Abstract

Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-14C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (∼300%), but lower plantaris and gastrocnemius masses (−21–24%). Plasma BCAAs and BCKAs were elevated 45–69% and ∼100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (−47–66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23–29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193–418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and protein turnover along with impaired BCKDC activity. Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation.

Highlights

  • Branched chain amino acids [Branched-chain amino acids (BCAAs), including leucine (Leu), valine (Val) and isoleucine (Ile)] are important nutrient signals increasing insulin secretion in islet beta cells and mammalian Target of Rapamycin signaling in most tissues

  • 1-MeHis, the amino acid from the muscle dipeptide anserine was unchanged in urine and lower in the plasma (Table 4). These findings suggest a specific effect on proteolysis as opposed to muscle toxicity where both methylhistidines isomers increase in urine [47]. 4-Hydroxyproline is a modified amino acid found in collagen

  • In conclusion, we report that branched-chain keto-acid (BCKA) were elevated more than

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Summary

Introduction

Branched chain amino acids [BCAAs, including leucine (Leu), valine (Val) and isoleucine (Ile)] are important nutrient signals increasing insulin secretion in islet beta cells and mammalian Target of Rapamycin (mTOR) signaling in most tissues They regulate satiety and affect glucose metabolism through peripheral and central mechanisms [1,2,3,4,5,6]. Other studies have indicated beneficial metabolic effects of BCAA or BCAA-rich diets, and associations between insulin action and BCAA-specific activation of mTOR are not entirely consistent [12], for review see [13] This raises the possibility that elevations in circulating BCAA reflect insulin resistance and are not causative

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