The impact of the postmenopausal hormonal milieu on brown fat activity and energy expenditure

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Summary The menopause is associated with an increase in fat mass (FM), particularly visceral fat, increasing the risk of chronic metabolic disease. The loss of ovarian function during the menopause leads to marked decreases in sex steroids (estrogens and progestins) and increases in gonadotropins (e.g., follicular stimulating hormone (FSH)). A mechanism contributing to weight gain with loss of ovarian function is reductions in energy expenditure (EE). We have shown that suppressing ovarian function in premenopausal women reduces resting energy expenditure (REE), and this is prevented by adding back estradiol (E2). In the previous award period, we studied whether ovarian function impacts brown adipose tissue (BAT) and whether reductions in BAT activity contribute to the reductions in REE. We showed that BAT oxidative metabolism is lower in post- than premenopausal women, and that suppressing ovarian function causes marked reductions in BAT oxidative metabolism. These results suggest that E2 modulates BAT activity. However, recent pre-clinical evidence suggests that blocking FSH activity increases REE and BAT activity and decreases FM. Whether E2 and FSH affect BAT activity in postmenopausal women is not known. Active BAT also takes up circulating substrates (e.g., triglycerides) which may confer additional metabolic benefits. In this competing renewal application, we propose to determine the impact of the postmenopausal hormonal milieu on EE, BAT activity, and post-prandial triglycerides. We hypothesize that E2 increases and FSH decreases BAT activity, and that higher levels of BAT activity will be associated with a) higher REE and 24 h EE, and b) lower post-prandial lipids. To test these hypotheses, we will use a gonadotropin releasing hormone antagonist (GnRHANT) and transdermal estrogen (E2) to isolate the effects FSH and E2 on BAT activity in postmenopausal women. Women will be studied before and after 6 months of treatment. The three treatment arms will be GnRHANT + Placebo (PL), GnRHANT + E2, and a double placebo arm. BAT activity will be quantified using dynamic positron emission topography/computed tomography (PET/CT) imaging combined with 11C-acetate and 18flourodeoxyglucose (18FDG) tracers. In both aims, we will also measure REE, 24 h EE, and post-prandial substrates. Studying the E2- and FSH-mediated effects on BAT and EE will increase our understanding of how the loss of ovarian function during the menopausal transition contributes to weight gain and an increase in visceral adipose tissue, increasing the risk of obesity-related chronic diseases. This could lead to development of behavioral or pharmacologic interventions to attenuate decreases in EE and reduce risk for weight gain.