Essential amino acids and their metabolites as important metabolic regulators

Contact: Christopher Bishop

Epidemiological studies link dairy intake to beneficial as well as detrimental metabolic effects. To reconcile these conflicting results, we are investigating possible differential effects of specific branched-chain amino acids (BCAA) which are essential dietary amino acids and major constituents of dairy protein. Current data regarding their role in metabolic health are rather conflicting, as both positive and negative effects have been attributed to their intake.

Detrimental effects of branched-chain amino acids in glucose tolerance can be attributed to valine induced glucotoxicity in skeletal muscle.

We focused on leucine and valine, two of the three BCAA that have different metabolic fates: leucine is a ketogenic while valine is a glucogenic amino acid. While the molecular actions of leucine have been well studied, little is known about specific effects of valine. Focusing on hepatic lipid metabolism and using in vivo (short term feeding) and in vitro (primary hepatocytes) approaches we first confirmed the already known acute activation of mechanistic target of rapamycin (mTOR) signalling by leucine. In contrast, valine acted as an agonist of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα), a major regulator of lipid metabolism (Bishop et al. FASEB J. 2020).

To assess long term metabolic outcomes and consequences of these differential molecular effects, we also performed long term mouse feeding studies in the context of diet induced obesity (DIO). Again, differential effects of leucine and valine supplementation could be observed. Leucine supplementation had beneficial effects on adiposity and insulin sensitivity, in part due to increasing energy expenditure - likely contributing to the beneficial effects of a higher milk protein intake. On the other hand, valine feeding led to an aggravation of health impairments, specifically to a worsening of obesity and reduction of glucose tolerance / insulin sensitivity. These negative effects were driven by an accumulation of valine and its metabolite 3-hydroxyisobutyrate (3-HIB) in the circulation, which might be due to a high fat diet induced disturbance of hepatic BCAA catabolism and possible shunting towards skeletal muscle. Higher plasma valine and 3-HIB levels increased basal skeletal muscle glucose uptake driving glucotoxicity and impairment of myocyte insulin signalling. This could be corroborated in vitro in lipid loaded C2C12 myocytes which were treated with valine and/or 3-HIB.

Thereby we could demonstrate the detrimental role of valine in an obesity context and uncovered a possible novel liver-muscle cross talk via 3-HIB, which seems to be of major importance in the development of BCAA-induced insulin resistance in obesity. We now concentrate on closer examination of the role of valine, valine catabolism pathways, 3-HIB, and other metabolites in the development of insulin resistance (Bishop et al. Nutrition & Diabetes 2022).