Central Feminization of Male Mice Reduces Metabolic Syndrome

Abstract

Metabolic syndrome encompasses a spectrum of conditions that increases the risk for adverse cardiovascular and metabolic diseases. Sexual dimorphism is clearly established, with men more predisposed to metabolic syndrome complications than women. It is widely accepted that the female sex hormone estrogen plays a protective role in premenopausal women through peripheral as well as central nervous system (CNS) mechanisms. However, most work to date has been based on the loss of estrogen in females (e.g. menopause). Interestingly, transgender individuals receiving feminizing gender affirming therapy (i.e. estrogen) appear to be relatively protected from metabolic syndrome conditions. Furthermore: 1) CNS estrogen is critically involved in metabolic regulation; and 2) CNS estrogen receptors in several nuclei are present at the same density in males and females. Based on this, we hypothesized that central estrogen supplementation in males would rescue metabolic syndrome phenotypes. To investigate this, six week old male C57Bl/6J mice were fed a normal chow or high fat diet (HFD) for 10 wks and were then instrumented with intracerebroventricular cannulas (ICV; n=4-6). Following surgical recovery, β-Estradiol (E2;30 mg/kg/day) or saline control was administered ICV once daily over 6 days. One week of central E2 supplementation resulted in a slight, albeit significant, decrease in body weight (42± 3 vs 37±2 g, saline vs. E2, p<0.05), that was not accompanied by changes in food/water intake or energy expenditure. Upon sacrifice it was evident that estrogen supplementation significantly altered adiposity. In particular, estrogen supplementation resulted in decreases in visceral white adipose depots including abdominal (1±0.1 vs. 0.5±0.1 g, saline vs. E2, p<0.05) and epididymal fat, whereas subcutaneous inguinal and brown fat (0.18±0.02 vs. 0.15±0.02 g, saline vs. E2, p>0.05) were unchanged. Building on this, we also evaluated hepatic lipid accumulation, (i.e. non-alcoholic fatty liver disease), a liver disorder that is common in ~70% of metabolic syndrome individuals. Oil Red O staining of the liver demonstrated that, relative to control animals, one-week supplementation with E2 resulted in a clear reduction in hepatic steatosis (23.8±4.3 vs. 15.0±1.5 percent area, Saline vs E2, p=0.05). Together, these findings indicate that short-term central estrogen supplementation in males is an effective means to reduce metabolic syndrome risk factors including visceral adiposity and hepatic steatosis. Moreover, these data may help explain why premenopausal females and transgender females are relatively protected from metabolic syndrome.