Abstract
Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr–Igf1r–Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.
Highlights
Diet-induced obesity is a serious public health and economic problem
Metabolic assessment showed that our diet-induced obese mice developed prediabetes, which was characterized by fasting hyperglycaemia, impaired glucose tolerance and pronounced hyperinsulinaemia as well as insulin resistance (Extended Data Fig. 1r–u)
We found that an high-fat/high-sugar diet (HFHSD) reduces the number of Sox4+ early Enteroendocrine progenitor (EEP), increases the fraction of Ngn3+ EEPs, reduces the number of Lyz1−BrdU+ cells that correspond to label-retaining Lgr5+ enteroendocrine cells (EECs) and affects mature SILA and Reg4+ EC cells, which are most abundant in the duodenum (Fig. 3e–o and Extended Data Fig. 7e–i)[17]
Summary
Diet-induced obesity is a serious public health and economic problem. Obese people are at higher risk of developing type 2 diabetes (T2D), cardiovascular diseases and cancer, all leading causes of death worldwide (https://www.who.int). Constant overnutrition is thought to lead to intestinal maladaptation and dysfunction and to contribute to the development of obesity and prediabetes[8] This is evident as two hallmarks of obesity, excessive food intake and a reduced stimulation of postprandial insulin secretion by gut hormones, are linked to impaired gut function[9]. Regional identities are thought to be determined at the level of the ISCs by epigenetic mechanisms, and the crypt–villus compartmentalization is at least partly established by growth-factor. Articles gradients, but it is unknown whether and how the compartmentalization of gut functions is affected by an obesogenic diet[20,21]
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