Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss

Insulin resistance is a common metabolic complication of obesity and an important risk factor for the development of type 2 diabetes, the metabolic syndrome, and coronary heart disease (1, 2). It has been proposed that an increase in circulating branched-chain amino acids (BCAA), valine, leucine, and isoleucine, is involved in the pathogenesis of insulin resistance, because increased plasma BCAA concentrations are often observed in obese and insulin resistant states (3, 4), and weight loss leads to decreased plasma BCAA concentrations and improved insulin action (5, 6). However, the underlying mechanism(s) responsible for the relationship between BCAA metabolism and insulin resistance is not known. Monomethyl branched chain fatty acids (mmBCFA) could provide a link between BCAA metabolism and metabolic dysfunction. In most peripheral tissues, BCAA are deaminated by mitochondrial branched chain aminotransferase (BCAT2 or BCATm) to generate branched-chain α-ketoacids (7), which are then decarboxylated by the branched-chain α-ketoacid dehydrogenase complex (8). The resulting short-chain branched acyl moieties can be exported out of mitochondria (9) and undergo conventional de novo fatty acid biosynthesis, catalyzed by fatty acid synthase (FAS), to produce mmBCFA (10). Alternatively, the fatty acyl chain could be extended within mitochondria by using the mitochondrial fatty acid synthesis (FAS II) system (11) (Supplementary Figure S1). The predominant branching in mmBCFA is near the terminal end of the carbon chain with an isopropyl or isobutyl group denoted as iso- or anteiso-BCFA, respectively. mmBCFA are present in a large range of organisms from bacteria to mammals, indicating conserved metabolic pathways for their synthesis and function. The enzymes involved in BCAA metabolism are key regulators of both the degradation of BCAA and the synthesis of mmBCFA. Skeletal muscle and adipose tissue are the primary sites for BCAA degradation (12), whereas BCAA catabolism in the liver is minimal because of low levels of BCATm (7). A study conducted in a rodent model demonstrated that adipose tissue BCAA metabolism can modulate circulating BCAA concentrations (13), presumably because adipose tissue is a major site for plasma BCAA uptake and conversion to lipids (14). Whole tissue assessments of BCAA catabolic activities and kinetics also suggest that adipose tissue could play an important role in regulating whole body BCAA homeostasis in people (15, 16). Adipose tissue gene expression of enzymes involved in BCAA catabolism is lower in obese and insulin resistant mice and people than in their lean counterparts (17, 18). Therefore, it is possible that increased catabolism of BCAA and conversion to mmBCFA in adipose tissue could improve insulin sensitivity by clearing BCAA from plasma. The purpose of the present study was to evaluate the possibility that adipose tissue mmBCFA metabolism is associated with whole-body (primarily skeletal muscle) insulin sensitivity in obese subjects. Accordingly, we conducted: i) a cross-sectional study to assess the relationship between adipose tissue mmBCFA content and insulin sensitivity in lean and obese subjects, and ii) a longitudinal study to assess the effects of marked weight loss on adipose tissue mmBCFA metabolism and insulin sensitivity.