Metabolic hormones, such as leptin, alter the input organization of hypothalamic circuits1,2,3, resulting in increased pro-opiomelanocortin (POMC) tone, followed by decreased food intake and adiposity. The gonadal steroid estradiol can also reduce appetite and adiposity4,5, and it influences synaptic plasticity6. Here we report that estradiol (E2) triggers a robust increase in the number of excitatory inputs to POMC neurons in the arcuate nucleus of wild-type rats and mice. This rearrangement of synapses in the arcuate nucleus is leptin independent because it also occurred in leptin-deficient (ob/ob) and leptin receptor–deficient (db/db) mice, and was paralleled by decreased food intake and body weight gain as well as increased energy expenditure. However, estrogen-induced decrease in body weight was dependent on Stat3 activation in the brain. These observations support the notion that synaptic plasticity of arcuate nucleus feeding circuits is an inherent element in body weight regulation and offer alternative approaches to reducing adiposity under conditions of failed leptin receptor signaling.
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We thank M. Shanabrough and E. Borok for technical assistance and critical revision of our manuscript and J.M. Friedman for the wild-type POMC-GFP transgenic mice. T.L.H. thanks F. Naftolin and L.M. Garcia-Segura for their insight and leadership in promoting hypothalamic synaptic plasticity. This work was supported by the US National Institutes of Health (grants DK-060711 and DK-074386 to T.L.H.; DK061619 and DK-070039 to S.D.; DK061478 and DK-070723 to X.-B.G.; and DK-059635 to G.I.S.).
The authors declare no competing financial interests.
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Gao, Q., Mezei, G., Nie, Y. et al. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med 13, 89–94 (2007). https://doi.org/10.1038/nm1525
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