Location: Obesity and Metabolism Research
Project Number: 2032-51530-019-56-T
Project Type: Trust Fund Cooperative Agreement
Start Date: Feb 1, 2012
End Date: Dec 31, 2013
Elevated fat levels within tissues and reduced capacity/inefficiencies in long-chain fatty acid (LCFA) oxidative catabolism are highly correlated with muscle, liver, adipose, and whole-body insulin resistance and type 2 diabetes mellitus (T2DM). It is hypothesized that specific metabolites whose intra- or extra-cellular concentrations shift in response to changes in capacity or efficiency of mitochondrial LCFA combustion act as bioactive molecules that impact insulin signaling. We have leveraged metabolomics analysis platforms to discover new plasma metabolites that correlate with T2DM. One interesting outcome to date has been the identification of medium-chain fatty acylcarnitines (MCFA-carnitines, defined herein as C6-C14-carns and reflective of incomplete LCFA ß-oxidation) as entities increased in human T2DM plasma. These molecules and others that reflect ineffient metabolism can induce inflammation and contribute to poor metabolic health. The current proposal aims to test if low levels of a specific enzyme, branched chain alpha-ketoacid dehydrogenase (BCKD), is involved in driving inefficient metabolism and mitochondrial function observed in the obese insulin-resistant state. These proof-of-principle studies will determine if improving dietary protein quality through provision of branched chain amino acid (BCAA)-rich dairy-based protein can activate BCKD, improve mitochondrial function, and hence support metabolic health.
Objective 1 (Aim 1): Determine if increased intake of diets rich in dairy or dairy components modify blood biomarkers reflective of improved mitochondrial efficiency and health in humans. Metabolomics technologies will be applied to monitor changes in blood metabolites reflective of improved mitochondrial function and metabolic efficiency of nutrient utilization, in archived samples from obese subjects fed different forms of high-dairy-protein diets. Archived adipose tissue biopsy samples will be evaluated for expression of the BCKD enzyme comparing persons fed an adequate vs. low dairy diet.