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

URL: https://www.ncbi.nlm.nih.gov/pubmed/34646010
DOI: 10.1038/s41586-021-04010-3


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 > genomics and proteomics > small molecules > estrogen
organism description > animal behavior > motion
diseases & disorders > nutritional and metabolic diseases > obesity
CSHL Authors:
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: 01 Jun 2022 16:02
PMCID: PMC9113400
URI: https://repository.cshl.edu/id/eprint/40390

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving