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.

肠道中过多的营养吸收和激素分泌的改变会导致全身能量失衡，从而导致肥胖并增加患 2 型糖尿病和结直肠癌的风险。这种功能性适应不良被认为出现在肠道干细胞 (ISC) 水平。然而，尚不清楚肥胖饮食如何影响 ISC 的身份和命运。在这里，我们表明肥胖饮食诱导 ISC 和祖细胞过度增殖，增强 ISC 分化和细胞更新，并改变小鼠 ISC 和肠上皮细胞的区域特性。肠内分泌谱系的单细胞分辨率显示祖细胞和肽能肠内分泌细胞类型增加，血清素肠内分泌细胞类型减少。从机制上讲，我们将增加的脂肪酸合成联系起来，Ppar 信号传导和 Insr-Igf1r-Akt 通路导致黏膜变化。这项研究描述了饮食诱导的肠道适应不良的分子机制，这些机制会促进肥胖，因此是代谢综合征和相关并发症的发病机制的基础。