Rcan2 and estradiol independently regulate body weight in female mice.

Rcan2 increases food intake and plays an important role in the development of age- and diet- induced obesity in male mice. However, in females, wild-type mice grow almost at a similar rate as Rcan2-/- mice on normal chow diet from 6 weeks of age. Here we showed that the ability of Rcan2 to promote weight gain was attenuated by energy expenditure mediated by 17β-estradiol in female mice. Using ovariectomy-operated models, we found that 17β-estradiol deprivation did not alter food intake, but induced more weight gain in wild-type mice than Rcan2-/- mice. If wild-type mice ingested equally as Rcan2-/- mice, in the same ovarian state they exhibited similar weight changes, but the mice in ovariectomized groups were significantly heavier than the ovarian-intact mice, suggesting that body weight is not only regulated by Rcan2, but also by 17β-estradiol. Furthermore, we demonstrated that Rcan2 and 17β-estradiol independently regulated body weight even on high-fat diets. Therefore, our findings indicate that Rcan2 and 17β-estradiol regulate body weight through different mechanisms. Rcan2 increases food intake, whereas 17β-estradiol promotes energy expenditure. These findings provide novel insights into the sexual dimorphism of body weight regulation.