Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL‐10

Abstract

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte‐specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti‐inflammatory energy substrates. Instead, Atg7 ‐deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2‐mediated upregulation of Ephx1 . This shift reduced secretion of IL‐10 from adipose tissues, which was dependent on the cytochrome P450‐EPHX pathway, and lowered circulating levels of IL‐10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat‐gut crosstalk through an autophagy‐dependent regulation of anti‐inflammatory oxylipins via the cytochrome P450‐EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation. image Cell‐extrinsic effects of autophagy on inflammation remain poorly understood. This study identifies adipocyte autophagy as an important contributor to an adipose‐driven anti‐inflammatory response to intestinal inflammation. Adipocyte autophagy is induced by DSS‐induced colitis in mice and in Crohn's disease patients. Loss of autophagy in mature adipocytes results in an exacerbation of DSS‐induced intestinal inflammation. Augmented DSS‐induced intestinal inflammation upon adipocyte‐specific autophagy inhibition was not due to reduced adipose tissue lipolysis. Adipocyte‐specific autophagy loss resulted in altered oxylipin metabolism via activation of the cytochrome P450‐EPHX pathway. Oxylipin imbalance impaired IL‐10 secretion from adipose tissues of DSS‐treated mice.