Estrogenic re-mapping of the metabolic response to an energy deficit

Abstract

Endothermy is an adaptation that can be traced back hundreds of millions of years and is critical for nearly every aspect of mammalian biology. Despite the advantages associated with a stable internal temperature, endothermy is energetically expensive. To conserve energy when food is scarce, mice have evolved the ability to reversibly enter a regulated state of hypothermia and hypometabolism, known as torpor. We have found that circulating 17β-estradiol, a potent estrogen, inhibits fasting-induced torpor in ovariectomized female mice, yet the signaling mechanisms underlying this estrogenic re-mapping of the metabolic response to an energy deficit remain largely unknown. Recent studies have identified the medial preoptic area of the hypothalamus (MPO) as the central regulator of torpor. MPO neurons that express estrogen receptor alpha have been identified as central coordinators of torpor, and MPO neurons that are activated during torpor broadly express estrogen receptors, suggesting that circulating estrogens may directly modulate torpor-driving neurons in the MPO. To test the hypothesis that circulating estrogens inhibit torpor by acting directly on estrogen-sensitive neurons in the MPO, we delivered 17β-estradiol (E2) directly to the MPO before inducing torpor with a 48-hour fast. Surprisingly, we found that E2 delivered to the MPO was suffcient to inhibit fasting-induced torpor in gonad-intact, but not ovariectomized, female mice. These data demonstrate that E2 signaling in the MPO is insuffcient to inhibit torpor on its own and that there are likely MPO-independent nodes in the body that circulating estrogens act on to inhibit torpor. However, our data also demonstrate that E2 signaling in the MPO does play a role in tuning the torpor response when endogenous gonadal hormones are present, suggesting that the MPO can sense estrogens and engage the appropriate effector circuits to inhibit torpor in certain physiological contexts. Together, these data advance our understanding of how circulating estrogens inhibit torpor in mice — a critical step towards the broader goal of understanding how circulating estrogens influence energy expenditure, and how these pathways can be manipulated to improve metabolic health. NIH RO1 (R01AG066821) - "Estrogenic modulation of neural circuits that control temperature" AHA Predoctoral Fellowship (23PRE1019923) - Estrogenic modulation of hypothalamic neurons that control energy expenditure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.