Sex-specific Differences within the Central Melanocortin System: A Role for Estrogen

The central melanocortin system regulates energy homeostasisis by controlling food intake, energy partitioning, and activity. Sex-specific disparities within this system have emerged, emphasizing the importance of reproductive steroid hormones over the establishment as well as the maintenance of this system. The specific mechanisms regarding estrogen\u27s influence on the central melanocortin system and feeding behavior remain unclear. In ovariectomized (OVX) females, body weight and body composition (% fat) were elevated compared to sham at week 7. In addition, during indirect calorimetry, OVX females displayed lower levels of energy expenditure than the sham-operated females. OVX females also had greater serum leptin concentrations, correlating with the increase in fat mass, but did not exhibit altered serum insulin levels. Agouti-related peptide (AgRP) is the endogenous antagonist to the melanocortin 3 and 4 receptors within the central nervous system and promotes an extended period of hyperphagia following a single central injection, but in a sex-dependent manner. Previously, we reported a significant decrease in energy expenditure in females compared to males following central AgRP administration, suggesting estrogen either directly or indirectly influences the central melanocortin system or downstream targets. Using double-label immunofluorescence, we determined some AgRP neurons within the arcuate nucleus of the hypothalamus express estrogen receptor-alpha (ER-α), confirming estrogen\u27s capability to directly influence the central melanocortin system. There were no differences in expression between OVX and intact females or males or during the female estrus cycle. In a separate experiment, we used whole hypothalami from sham and OVX rats to measure Pomc, Estr1, Agrp, and Leptin receptor mRNA using real time PCR (QPCR). OVX females displayed approximately a 40% decrease in all four genes of interest (p\u3c0.05) compared to sham-operated females. The increased adiposity (leptin levels) of OVX females may explain the decreased hypothalamic AgRP and Leptin receptor mRNA. These data emphasize the need for consideration and further study on sex hormone influence on the central melanocortin system