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

Abstract

These authors contributed equally to the work. AbstractEpidemiological 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 (ERβ) 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 (ERα, ERβ, 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. ERα-selective PPT treatment had significant systemic effects, reducing body weight in both sexes, whereas ERβ-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 ERα and ERβ 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.

Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness

“…On the other hand, increased AR in female malignant tissues has been suggested to promote CRC aggressiveness by increasing classes III and V of b-tubulin protein, which are commonly activated in male patients and could underly the observed higher mortality rate in men (56). Collectively, Our findings correlate with earlier studies reporting gender-dependent expression of ERs (14)(15)(16), PGR (17-19), and AR (20-22) in normal colon, which supports the notion that sex steroid hormones contribution to colon biology could, at least in part, be gender-specific. Moreover, our data and prior studies advocate that ERb (33)(34)(35)(36) and PGR (30,36,52) mediate tumor suppressive actions, whereas overexpressed ERa (23-25) and AR (37-40) could incite oncogenicity in colon.…”

“…Although the production of sex steroid hormones mainly occurs in the gonads, other peripheral tissues, including colon, express the enzymes required for the biogenesis of sex hormones, including progesterone (P4), testosterone, and the most potent estrogen, 17bestradiol (E2) (11)(12)(13). Colonic mucosa could also respond to sex hormones, since estrogen (ERa & ERb) (14)(15)(16), progesterone (PGR) (17-19), and androgen (AR) (20-22) receptors were detected and showed gender-dependent expression profiles. Moreover, ERb, PGR and AR in normal colonic tissue are abundant, whilst ERa is weakly expressed (14)(15)(16)(17)(18)(19)(20)(21)(22).…”

“…Colonic mucosa could also respond to sex hormones, since estrogen (ERa & ERb) (14)(15)(16), progesterone (PGR) (17-19), and androgen (AR) (20-22) receptors were detected and showed gender-dependent expression profiles. Moreover, ERb, PGR and AR in normal colonic tissue are abundant, whilst ERa is weakly expressed (14)(15)(16)(17)(18)(19)(20)(21)(22). However, the protein expression of ERa (23-25) and AR (26) increases, whereas ERb (27-29) and PGR (23, [30][31][32] decline, markedly in cancerous colonic tissues, and they correlated with the tumor clinicopathological characteristics and/or prognosis.…”

Diet-induced obesity alters intestinal monocyte-derived and tissue-resident macrophages in female mice independent of TNF

“…However, we have observed that while both obese male and female mice have an increase in circulating inflammatory TNF-producing Ly6C high monocytes and adipose tissue macrophage accumulation, in female mice the metabolic dysregulation is attenuated, and these changes are not dependent on TNF (Breznik et al, 2018;Breznik et al, 2021b). While turnover of intestinal macrophages has been reported to be similar in non-obese young male and female mice (Bain et al, 2016;Liu et al, 2019), it has been found that estrogen treatment has anti-inflammatory effects in mouse models of colitis (Verdú et al, 2002;Bábíčková et al, 2015), and moreover, estrogen may attenuate effects of diet-induced obesity in the colon (Hases et al, 2020). A priori consideration of biological sex and hormones may therefore be indispensable in disentangling the complex effects of TNF in both acute and chronic intestinal inflammation.…”