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Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals

Abstract

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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Figure 1: Estrogen regulates the type and number of axosomatic synapses on POMC perikarya in wild-type rodents of both sexes.
Figure 2: The increase in the number of glutamatergic, excitatory synapses on POMC perikarya increases arcuate POMC tone.
Figure 3: Estrogen exerts an antiobesity effect independent of functional genes encoding leptin and leptin receptor.
Figure 4: Estrogen mimics leptin's effect on the rewiring of melanocortin cells and increasing POMC tone, independent of leptin receptor–mediated signaling.

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Acknowledgements

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.).

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Q.G. contributed to the design, execution and analysis of experiments, and to the writing of the paper. G.M. carried out the original estrogen treatment experiments on ob/ob animals. Y.N. contributed to the design end execution of the Stat-3 analysis. Y.R. carried out electrophysiological recordings. C.S.C. carried out energy expenditure analysis on experimental animals. I.B. designed and carried out glutamate receptor expression experiments in the hypothalamus. C.L. contributed to the generation of post-embedding labeling for glutamate, for electron microscopy. D.T.-A. oversaw the experiments involving ERá-knockout animals. C.A.P., J.L.R. and C.M. conducted experiments involving c-Fos. X.-B.G. supervised and analyzed the electrophysiological experiments. G.I.S. supervised and analyzed the experiments involving whole-animal energy metabolism. S.D. contributed to the design of the experiments, the execution of glutamate receptor experiments and the analysis of data. T.L.H. designed the project, contributed to the analysis of all the data and to the writing of the paper, and analyzed the synaptology of POMC neurons.

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Correspondence to Qian Gao or Tamas L Horvath.

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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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