Ovarian estradiol supports female sexual behavior and metabolic function. While ovariectomy (OVX) in rodents abolishes sexual behavior and enables obesity, OVX in nonhuman primates decreases, but does not abolish, sexual behavior, and inconsistently alters weight gain. We hypothesize that extra-ovarian estradiol provides key support for both functions, and to test this idea, we employed aromatase inhibition to eliminate extra-ovarian estradiol biosynthesis and diet-induced obesity to enhance weight gain. Thirteen adult female marmosets were OVX and received: (1) estradiol-containing capsules and daily oral treatments of vehicle (E2; n=5); empty capsules and daily oral treatments of either (2) vehicle (VEH, 1ml/kg, n=4), or (3) letrozole (LET, 1 mg/kg, n=4). After 7 months, we observed robust sexual receptivity in estradiol, intermediate frequencies in VEH, and virtually none in LET females (p=0.04). By contrast, few rejections of male mounts were observed in estradiol, intermediate frequencies in VEH, and high frequencies in LET females (p=0.04). Receptive head turns were consistently observed in estradiol, but not in VEH and LET females. LET females, alone, exhibited robust aggressive rejection of males. VEH and LET females demonstrated increased % body weight gain (p=0.01). Relative estradiol levels in peripheral serum were E2>>>VEH>LET, while those in hypothalamus ranked E2=VEH>LET, confirming inhibition of local hypothalamic estradiol synthesis by letrozole. Our findings provide the first evidence for extra-ovarian estradiol contributing to female sexual behavior in a nonhuman primate, and prompt speculation that extra-ovarian estradiol, and in particular neuroestrogens, may similarly regulate sexual motivation in other primates, including humans.

Declining serum estradiol (E2) 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 (1st day: ERαKD 0.087±0.001 vs. Control 0.104±0.002 kcal/min/kg, p<0.0002; 2nd 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 (1st day, 0.757±0.010, 2nd day, 0.732±0.031) compared to control females (1st day, 0.728±0.007, 2nd 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.

Declining serum estradiol (E2) levels during the menopausal transition are associated with increased central adiposity and heightened risk for metabolic disease. Ovarian estradiol, E2, supports female metabolic function. While ovariectomy (OVX) in rodents enables obesity, OVX in nonhuman primates (NHPs) inconsistently alters weight gain. We therefore hypothesized that in female NHPs, extra-ovarian E2 provides key support for metabolic homeostasis. To test this, we employed aromatase inhibition to eliminate extra-ovarian E2 biosynthesis together with diet-induced obesity (DIO) to enhance weight gain. Thirteen adult female marmoset monkeys were OVX and received: (1) E2-containing capsules and daily oral treatments of vehicle (E2; n=5); empty capsules and daily oral treatments of either vehicle (VEH, 1ml vehicle/kg, n=4), or (3) letrozole (LET, 1 mg/kg in 1ml vehicle/kg, n=4). After 6-7 months, VEH and LET compared to E2 females demonstrated increased % body weight gain (p=0.01) and increased caloric intake VEH (p<0.001) and LET (p<0.001) corrected for fat-free mass. Dual energy x-ray absorptiometry (DXA)-determined body composition at 6 months showed no between female group differences in total fat mass or fat mass in validated body regions of interest. Total body (p=0.014), abdominal region (p=0.002) and upper leg region (p=0.025) DXA-determined fat free mass, however, increased ∼5-10% in all female groups. In addition, lumbar spine and total body DXA-determined bone mineral density (BMD) and bone mineral content (BMC) were comparable across all female groups. Relative circulating E2 levels were E2>>>VEH>LET, while those in hypothalamus ranked E2=VEH>LET, confirming aromatase inhibition of local hypothalamic E2 in LET females. Our findings demonstrate ovarian E2 and extra-ovarian E2 depletion induce comparable increases in DIO weight gain without bone loss in female marmoset monkeys and highlight E2 as a key regulator of female metabolic homeostasis in NHPs. Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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