| Autor: |
Zhao, Shangang, Li, Na, Xiong, Wei, Li, Guannan, He, Sijia, Zhang, Zhuzhen, Zhu, Qingzhang, Jiang, Nisi, Ikejiofor, Christian, Zhu, Yi, Wang, May-Yun, Han, Xianlin, Zhang, Ningyang, Solis-Herrera, Carolina, Kusminski, Christine, An, Zhiqiang, Elmquist, Joel K., Scherer, Philipp E. |
| Předmět: |
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| Zdroj: |
Diabetes; Feb2024, Vol. 73 Issue 2, p197-210, 14p |
| Abstrakt: |
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. Article Highlights: Weight loss agents in the glucagon-like peptide 1 receptor and FGF21 group induced a rapid suppression of leptin immediately upon agonist exposure. This leptin suppression significantly contributed to the weight loss. Further leptin suppression with a leptin neutralizing antibody enhanced weight loss and further improved insulin sensitivity. Enhanced leptin reduction leads to further reduction in hepatic steatosis and fibrosis. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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