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

Krause, William C, Rodriguez, Ruben, Gegenhuber, Bruno, Matharu, Navneet, Rodriguez, Andreas N, Padilla-Roger, Adriana M, Toma, Kenichi, Herber, Candice B, Correa, Stephanie M, Duan, Xin, Ahituv, Nadav, Tollkuhn, Jessica, Ingraham, Holly A (October 2021) Oestrogen engages brain MC4R signalling to drive physical activity in female mice. Nature. ISSN 0028-0836

Abstract

Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes1,2, 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 obesity8 - beyond the regulation of food intake and rationalize reported sex differences in melanocortin signalling, including greater disease severity of MC4R insufficiency in women9. This hormone-dependent node illuminates the power of oestrogen during the reproductive cycle in motivating behaviour and maintaining an active lifestyle in women.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics Investigative techniques and equipment organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions Investigative techniques and equipment > CRISPR-Cas9 bioinformatics > genomics and proteomics > small molecules > estrogen organs, tissues, organelles, cell types and functions > tissues types and functions > hippocampus organism description > animal > mammal organism description > animal behavior > motion organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons diseases & disorders > nutritional and metabolic diseases > obesity organs, tissues, organelles, cell types and functions organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > small molecules organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Gegenhuber, Bruno Tollkuhn, Jessica
Communities:	CSHL labs > Tollkuhn lab School of Biological Sciences > Publications
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	13 October 2021
Date Deposited:	20 Oct 2021 13:40
Last Modified:	25 Jan 2024 14:37
PMCID:	PMC9113400
URI:	https://repository.cshl.edu/id/eprint/40390

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