BCAA Catabolic Defect Alters Glucose Metabolism in Lean Mice

Abstract

Recent studies show branched-chain amino acid (BCAA) catabolic pathway is defective in obese animals and humans, contributing to the pathogenesis of insulin resistance and diabetes. However, in the context of obesity, various processes including the dysfunctional lipid metabolism can affect insulin sensitivity and glycemic regulation. It remains unclear how BCAA catabolic defect may exert direct impacts on glucose metabolism without the disturbance of obesity. The current study characterized the glucose metabolism in lean mice in which the genetic deletion of PP2Cm leads to moderate BCAA catabolic defect. Interestingly, compared to the wildtype control, lean PP2Cm deficient mice showed enhanced insulin sensitivity and glucose tolerance, lower body weight, and the preference for carbohydrate over lipids utilization. Metabolomics profiling of plasma and tissues revealed significantly different metabolic patterns in the PP2Cm deficient mice, featured by the marked alterations in glucose metabolic processes, including gluconeogenesis/glycolysis, glycogen metabolism, and tricarboxylic acid cycle. The metabolic changes of glucose were predominantly observed in liver but not skeletal muscle or white adipose tissue. The elevated branched-chain keto acids (BCKAs) resulted from the BCAA catabolic defect may play a critical role in regulating the expression of key regulators of glucose metabolic processes and the activity of respiratory Complex II/succinate dehydrogenase in TCA cycle. Together, these results show BCAA catabolic defect significantly alters glucose metabolism in lean mice with some impacts different or even opposite from those in obese mice, highlighting the critical role of BCAA catabolism in glycemic regulation and the complex interplay between macronutrients in lean and obese animals.

Silencing branched-chain ketoacid dehydrogenase or treatment with branched-chain ketoacids ex vivo inhibits muscle insulin signaling

“…Interestingly, cardiomyocytes incubated with BCKAs acutely downregulated AKT signaling triggering cell death (91), suggesting that excessive mitogenic signaling including translation, can be an energetically expensive process compromising cellular survival. Supporting this paradigm we and others demonstrate that BCKAs suppress mitochondrial oxygen consumption in C2C12, cardiac (11), neuronal (37) and hepatic cells (77). BCKAs also increased the accumulation of acid soluble metabolites, a signature of incomplete fatty acid oxidation in C2C12 cells.…”

“…Moreover, in the liver and cultured hepatic cells, BCKAs has been demonstrated to upregulate the glycogenolytic enzyme, glycogen phosphorylase (77). However, it was unclear if BCKAs' effects on metabolism involved changes in insulin signaling.…”

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

“…Intraperitoneal tolerance tests in chow-fed Pp2cm KO and WT mice did not show differences in glucose clearance between the two genotypes (Supplemental Figure 3). These findings differ from recently published studies by Wang and colleagues, showing that chow-fed Pp2cm KO mice have improved glucose tolerance and insulin sensitivity (56). Wang and colleagues used wild-type C57BL/6 mice as controls and although the authors state that the controls are the same genetic background and aged-matched, it is unclear that these controls came from the same litters as Pp2cm KO mice.…”

Blood Metabolite Signature of Metabolic Syndrome Implicates Alterations in Amino Acid Metabolism: Findings from the Baltimore Longitudinal Study of Aging (BLSA) and the Tsuruoka Metabolomics Cohort Study (TMCS)

“…More generally, BCAAs have been frequently studied in the context of metabolic disorders and obesity. Among healthy-weight individuals, BCAAs appear to exert beneficial effects, including a decreased risk of obesity, increased muscle mass, potential improvements in glucose sensitivity, and possible therapeutic effects for patients with hepatic cirrhosis and encephalopathy [41][42][43][44]. However, long-term exposure to elevated BCAAs stimulates hyperphagia and obesity, has been correlated positively with LDL and triglyceride levels and negatively with HDL-C, and directly inhibits the TCA cycle through BCKA accumulation [43,45,46].…”