski,Zhiqiang An,Joel K. Elmquist,Philipp E. Scherer
出处
期刊:Diabetes
[American Diabetes Association]
日期:2023-11-07
卷期号:73 (2): 197-210
摘要
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.
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