Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss

Abstract

Aims/hypothesis Insulin resistance (IR) improves with weight loss, but this response is heterogeneous. We hypothesised that metabolomic profiling would identify biomarkers predicting changes in IR with weight loss. Methods Targeted mass spectrometry-based profiling of 60 metabolites, plus biochemical assays of NEFA, β-hydroxybutyrate, ketones, insulin and glucose were performed in baseline and 6 month plasma samples from 500 participants who had lost ≥4 kg during Phase I of the Weight Loss Maintenance (WLM) trial. Homeostatic model assessment of insulin resistance (HOMA-IR) and change in HOMA-IR with weight loss (ΔHOMA-IR) were calculated. Principal components analysis (PCA) and mixed models adjusted for race, sex, baseline weight, and amount of weight loss were used; findings were validated in an independent cohort of patients (n=22). Results Mean weight loss was 8.67±4.28 kg; mean ΔHOMA-IR was −0.80±1.73, range −28.9 to 4.82). Baseline PCA-derived factor 3 (branched chain amino acids [BCAAs] and associated catabolites) correlated with baseline HOMA-IR (r=0.50, p<0.0001) and independently associated with ΔHOMA-IR (p<0.0001). ΔHOMA-IR increased in a linear fashion with increasing baseline factor 3 quartiles. Amount of weight loss was only modestly correlated with ΔHOMA-IR (r=0.24). These findings were validated in the independent cohort, with a factor composed of BCAAs and related metabolites predicting ΔHOMA-IR (p=0.007). Conclusions/interpretation A cluster of metabolites comprising BCAAs and related analytes predicts improvement in HOMA-IR independent of the amount of weight lost. These results may help identify individuals most likely to benefit from moderate weight loss and elucidate novel mechanisms of IR in obesity.

Metabolomics identifies changes in fatty acid and amino acid profiles in serum of overweight older adults following a weight loss intervention

“…BCAAs predicted improvements in insulin resistance in patients participating in a weight loss intervention [31,49], and a positive association between BCAAs and insulin resistance has been also reported [34,49]. In the current study, insulin levels were not determined.…”

Branched-chain amino acids alter neurobehavioral function in rats

“…Moreover, a very similar metabolite cluster predicts incident type 2 diabetes in longitudinal studies in humans (64) and, when measured at baseline in obese subjects, also predicts improvement in insulin sensitivity in response to a dietary/behavioral weight loss intervention (63). These findings suggest the possibility that elevated BCAA could be linked to behavioral disorders.…”

“…In the current study, we have built upon recent findings of strong associations between the levels of BCAA and AAA, obesity, and obesity-related metabolic dysregulation (10,43,63) and have begun to explore the possible connection between BCAA, AAA, and behavioral modifications. We have found that dietary supplementation of BCAA in either of two energydense diets, a low-fat, high-sucrose diet or a high-fat diet, has a clear effect to decrease exploratory behavior in rats subjected to an EPM test, indicating increased stress/anxiety (49,53).…”

Benzothiophene Carboxylate Derivatives as Novel Allosteric Inhibitors of Branched-chain α-Ketoacid Dehydrogenase Kinase

“…These metabolites are prognostic of obesity intervention outcomes (40) and show favorable responses to therapeutic procedures such as gastric bypass (41). These strong associations of BCAA with human disease argue for a better understanding of the mechanisms that drive changes in their circulating levels and for testing the therapeutic impact of new methods for altering BCAA metabolism (42).…”

“…However, these BDK inhibitors are either nonspecific (e.g. phenylbutyrate) or less than robust as BDK inhibitors, with reported I 40 (concentration for 40% inhibition) in the submillimolar range (e.g. CIC, phenylpyruvate, and clofibric acid).…”