1921-P: The Role of BCAA Catabolism in Glucose Homeostasis

Abstract

The rate limiting step of BCAA (Branched-chain amino acid; Valine, Leucine and Isoleucine) catabolism is regulated by the branched-chain keto acid dehydrogenase complex (BCKDC). PPM1K is a phosphatase which regulates BCAA catabolism by activating BCKDC through dephosphorylation. We and other groups have reported impaired BCAA catabolism and elevated blood BCAA levels in PPM1K-defiient mice (KO). Several studies have shown that elevated blood BCAA levels are associated with obesity and glucose intolerance. In addition, PPM1K expression is reduced in obesity model animals (leptin-deficient mice, etc.) and GWAS data shows loss-of-function SNP of PPM1K gene is associated with diabetes. Based on these findings, loss/reduction of PPM1K is thought to induce glucose intolerance. However, no previous study has directly analyzed the role of PPM1K in obesity and glucose metabolism. Therefore, in this study, we analyzed KO and wild type mice (WT) with diet-induced obesity. Firstly, KO and WT were fed with either normal chow diet (NCD) or high-fat diet (HFD; 60% of kcal from fat). KO showed normal body weight gain in both NCD and HFD condition. Next, KO and WT underwent intra-peritoneal glucose tolerance test (ipGTT). NCD-fed KO showed normal glucose tolerance. Surprisingly, HFD-fed KO showed significantly better glucose tolerance (AUC WT 58192±7828 vs. KO 47526±6646 min*mg/dL, p<0.05). As impaired BCAA catabolism leads to both decreased BCAA catabolite and increased BCAAs, to distinguish the effect of these two factors, we did ipGTT in WT fed with BCAA-restricted diet (LB; the amount of BCAA were reduced to one-third of control), which has decreased BCAA catabolite without increased BCAAs. LB showed improved glucose tolerance (AUC Cont 38639±5748 vs. LB 32087±5072 min*mg/dL, p<0.05), indicating that decreased BCAA catabolite rather than increased BCAAs may cause better glucose tolerance in KO. In summary, these results suggest the critical role of PPM1K and BCAA catabolism in the regulation of glucose homeostasis. Disclosure K. Nishi: None. L. Abell: None. T. McMillen: None. R. Tian: None. Funding Japan Heart Foundation; National Institutes of Health