A homeostatic metabolic role for estrogen receptor α in the subfornical organ

Abstract

Approximately 70% of American adults are considered overweight or obese putting them at increased risk for metabolic syndrome, which includes a constellation of abnormalities that can result in cardiovascular disease, type II diabetes, and fatty liver. Sexual dimorphism in metabolic syndrome is clearly established. Adult men display increased prevalence of metabolic syndrome comorbidities when compared to fertile women. However, post-menopause, the incidence of metabolic syndrome in women significantly increases. It is widely proposed that the increased post-menopausal incidence of metabolic syndrome is due, in part, to estrogen deficiency. Within the brain, estrogen regulates metabolism primarily through actions on estrogen receptor alpha (ERα). While a major emphasis has been placed on hypothalamic nuclei, whether there is a distributed neural network of ERα that works through autonomic and endocrine actions to influence metabolism remains incompletely defined. We have recently shown a critical role for the subfornical organ (SFO), a circumventricular region that lies outside the blood barrier, in the regulation of peripheral metabolism in males. However, whether this brain nucleus and further estrogen signaling within this region is involved the control of metabolism in females is unknown. Taken together, we hypothesized that ERα in the SFO may regulate peripheral metabolism in female mice during obesity. To investigate this, 6 wk old female ESRα flox mice received targeted SFO microinjections of AAV-Cre-GFP and titer matched control AAV-LacZ-GFP. Following 2 wks of viral incorporation, mice were fed a high fat diet (HFD; 60% kcal from fat) for 10 weeks. Indirect calorimetry measurements indicated that SFO ERα removal resulted inhyperphagic behavior during HFD feeding (Cumulative food intake: 27.4±2.7 g vs 37.5±3.3 g, GFP vs. Cre, n=7-8, p<0.05) that was counterbalanced by increased energy expenditure (0.46±0.02 vs. 0.51±0.02 kcal/hr, GFP vs. Cre, n=7-8, p<0.05) resulting in no influence on body weight (ΔBody weight: 18.9±3.2 vs. 20.3±1.6 g, GFP vs. Cre, n=4, p>0.05) or adiposity. Interestingly, SFO ERα knockdown exacerbated hepatic steatosis during diet-induced obesity (Oil Red staining, 8.8±1.9 vs 18.8±2.8 au x 107, GFP vs. Cre, n=7-8, p<0.05), although this was in contrast to improved whole-body glucose tolerance in response to an i.p. glucose load (6.1±0.2 vs 4.7±0.5 AUC x 104, GFP vs. Cre, n=5-6, p<0.05) and upregulation of skeletal muscle long-chain fatty acid b-oxidation genes (e.g. Cpt1: 2.3±0.7 Cre fold GFP, n=4-5, p<0.05). Finally, deletion of SFO ERα was associated with a reduction in circulating estrogen during obesity (80.0±4.3 vs 45.2±12.5 pg/mL, GFP vs. Cre, n=3-4, p=0.06). Collectively, these findings indicate that SFO ERα may differentially regulate target organs during obesity and points to a complex set of interactions whereby SFO estrogen signaling can both positively and negatively regulate peripheral metabolism. R01DK117007, R01HL141393, F31 NIDDK12829388 This is the full abstract presented at the American Physiology Summit 2023 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.