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Adipose Tissue_Appetite_and Obesity

MON-681 - Extra-Ovarian Estradiol Depletion Invokes Subcutaneous and Visceral Hypertrophic Adipocytes Without Increased Abdominal Circumference in Adult Female Rhesus Monkeys

Monday, June 15, 2026
9:00 AM - 2:00 PM CT
Location: ENDOExpo; Poster Floor
The menopausal transition is notable for an increased risk for metabolic disease and increased central adiposity characterized by an increase in visceral relative to subcutaneous adiposity, with or without an increase in overall body weight. Ovarian E2 supports female metabolic function. While ovariectomy (OVX) in rodents is associated with obesity, weight gain is variable after OVX in nonhuman primates (NHPs). We therefore hypothesized that in female NHPs, extra-ovarian E2 provides key support for metabolic homeostasis. To test this, we employed aromatase inhibition, via letrozole, to eliminate extra-ovarian E2 biosynthesis. Nineteen adult female rhesus monkeys were OVX and received: (1) E2 containing capsules and daily oral treatments of letrozole (E2 + LET; n=5); empty capsules and daily oral treatments of either (2) vehicle (VEH, 1mL vehicle/kg, n=7) or (3) letrozole (LET, 1 mg/kg in 1ml vehicle/kg, n=7). E2-filled capsules maintained a systemic level of E2 (E2 + LET, 87.91 +/- 16.8 pg/mL) whereas in VEH (4.90 +/- 1.0 pg/mL) and LET (2.46 +/- 0.9 pg/mL), circulating E2 levels were significantly diminished. Subcutaneous white adipocytes microscopic analyses (>300 adipocytes per animal) demonstrated larger adipocytes in the LET group (12,446 +/- 251.7 um2) compared to E2 + LET (8,980 +/- 254.1 um2, p< 0.0001) and VEH (11,099 +/- 239.6 um2, p=0.0004), whereas, in the visceral abdominal depot, both the LET (10,411 +/- 234.0 um2, p< 0.0001) and VEH (11,274 +/1 291.6 um2, p< 0.0001) group presented with larger adipocytes compared to the E2 + LET group (8,004 +/- 218.2 um2). After 17 months, segmentation of abdominal subcutaneous adipose tissue via MRI revealed no differences between the groups. Dual-energy x-ray absorptiometry (DXA) scans at baseline, 6 months- and 12 months- post treatment onset did not reveal any differences in abdominal circumference, total fat mass or total fat-free mass between the groups. Our novel findings suggest both ovarian and extra-ovarian E2 contribute to lipid storage in subcutaneous and visceral white fat depots. Further, the results indicate reduced E2 encourages potentially pro-inflammatory large adipocyte development and future studies will determine if adipocyte hypertrophy is associated with lipotoxicity prompting further investigation into lipotoxic pathogenesis in females. Our finding of adipocyte hypertrophy is consistent with observations in menopausal women. However, the study duration (17 months) is a limitation, as it is shorter than the typical 4-year period during which perimenopausal and early postmenopausal women experience the greatest weight gain. In conclusion, our data suggest that both ovarian and non-ovarian sources of E2 influence adipocyte biology. E2 deficiency may drive early adipocyte architectural remodeling that precedes whole-body weight gain and warrants further investigation.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*