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

William C. Krause, Ruben Rodriguez, Bruno Gegenhuber, Navneet Matharu, Andreas N. Rodriguez, Adriana M. Padilla-Roger, Kenichi Toma, Candice B. Herber, Stephanie M. Correa, Xin Duan, Nadav Ahituv, Jessica Tollkuhn () and Holly A. Ingraham ()
Additional contact information
William C. Krause: University of California San Francisco
Ruben Rodriguez: University of California San Francisco
Bruno Gegenhuber: Cold Spring Harbor Laboratory
Navneet Matharu: University of California San Francisco
Andreas N. Rodriguez: University of California San Francisco
Adriana M. Padilla-Roger: University of California San Francisco
Kenichi Toma: University of California San Francisco
Candice B. Herber: University of California San Francisco
Stephanie M. Correa: University of California San Francisco
Xin Duan: University of California San Francisco
Nadav Ahituv: University of California San Francisco
Jessica Tollkuhn: Cold Spring Harbor Laboratory
Holly A. Ingraham: University of California San Francisco

Nature, 2021, vol. 599, issue 7883, 131-135

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-04010-3

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