SAT-597 Hypothalamic ESR1 Gene Knockdown Elicits Intermittent Decrement in Postprandial Energy Expenditure Associated with Obesity Onset in Female Rhesus Monkeys

Declining serum estradiol (E(2)) levels during the menopausal transition are associated with increased central adiposity and heightened risk for metabolic disease. Estrogenic effects on adiposity and metabolism in female rodents are primarily mediated by estrogen receptor alpha (ESR1) activation in ventromedial (VMN) and arcuate (ARC) nuclei within the mediobasal hypothalamus (MBH). The role of hypothalamic ESR1 in the menopausal transition, and in regulating body weight, body composition and energy homeostasis in female primates, however, remains unclear. To investigate the involvement of ESR1 in regulating female primate body weight, we employed RNAi technology to assess ESR1 gene knockdown throughout the MBH of adult, full-grown, ovary intact female rhesus macaques. Using MRI-guided stereotaxic targeting, adeno-associated viral vector 8 (AAV8) expressing shRNA-ESR1 (ERαKD) (n=6), or a scrambled control sequence (n=4), were infused bilaterally into the MBH to knockdown ESR1 expression. Results: ERαKD females exhibited a ~22% (+2.0 ± 0.1 kg) increase in body weight to attain 10.4±0.9 kg after ~12-24 months (mo) (p<0.05), compared to ~12% increase in controls (+ 1.1±0.1 kg) attaining 9.1±1.0 kg body mass. The divergence in body weights between female groups, however, began at 6 mo. Daily calorie consumption at ~26 mo was comparable between groups. Assessments at ~28 months enabled customized metabolism cage analysis of energy expenditure (EE) corrected for fat-free mass and respiratory exchange ratio (RER). Postprandial EE (hours (h) 1-5 after once daily feeding) was inconsistently diminished in ERαKD compared to control females (1(st) day: ERαKD 0.087±0.001 vs. Control 0.104±0.002 kcal/min/kg, p<0.0002; 2(nd) day: ERαKD 0.092±0.0004 vs. Control 0.095±0.002 kcal/min/kg, NS). Overnight fasted RER (hours -1 to -2 prior to feeding) tended (p<0.06) to remain higher in ERαKD (1(st) day, 0.757±0.010, 2(nd) day, 0.732±0.031) compared to control females (1(st) day, 0.728±0.007, 2(nd) day, 0.728±0.060) suggesting constrained switching between lipids and other carbon sources for energy metabolism during fasting in ERαKD females. We found no significant differences in 24 hr, 12 hr light or 12 hr dark EE and RER. Overall, these findings highlight MBH ESR1 roles in regulating body weight, energy expenditure and carbon sources utilized in daily energy metabolism, and suggest a discrete MBH location for development of therapeutic targeting to combat female obesity.