High-fat diet impacts the colon and its transcriptome in a sex-dependent manner that is modifiable by estrogens

Abstract

Epidemiological studies highlight a strong association between obesity and colorectal cancer (CRC), especially in men. Estrogen, on the other hand, is associated with protection against both the metabolic syndrome and CRC. The colon is the first organ to respond to a high-fat diet (HFD), and estrogen receptor beta (ER{beta}) in the intestine appears to prevent CRC. How estrogen impacts the colon under HFD condition has, however, not been investigated. Estrogen can act through three different receptors (ER, ER{beta}, GPER1) which all may impact metabolism. In an effort to dissect this, we fed mice a control diet or a high-fat diet (HFD) for 13 weeks and administered receptor-selective estrogenic ligands for the last three weeks. We recorded corresponding physiological impact on fat distribution, fasting glucose, colon crypt proliferation and immune cell infiltration, and the colon transcriptome response. We identify clear sex-differences at the transcriptome level, both at base line and after HFD and ligand treatments. An unexpected observation was the significant sex-differences and impact by HFD and estrogens on circadian clock gene expression, such as Npas2 and Arntl (Bmal1), in the colon. Both sexes also exhibited an increased infiltration of F4/80+ macrophages as a result of HFD. In males, but not females, this was accompanied by changes in colonic epithelial cell proliferation. ER-selective PPT treatment had significant systemic effects, reducing body weight in both sexes, whereas ER{beta}-selective DPN treatment did not impact body weight, but reduced infiltration of F4/80+ macrophages in colon of both sexes and attenuated HFD-induced proliferation of male colon crypts. Both ER and ER{beta} activation contributed to circadian clock gene regulations. We detail for the first time how HFD and estrogens modulate the colon transcriptome and physiology in a sex and ER-specific manner.