17α‐estradiol acts through hypothalamic pro‐opiomelanocortin expressing neurons to reduce feeding behavior

Abstract

SummaryWeight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age‐related disease. We previously reported that 17α‐estradiol (17α‐E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α‐E2 acts through pro‐opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body mass in mouse models of obesity. These results confirm that 17α‐E2 modulates appetite through selective interactions within hypothalamic anorexigenic pathways. Interestingly, some peripheral markers of metabolic homeostasis were also improved in animals with near complete loss of ARC Pomc transcription. This suggests that 17α‐E2 might have central and peripheral actions that can beneficially affect metabolism cooperatively or independently.

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

“…Almost immediately after 17α-E2 treatment began, WT mice displayed significant reductions in mass (Figure 2A-B) and adiposity ( Figure 2C-D). This is aligned with our previous reports demonstrating that 17α-E2 administration quickly reduced body mass and adiposity [22][23][24], which we have linked to hypothalamic regulation of anorexigenic signaling pathways [23]. Indeed, WT mice in the current study also displayed robust declines in calorie consumption during the first four weeks of treatment ( Figure 2E).…”

“…Given the close association between adiposity and metabolic homeostasis, coupled with our previous work demonstrating the ability of 17α-E2 to improve metabolic parameters [22,23], we also assessed several metabolic variables in these studies. Similar to the mass and adiposity data described above, WT mice receiving 17α-E2 displayed significant improvements in fasting insulin ( Figure 3B Supplementary Figure 1); whereas ERα KO mice receiving 17α-E2 failed to recapitulate these findings.…”

“…Our group has been exploring potential mechanisms by which 17α-E2 may improve healthspan and extend lifespan in a sex-specific manner. We have found that 17α-E2 administration reduces food intake and regional adiposity in combination with significant improvements in a multitude of systemic metabolic parameters in both middle-aged obese and old male mice without inducing deleterious effects [22][23][24]. Other groups have also determined that lifelong administration of 17α-E2 beneficially modulates metabolic outcomes, including glucose tolerance, mTORC2 signaling, and hepatic amino acid composition and markers of urea cycling, which were reported to be dependent upon the presence of endogenous androgens [25,26].Additionally, multiple lifespan extending compounds, including 17α-E2, exhibit similar modifications in liver function [27].…”

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

“…It has previously been shown that some responses to 17aE2, particularly changes in feeding behavior, are dependent on the presence of functional POMC neurons (Steyn et al 2018), although other metabolic responses to 17aE2 remain intact. The ARC of the hypothalamus, where we observe changes in the expression of ERα and reduced inflammation with 17aE2, contains POMC neurons.…”

“…Moreover, in a subsequent study, it was shown that some of the short-term metabolic responses to 17aE2, particularly feeding behavior on a high-fat diet, are dependent on the functional presence of pro-opiomelanocortin (POMC) neurons (Steyn et al 2018), a subset of neurons found in the arcuate nucleus of the hypothalamus (ARC). This indicates that hypothalamic actions of 17aE2 are involved in some of the metabolic responses to this drug, at least in the context of obesity.…”