The role of ovarian hormone dynamics in metabolic phenotype and gene expression in female mice.

Ovarian hormones, particularly estradiol, play an important role in the regulation of metabolic function including in food intake, thermogenesis, activity, fat distribution, and overall weight management. While it is known that weight and food intake follow cyclical patterns across the rodent estrous cycle, the majority of metabolic studies still focus on ovariectomized rodent models and estrogen replacement. Here we provide a comprehensive metabolic profiling of female mice under different ovarian hormone states, from having naturally-cycling ovarian hormone levels to complete ovarian hormone depletion and "estrous cycle-like" estrogen replacement (0.2 or 1 μg estradiol benzoate every 4 days). Every domain of metabolic function that we examined including activity levels, food intake, and body composition was affected by ovariectomy and contributed to >30 % weight gain and nearly two-fold increase in fat mass in ovarian hormone-depleted mice over the 12-week period. By combining physiological and hormone replacement paradigms, we show that cyclical estrogen levels are necessary and sufficient to maintain optimal body weight and fat mass. We show that the hypothalamic expression of genes encoding estrogen receptor alpha (Esr1) and neuropeptides involved in feeding behavior (Agrp, Pomc) changes across the cycle and with ovariectomy, and is partially "rescued" by cyclical estrogen treatment. The drastic fat mass changes following ovariectomy are accompanied by changes in adipose tissue gene expression, including a decreased responsiveness to estrogens due to Esr1 down-regulation. Our study highlights the importance of understanding the dynamic regulation of metabolic function by ovarian hormones and calls for more naturalistic and higher-resolution approaches to studying the molecular basis of ovarian hormone action.