A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

Abstract

Summary Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA) or standard chow (SC) diets. Despite having reduced food intake and weight gain equivalent to the SC group, HF/BCAA rats were equally insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1(ser307), accumulation of multiple acylcarnitines in muscle, and was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a poor dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…In addition, we studied 3 major groups along the HF spectrum; used large cohort sizes compared with previous HF metabolomic analyses; used a targeted metabolomic approach permitting metabolite quantitation; and used state‐of‐the‐art assessment and analytic techniques 18, 30, 31, 32…”

“…Three conventional metabolites (ketones, nonesterified fatty acids, and 3‐hydroxybutyrate) were assayed using a Beckman‐Coulter DXC600 analyzer and reagents from Wako Chemicals (Richmond, VA). More‐detailed methodology and coefficients of variation have been previously reported 32, 33, 34, 35, 36. Metabolite measurements were performed at the Sarah W. Stedman Nutrition Center and Metabolomics Core Laboratory at the Duke Molecular Physiology Institute.…”

Perinatal western‐type diet and associated gestational weight gain alter postpartum maternal mood

“…Plasma amino acids were measured by flow injection tandem mass spectrometry using stable isotope dilution techniques as described previously (Haqq et al., 2005; Laferrère et al., 2011; Lien et al., 2009; Newgard et al., 2009). Data were acquired using a Waters triple quadrupole detector equipped with Acquity UPLC system and controlled by the MassLynx 4.1 MS software platform (Waters, Milford, MA).…”

Gene expression analysis of mTOR pathway: association with human longevity

“…Additionally, a primary hallmark of calorie restriction (CR) in rodents, which leads to inhibition of the mTORC1 pathway, is a dramatic reduction in age-associated cancer incidence and growth rate (Spindler, 2005), implying that enhanced mTOR signalling plays a central role in cancer progression. In rats, the mTOR pathway has also been implicated in both Type 1 and Type 2 diabetes, with chronic activity of mTORC1 contributing to obesity and insulin insensitivity (Newgard et al, 2009). Because reduced mTOR signalling in model organisms extends lifespan and is associated with better metabolic health, we postulated that a similar reduction in this signalling pathway may also contribute to longevity and healthy aging in humans.…”