2025-03-04 ロックフェラー大学
<関連情報>
- https://www.rockefeller.edu/news/37433-researchers-discover-a-cause-of-leptin-resistance-and-how-to-reverse-it/
- https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00001-4
レプチン抵抗性の細胞および分子基盤 A cellular and molecular basis of leptin resistance
Bowen Tan∙ Kristina Hedbacker∙ Leah Kelly∙ … ∙ Ji-Dung Luo∙ Joshua D. Rabinowitz∙ Jeffrey M. Friedman
Cell Metabolism Published:January 2, 2025
DOI:https://doi.org/10.1016/j.cmet.2025.01.001
Graphical abstract
Highlights
•Rapamycin, an mTOR inhibitor, reduces food intake and fat mass in DIO mice
•Rapamycin’s effect requires intact leptin-melanocortin signaling
•Rapamycin pre-treatment of DIO mice reverses leptin resistance in POMC neurons
•Increased mTOR activity in POMC neurons causes leptin resistance
Summary
Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin’s actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.
