High-fat diet (HFD) leads to obesity and insulin resistance, which are key risk factors for type 2 diabetes (T2D). Many studies have investigated the effects of HFD on several metabolic tissues, but the intestine is highly underexplored. The small intestine is the primary site of the positive metabolic effects of the most successful pharmacologic treatments (metformin) and surgical interventions (bariatric surgery) for T2D. The innermost cell layer of the small intestine is the epithelium, which is the most rapidly renewing tissue in the body and is comprised of several cell types that mediate nutrient absorption and energy homeostasis. The high renewal rate for these cells is driven by a small but highly proliferative population of intestinal stem cells (ISCs). In this study, we showed that an obesogenic HFD significantly increases proliferation of ISCs, and alters allocation of ISCs to different lineages in mice. To define the molecular mechanisms that underpin these effects, we performed whole transcriptome analyses (both small RNA-seq to profile microRNAs (miRNAs) and RNA-seq for long, non-coding RNAs and mRNAs) in Lgr5+ ISCs. We demonstrated that HFD shifts the miRNA profile of ISCs toward that of enterocytes, the cells involved in nutrient absorption. Further bioinformatics analysis revealed that this shift is driven primarily by changes in two miRNAs, miR-194 and miR-375. Specifically, HFD suppresses miR-375 by over five-fold (P < 0.05). Notably, follow-up studies showed that vertical sleeve gastrectomy, which reverses the effects of HFD, significantly rescues the levels of miR-375 in Lgr5+ ISCs. We hypothesized that suppression of miR-375 promotes ISC proliferation and allocation to enterocytes. To test this hypothesis, we generated miR-375-/- mice and showed that loss of miR-375 in vivo leads to a marked increase in ISC proliferation and villus height, mimicking the effects of HFD. Currently we are investigating whether miR-375 is essential for the effects of bariatric surgery.


P. Sethupathy: None.

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