Estrogen-sensitive medial preoptic area neurons coordinate torpor in mice

Zhi Zhang,India Nichols,Shawn Anderson,Nilla Sivakumar,Johnathon R Divittorio,Fernando M C V Reis,Yong Xu,Jae W Park,Michael Shum,Megan G Massa,Sandra Maesta-Pereira,Olujimi A Ajijola,Stephanie M Correa,Ketema Paul,J Edward Van Veen,Avishek Adhikari,Marc Liesa,Yanlin He

doi:10.1038/s41467-020-20050-1

Abstract

Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Recent advances have revealed the medial preoptic area (MPA) as a key site for the regulation of torpor in mice. The MPA is estrogen-sensitive and estrogens also have potent effects on both temperature and metabolism. Here, we demonstrate that estrogen-sensitive neurons in the MPA can coordinate hypothermia and hypometabolism in mice. Selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, whereas selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor in both female and male mice, their effects on thermoregulation and torpor bout initiation exhibit differences across sex. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency.

Highlights

Homeotherms maintain a stable internal body temperature despite changing environments
To visualize the anatomical distribution of ERα neurons in the medial preoptic area (MPA), we evaluated ERα immunoreactivity in brain sections ranging from anterior preoptic area (POA) (Bregma 0.6 mm) to posterior POA (Bregma −0.4 mm) according to the mouse brain atlas[35] in both male and female mice
Torpor has been investigated in numerous species, yet the neuronal mechanisms allowing endotherms to actively depress body temperature and metabolism in response to nutrient scarcity are only fragmentally understood[1,3]

Summary

Introduction

Homeotherms maintain a stable internal body temperature despite changing environments. Whereas selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor in both female and male mice, their effects on thermoregulation and torpor bout initiation exhibit differences across sex. Together, these findings suggest a role for estrogensensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency. Maintaining a stable internal body temperature requires complex responses that coordinately modulate facultative thermogenesis, heat dissipation, and basal metabolic rate These thermoregulatory effectors are energetically demanding and may be downregulated when energy is scarce. We find that chemogenetic activation of ERα+ MPA neurons is sufficient to induce hypothermia and hypometabolism, that the natural activity of ERα+ MPA neurons is elevated during fasting-induced torpor, and that ERα+ MPA neurons are required for the full expression of fasting-induced torpor in mice

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Conclusion