Estradiol-induced anorexia is independent of leptin and melanin-concentrating hormone

Objective: Treatment of male rodents with estradiol (E-2) is associated with anorexia and weight loss by poorly understood mechanisms. We examined the role of the orexigenic hypothalamic peptide melanin-concentrating hormone (MCH) and the appetite-inhibiting, fat-derived hormone leptin in mediating E-2-induced anorexia. Research Methods and Procedures: We studied the effect of E-2 treatment (implantation of either E-2 pellet or matching placebo) in male C57B1/6J mice, as well as in a lean mouse model (MCH knockout mice) and an obese model (leptin-deficient ob/ob mice). We also studied the effect of E-2 treatment in the context of high-fat diet. Results: We confirmed E-2 dose-dependent anorexia in male wild type mice fed a normal chow diet. E-2 treatment was associated with a significant decrease in body fat, serum leptin levels, and arcuate hypothalamic proopiomelanocortin expression. E-2-implanted mice also showed increased hypothalamic neuropeptide Y and MCH expression. As MCH has been implicated in E-2-induced hypophagia, we performed E-2, pellet implantation in MCH knockout mice and observed hypophagia and weight loss, indicating that MCH is not an essential mediator of E-2-induced anorexia. E-2-implanted ob/ob mice also had hypophagia and weight loss, indicating that leptin is not essential for E-2-induced anorexia. High-fat diet significantly exacerbated the effect of E-2 treatment, leading to a 99.6% decrease in food intake at 48 hours and a 30% loss of body weight within 1 week. Discussion: The anorectic effects of E-2 were independent of MCH and leptin. Our results suggested that E-2 may have effects on nutrient preferences.