肠上皮
脂质代谢
脂肪组织
白色脂肪组织
炎症
下调和上调
信号转导
医学
内分泌学
生物
上皮
内科学
细胞生物学
生物化学
免疫学
基因
遗传学
作者
Stephen Gaudino,Ankita Singh,Hanchun Huang,Jyothi Padiadpu,Makheni Jean-Pierre,Cody Kempen,Tej Bahadur,Keijiro Shiomitsu,Richard S. Blumberg,Kenneth R. Shroyer,Semir Beyaz,Natalia Shulzhenko,Andrey Morgun,Perikala V. Kumar
标识
DOI:10.1038/s41467-024-45568-6
摘要
IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.
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