Impact of Diet-Induced Obesity on Intestinal Stem Cells: Hyperproliferation but Impaired Intrinsic Function That Requires Insulin/IGF1

Abstract

Nutrient intake regulates intestinal epithelial mass and crypt proliferation. Recent findings in model organisms and rodents indicate nutrient restriction impacts intestinal stem cells (ISC). Little is known about the impact of diet-induced obesity (DIO), a model of excess nutrient intake on ISC. We used a Sox9-EGFP reporter mouse to test the hypothesis that an adaptive response to DIO or associated hyperinsulinemia involves expansion and hyperproliferation of ISC. The Sox9-EGFP reporter mouse allows study and isolation of ISC, progenitors, and differentiated lineages based on different Sox9-EGFP expression levels. Sox9-EGFP mice were fed a high-fat diet for 20 weeks to induce DIO and compared with littermates fed low-fat rodent chow. Histology, fluorescence activated cell sorting, and mRNA analyses measured impact of DIO on jejunal crypt-villus morphometry, numbers, and proliferation of different Sox9-EGFP cell populations and gene expression. An in vitro culture assay directly assessed functional capacity of isolated ISC. DIO mice exhibited significant increases in body weight, plasma glucose, insulin, and insulin-like growth factor 1 (IGF1) levels and intestinal Igf1 mRNA. DIO mice had increased villus height and crypt density but decreased intestinal length and decreased numbers of Paneth and goblet cells. In vivo, DIO resulted in a selective expansion of Sox9-EGFP(Low) ISC and percentage of ISC in S-phase. ISC expansion significantly correlated with plasma insulin levels. In vitro, isolated ISC from DIO mice formed fewer enteroids in standard 3D Matrigel culture compared to controls, indicating impaired ISC function. This decreased enteroid formation in isolated ISC from DIO mice was rescued by exogenous insulin, IGF1, or both. We conclude that DIO induces specific increases in ISC and ISC hyperproliferation in vivo. However, isolated ISC from DIO mice have impaired intrinsic survival and growth in vitro that can be rescued by exogenous insulin or IGF1.

Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status

“…[9,13,14,57–59] Recent studies in murine models have demonstrated that prolonged high-fat load can increase the proportion of intestinal stem cells (ISCs), augment stem cell self-renewal, and provide non-ISCs (differentiated intestinal cells) with stemness attributes through activation of PPARD signaling, all of which may contribute to tumor development. [14,15] Additional studies have shown that the number of ISCs may be reduced by fasting and increased by refeeding.…”

Long-term effect of parasympathetic or sympathetic denervation on intestinal epithelial cell proliferation and apoptosis

“…These data support the idea that the kcal amount of food alters intestinal epithelial proliferation and that there can be lasting effects of the amount of food eaten on the proliferative capacity of the intestinal epithelium. 8,37,38 Compensatory mechanisms occur after ANS denervation in order to reestablish intestinal function under a variety of conditions and include (1) an upregulation of gastrointestinal (GI) receptor expression, (2) compensation by the nondenervated ANS branch and (3) enteric nervous system modulation. For example, PNS denervation initially decreases intestinal motility, 39 a process which is heavily mediated by serotonin.…”

Dietary Regulation of Adult Stem Cells

“…For example, a long-term (more than six months) HFD expands ISC numbers and reduces the numbers of their niche Paneth cells (Fig. 1) [44–47]. In addition to these quantitative changes, ISCs, identified by the Lgr5-eGFP high reporter, and non-stem cell progenitors (Lgr5-eGFP low ) undergo qualitative changes: 1) ISCs acquire niche independence—no longer requiring Paneth cells to initiate ex vivo organoids, and 2) non-stem cell progenitors obtain features of stemness—acquiring the potential to form ex vivo organoids [46••].…”