The role of branched-chain amino acids and their catabolism in regulating energy metabolism via adipose tissue in mice

Abstract

Adipose tissue is a dynamic metabolic organ that regulates systemic energy balance. In response to starvation, triglyceride stored in white adipose tissues (WAT) is released for the production of energy. On the other hand, under cold environment, brown adipose tissue (BAT) is activated to produce heat in the mitochondria. Branched-chain amino acids (BCAA) including leucine, isoleucine and valine are three essential amino acids not only serving as nutrient supplies, but also known as important regulators of glucose and lipid metabolism. Elevated circulating levels of BCAA is known to positively correlate with obesity and future development of type 2 diabetes. Apart from skeletal muscle and liver, BCAA can be catabolized into alpha-keto acids and acylcarnitines in adipose tissues via the BCAA catabolic enzymes including BCAT2 and BCKDH complex. Aberrant expression or activity of these catabolic enzymes has been linked to elevated circulating levels of BCAA in human and rodents with obesity. Although decreased consumption of BCAA has been shown to improve insulin resistance in obesity, its effect on energy metabolism and adiposity remains controversial. In addition, a recent study demonstrated that BCAA catabolism in WAT is altered upon cold challenge, suggesting that BCAA catabolism may be crucial for the browning of WAT, a process has been shown to increase energy expenditure and improve systemic metabolic health.

In this study, I aim to investigate: 1) the effect of acute cold challenge on BCAA catabolism in different metabolic tissues including WAT and BAT; 2) whether restriction of BCAA consumption has any effect on energy homeostasis, adiposity and browning of adipose tissues; 3) whether 3-adrenergic receptor is indispensable for the energy regulatory effect of BCAA restriction and 4) whether subcutaneous WAT (sWAT) is required for the effect of BCAA restriction on energy expenditure.

Key findings: 1. Circulating BCAA was significantly elevated in mice exposed to both chronic and acute cold challenge, while its downstream metabolites including alpha-keto acids and acylcarnitines were not affected. 2. The intracellular levels of BCAA and C3- and C5-acylcarnitines were markedly elevated in sWAT and BAT of mice upon cold exposure. The immunoblotting analysis and 13C metabolic flux analysis revealed the enhancement of BCAA catabolism in sWAT of cold-challenged mice. 3. Reduced consumption of BCAA markedly enhanced energy expenditure and induced cold resistant and browning of sWAT in mice, which were accompanied by altered BCAA catabolism in the adipose tissues. 4. Pharmacological activation of BCAA catabolism inhibited differentiation of stromal vascular fraction (SVF) into beige adipocyte and expression of thermogenic genes. 5. Treatment with 3-adrenergic receptor inhibitor or surgical removal of sWAT did not influence the energy promoting effect of BCAA restriction in mice.

These results collectively indicate that consumption and catabolism of BCAA is crucial for energy metabolism in rodent model. In addition, modulating BCAA catabolism in adipose tissue might represent a novel approach to promote energy expenditure by induction of browning in sWAT. Further investigation is needed to elucidate the underlying mechanism by which BCAA catabolism is linked to adipose tissue remodeling.