Sex differences influence intestinal epithelial stem cell proliferation independent of obesity

The intestinal epithelium is continuously regenerated by cell renewal of intestinal epithelial stem cells (IESCs) located in the intestinal crypts. Obesity affects this process and results in changes in the size and cellular make-up of the tissue, but it remains unknown if there are sex differences in obesity-induced alterations in IESC proliferation and differentiation. We fed male and female mice a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 3 months and investigated the differences in (1) the expression of markers of different intestinal epithelial cell types in vivo, and (2) lasting effects on IESC growth in vitro. We found that the growth of IESCs in vitro were enhanced in females compared with males. HFD induced similar in vivo changes and in vitro early growth of IESCs in males and females. The IESCs isolated and grown in vitro from females, though, showed an enhanced growth that was independent of obesity. To determine whether this effect was driven by sex steroid hormones, we used primary intestinal crypts isolated from male and female mice and investigated the differences in (1) the expression of steroid hormone receptors, and (2) cell proliferation in response to steroid hormones. We found that estrogen receptor α was expressed in crypts from both sexes, but estrogen had no effect on proliferation in either sex. These results suggest that obesity similarly effects IESCs in males and females, but IESCs in females have greater proliferation ability than males, but this is not driven by a direct effect of sex steroid hormones on IESCs or other crypt cells that provide essential niche support for IESCs.