Key result
Adeno-associated virus-mediated overexpression of ACE2 significantly improved glycolipid metabolism in high-fat diet-induced obese mice through a novel gut-islet axis mediated by tryptophan.
Why the study?
ACE2 regulates intestinal tryptophan transport and homeostasis, but its functional relationship with tryptophan in regulating glucose metabolism under metabolic stress remains to be investigated.
Does tryptophan supplementation improve glucose metabolism in high-fat diet-induced obese mice with altered ACE2 expression?
Does tryptophan supplementation improve glucose metabolism in high-fat diet-induced obese mice with altered ACE2 expression?
Intestinal ACE2 regulates systemic glucose metabolism through a tryptophan-mediated gut-islet axis, offering a potential therapeutic target for obesity and diabetes.
Hypothesis-generating for intestinal ACE2 modulation in obesity; human trials needed before clinical consideration.
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: AT1 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.
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Chen et al. (2023) studied Diet-induced obesity and metabolic stress. Adeno-associated virus-mediated overexpression of ACE2 and tryptophan gavage vs. ACE2-knockout mice was evaluated on Glycolipid metabolism and serum tryptophan levels. Adeno-associated virus-mediated overexpression of ACE2 significantly improved glycolipid metabolism in high-fat diet-induced obese mice through a novel gut-islet axis mediated by tryptophan.
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