Oestrogen engages brain MC4R signalling to drive physical activity in female mice.

Autor: Krause WC; Department of Cellular and Molecular Pharmacology, School of Medicine, University of California San Francisco, San Francisco, CA, USA., Rodriguez R; Department of Cellular and Molecular Pharmacology, School of Medicine, University of California San Francisco, San Francisco, CA, USA., Gegenhuber B; School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA., Matharu N; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA., Rodriguez AN; Department of Cellular and Molecular Pharmacology, School of Medicine, University of California San Francisco, San Francisco, CA, USA., Padilla-Roger AM; Graduate Program in Neuroscience, University of California San Francisco, San Francisco, USA., Toma K; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.; Department of Physiology, University of California San Francisco, San Francisco, CA, USA., Herber CB; Department of Cellular and Molecular Pharmacology, School of Medicine, University of California San Francisco, San Francisco, CA, USA., Correa SM; Department of Cellular and Molecular Pharmacology, School of Medicine, University of California San Francisco, San Francisco, CA, USA.; Department of Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, CA, USA., Duan X; Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.; Department of Physiology, University of California San Francisco, San Francisco, CA, USA., Ahituv N; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.; Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA., Tollkuhn J; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. tollkuhn@cshl.edu., Ingraham HA; Department of Cellular and Molecular Pharmacology, School of Medicine, University of California San Francisco, San Francisco, CA, USA. holly.ingraham@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Nov; Vol. 599 (7883), pp. 131-135. Date of Electronic Publication: 2021 Oct 13.
DOI: 10.1038/s41586-021-04010-3
Abstrakt: Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes 1,2 , underscoring the conserved metabolic benefits of oestrogen that inevitably decrease with age. In rodents, the preovulatory surge in 17β-oestradiol (E2) temporarily increases energy expenditure to coordinate increased physical activity with peak sexual receptivity. Here we report that a subset of oestrogen-sensitive neurons in the ventrolateral ventromedial hypothalamic nucleus (VMHvl) 3-7 projects to arousal centres in the hippocampus and hindbrain, and enables oestrogen to rebalance energy allocation in female mice. Surges in E2 increase melanocortin-4 receptor (MC4R) signalling in these VMHvl neurons by directly recruiting oestrogen receptor-α (ERα) to the Mc4r gene. Sedentary behaviour and obesity in oestrogen-depleted female mice were reversed after chemogenetic stimulation of VMHvl neurons expressing both MC4R and ERα. Similarly, a long-term increase in physical activity is observed after CRISPR-mediated activation of this node. These data extend the effect of MC4R signalling - the most common cause of monogenic human obesity 8 - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women 9 . This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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