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A Cellular and Molecular Basis of Leptin Resistance

GSE281687 Mus musculus Expression profiling by high throughput sequencing; Other 6 samples Submitted 2025/04/09 Platform GPL23479
Summary
Humans with obesity and diet-induced obese mice (DIO) have high leptin levels and fail to respond to the exogenous hormone suggesting that 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 inhibit 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 while 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.
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Also filed as BioProject PRJNA1185223 and SRA study SRP544766. Searching any of these in the dataset finder brings you back here.

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