Estrogen Receptor‐a in the Subfornical Organ Controls Glucose Homeostasis During Obesity in Males
Authors: Blackmore Katherine , Simonyan Hayk , Young Colin N. 
Published: May 2022

Metabolic syndrome encompasses a spectrum of conditions that increases the risk for adverse cardiovascular and metabolic diseases, including hyperglycemia associated with type II diabetes. While the etiology of type II diabetes is multifactorial, sexual dimorphism is clearly established. Specifically, the sex hormone estrogen plays a metabolic protective role in premenopausal women. However, a growing body of literature also supports a critical role for estrogen in metabolic regulation in men. Notably, male mice with a global genetic deletion of estrogen‐receptor‐a (ERa) exhibit a pronounced dysregulation of glucose homeostasis. Importantly, estrogens have tissue specific physiological effects, both positive and negative. Thus, identification of specific sites of estrogen action is imperative to develop selective estrogen therapies that can ameliorate metabolic‐syndrome related hyperglycemia. Recently, the subfornical organ (SFO), a forebrain circumventricular region lacking a blood brain barrier, has been implicated in the regulation of energy balance. Moreover, dense ERa expression is present in the SFO of males. Taken together, we hypothesized that deletion of ERa in the SFO would impair glucose control in obese male mice. To investigate this, six‐week‐old male ERfl/fl mice underwent SFO targeted delivery of an adeno‐associated vector encoding Cre‐recombinase (AAV‐Cre‐eGFP) to selectively remove SFO ERa. AAV‐eGFP served as a control (n=3/group). Following recovery, mice were fed a high fat diet (HFD; 60% fat) during which glucose tolerance testing (2g/kg body weight, i.p.) was performed at 0, 2, 5 and 10 weeks, and the area under the glucose response curve (AUC) was calculated. As expected, glucose tolerance at baseline (week 0) was not different between groups. However, removal of SFO ERa significantly reduced glucose tolerance (AUC: 46,442 ± 5648 vs. 58,175 ± 2862, AAV‐eGFP vs. AAV‐Cre‐eGFP, p<0.05) within 2 weeks of HFD feeding. This reduction in glucose tolerance persisted at week 5 (AUC: 52,360 ± 4,807 vs 65,460 ± 4749, AAV‐eGFP vs. AAV‐Cre‐eGFP, p<0.05), and tended to be different between groups at week 10 (AUC: 61,370 ± 2736 vs 68,077 ± 2988, AAV‐eGFP vs. AAV‐Cre‐eGFP, p=0.1). In addition, removal of SFO ERa elevated fasting blood glucose at weeks 5 (165 ± 10 vs. 205 ± 8 mg/dL, AAV‐eGFP vs. AAV‐Cre‐eGFP, p<0.05) and 10 (184 ± 14 vs. 247 ± 16 mg/dL, AAV‐eGFP vs. AAV‐Cre‐eGFP, p<0.05) suggesting a role for SFO ERa in homeostatic control of fasting blood glucose in males. Importantly, the alterations in glucose regulation occurred independent of body weight (10 weeks: 44.6 ± 1.3 vs. 42 ± 1.8 g, AAV‐eGFP vs. AAV‐Cre‐eGFP, p>0.05), food intake, energy expenditure, and ambulatory activity, as evaluated by indirect calorimetry recordings. Collectively, these findings indicate that removal of SFO ERa reduces glucose tolerance in obese male mice, indicating that the protective role of central estrogen signaling in glucose homeostasis is not limited to females. Furthermore, these findings suggest that manipulating estrogen signaling in the SFO, in the context of obesity, may be a novel approach to target type II diabetes.