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

ABSTRACT: 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 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.

SUBMITTER: Krause WC

PROVIDER: S-EPMC9113400 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Krause William C WC Rodriguez Ruben R Gegenhuber Bruno B Matharu Navneet N Rodriguez Andreas N AN Padilla-Roger Adriana M AM Toma Kenichi K Herber Candice B CB Correa Stephanie M SM Duan Xin X Ahituv Nadav N Tollkuhn Jessica J Ingraham Holly A HA

Nature 20211013 7883

Oestrogen depletion in rodents and humans leads to inactivity, fat accumulation and diabetes<sup>1,2</sup>, 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)<sup> ...[more]

PMID: 34646010

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

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

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