Intestinal ACE2 regulates glucose metabolism in diet‐induced obese mice through a novel gut‐islet axis mediated by tryptophan

Objective Angiotensin-converting enzyme 2 (ACE2) plays a vital role in regulating intestinal tryptophan (Trp) transport and maintaining Trp homeostasis. This study aimed to investigate the functional relationship between intestinal ACE2 and Trp in the regulation of glucose metabolism under metabolic stress. Methods ACE2-knockout mice and mice with adeno-associated virus-mediated overexpression of ACE2 were fed with a high-fat diet for 12 weeks to establish a high-fat-induced metabolic stress model. They were subjected to a Trp gavage intervention for another 4 weeks. Results Here, it is reported that ACE2 regulates intestinal Trp absorption by stabilizing neutral amino acid transporter B0AT1. Notably, in ACE2-knockout mice, it was found that B0AT1 and serum Trp levels were significantly reduced, which was not reversed by Trp supplementation. However, mice receiving adeno-associated virus-ACE2 did the opposite and showed significantly improved glycolipid metabolism. It was then confirmed that Trp potentiated glucagon-like peptide 1 production from intestinal and islet α-cells. Meanwhile, Trp-treated MIN6 cells ameliorated mitochondrial function and safely guarded MIN6 cells against reactive oxygen species exposure. Conclusions This study highlights an essential role of ACE2 in the maintenance of systemic metabolism to optimize the function of the islets through a novel gut-islet axis mediated by Trp. These results provide proof-of-concept evidence for treating obesity and diabetes.