2041-P: Genetic Intervention in Kynurenine Pathway Alters Glucose Metabolism in Mice

Abstract

Most of tryptophan is metabolized to kynurenine (KYN) to synthesize NAD+, while a subsidiary pathway changes KYN to kynurenic acid (KYNA) by kynurenine aminoltransferases (KATs). We previously reported genetic association of a mutation in the gene encoding KAT-1, an isoform of KATs, with hypertension, adiposity and glucose intolerance in rats. Although it is widely known that KYNA negatively regulates central nervous system by antagonizing neuro-receptors, its physiological role in glucose metabolism remains unclear. To explore such role, first, we have established KAT-1 knockout mice that showed decreased levels of KAT activity in liver and brain (p<0.01) and KYNA levels decreased significantly in brain and blood (p<0.05) and tending to decrease in liver. The KAT-1 knockout mice also showed significantly deteriorated glucose tolerance (p<0.05 at 60min after glucose i.p.) and insulin sensitivity (p<0.05 at 45, 60, 75 and 90min after insulin i.p.) as compared with wild littermates. Next, to establish mice with endogenously increased levels of KYNA, the hepatic gene encoding kynurenine mono-oxygenase (KMO), a rate-limiting enzyme for conversion of KYN to NAD+, was knocked down by shRNA adenovirus. The hepatic KMO knockdown in normal mice markedly increased endogenous KYNA levels in liver, blood and several other tissues, whereas the levels of 3-hydroxykynurenine, a downstream product of KMO, were decreased in liver (p<0.001). Finally, the hepatic KMO knockdown in diet-induced obese mice significantly ameliorated glucose intolerance and improved insulin sensitivity and pyruvate tolerance independently of food intake or body weight. Among the enzymes related to glucose metabolism, both the gene expression (p<0.01) and the enzymatic activity (p<0.05) of glucokinase were increased in the liver of the KMO knockdown group as compared with controls. These results indicated that alterations in KYNA pathway influence glucose metabolism in vivo. Disclosure T. Yamamoto: None. T. Gotoda: None.