Angiotensin-Converting Enzyme 2 improves hepatic insulin resistance by regulating GABAergic signaling in the liver

The angiotensin-converting Enzyme 2 (ACE2)/angiotensin 1-7 (A1-7)/MAS axis and the GABAergic signaling system have both been shown to have the dual potential to improve Insulin resistance (IR) and hepatic steatosis associated with obesity in the liver. Recent studies have demonstrated that ACE2 can regulate the Gamma-aminobutyric acid (GABA) signal in various tissues. Notwithstanding this evidence, the functional relationship between ACE2 and GABA signal in the liver under Insulin resistance remains elusive. Here, we used high-fat-diet induced models of Insulin resistance in C57BL/6 mice, as well as ACE2 knockout and AVV-mediated ACE2 overexpression mouse models to address this knowledge gap. Our analysis showed that glutamate decarboxylase (GAD)67/GABA signaling was weakened in the liver during Insulin resistance, while the expression of GAD67 and GABA decreased significantly in ACE2 knockout mice. Furthermore, exogenous administration of A1-7 and AVV- or Lentivirus-mediated overexpression of ACE2 significantly increased hepatic GABA signaling in models of Insulin resistance both in vivo and in vitro. We found this treatment prevented lipid accumulation and promoted fatty acid β oxidation in hepatocytes as well as inhibited the expression of gluconeogenesis- and inflammation-related genes, which could be reversed by allylglycine, a specific GAD67 inhibitor. Collectively, our findings show that signaling via the ACE2/A1-7/MAS axis can improve hepatic Insulin resistance by regulating hepatic GABA signaling. We propose this research might indicate a potential strategy for the management of diabetes.

angiotensin-converting enzyme 2; hepatic steatosis; inflammation; insulin resistance; γ-Aminobutyric acid.