Obesity, independent of diet, drives lasting effects on intestinal epithelial stem cell proliferation in mice.

The intestinal epithelium plays an essential role in nutrient absorption, hormone release, and barrier function. Maintenance of the epithelium is driven by continuous cell renewal by intestinal epithelial stem cells located in the intestinal crypts. Obesity affects this process and results in changes in the size and function of the tissue. Because both the amount of food intake and the composition of the diet are contributing factors to developing and maintaining obesity, it is necessary to tease apart the separate contributions of obesity versus the type/amount of diet in driving the epithelial changes. C57BL/6J mice were fed a 60% high-fat diet versus a 10% low-fat diet for three months. A pair fed group was included (mice were fed with high-fat diet, but in equal kcal as that eaten by the low-fat diet- fed mice to keep them lean). We investigated the differences in (1) crypt-villus morphology in vivo, (2) the number and function of differentiated epithelial cell types in vivo, and (3) lasting effects on intestinal epithelial stem cell proliferation and growth in vitro. We found that high-fat diet-induced obesity, independent of the high-fat diet, increased crypt depth, villus height, the number of intestinal epithelial stem cells and goblet cells in vivo, and enhanced the size of the enterospheres developed from isolated IESCs in vitro. In addition, there is an interaction of obesity, type of diet, and availability of the diet (pair fed versus ad libitum) on protein and mRNA expression of alkaline phosphatase (an enzyme of enterocytes). These results suggest that high-fat diet-induced obesity, independent of the high-fat diet, induces lasting effects on intestinal epithelial stem cell proliferation, and drives the differentiation into goblet cells, but an interaction of obesity and diet drives alterations in the function of the enterocytes. Impact statement This study investigates whether obesity or the type/amount of diet differentially alters the proliferation, differentiation, growth, and function of the intestinal epithelial tissue. Although diet-induced obesity is known to alter the growth and function of the epithelium in vivo and cause lasting effects in intestinal epithelial stem cells (IESCs) in vitro, we are the first to tease apart the separate contributions of obesity versus the type/amount of diet in these processes. We found that high-fat diet (HFD)-induced obesity, independent of the HFD, drives lasting effects on IESC proliferation and differentiation into goblet cells, which may contribute to the growth of the epithelium. In addition, there is an interaction of obesity, type of diet, and availability of the diet (PF versus ad libitum) on the function of enterocytes. Identification of the factors driving the epithelial changes may provide new therapeutic strategies to control altered tissue growth and function associated with obesity.