The ultimate measure of the Core’s success is not technical capabilities but research impact. We have maintained a steady stream of over 5000 DRC sample runs annually. The resulting data has contributed to 41 DRC publications, 34 as a Primary Core. The quality of these paper is extraordinary, including articles in Cell, Science, Nature x 2, Journal of Clinical Investigation x 2, Nature Metabolism x 3, and Cell Metabolism x 7! See below for selected examples.
Lazar Lab:
The hepatocyte clock and feeding control chronophysiology of multiple liver cell types
Metabolic control of endothelial proliferation, migration, and vascular integrity. Endothelial dysfunction in diabetes contributes to major negative symptoms including atherosclerosis, impaired vascular integrity, and cardiovascular disease. Through the Core, we investigated glutamine metabolism in endothelial cells with metabolomics and isotope tracing. We found that glutamine supplies the majority of carbons in the TCA cycle of endothelium, and that glutamine metabolism is required for the proliferation (but not migration) of endothelial cells50. Next, we investigated the role of the M2 isoform of pyruvate kinase (PKM2) in endothelial function. Metabolomics and isotope tracing with the Core revealed that PKM2 knockdown impaired glycolysis. Surprisingly, pyruvate kinase activity was not required for other functions of PKM2, including maintenance of the vascular barrier51. Together, this work links endothelial metabolism to critical endothelial functions.
Natural human genetic variation determines basal and inducible expression of PM20D1, an obesity-associated gene52. The brown fat-associated gene PM20D1 was recently identified as an enzyme that condenses fatty acids and amino acids to form N-acyl-amino acids. In this work, we discovered that PM20D1 is also an obesity-associated gene, and differentially regulated in human adipose tissue by genetic variants, including one that determines its regulation by PPAR-gamma and antidiabetic drugs. Through the DRC Regional Metabolomics and Fluxomics Core, we measured N-acyl-amino acids in human serum and adipose tissue samples, finding unexpectedly that N-acyl-amino acids were not significantly related to PM20D1 expression in adipose tissue. This novel measurement of N-acyl-amino acids was only possible with the expertise and technology available with the core.
Beier Lab:
Role of the NAD+:NADH redox state in the control of T cell proliferation and function. T cell dysfunction is associated with type 1 diabetes. Through 13C-lactate tracing via the Core, we observed that lactate is taken up by T cells and oxidized to pyruvate, causing a reductive imbalance (NADH>NAD+), which in turn blocks NAD-dependent glucose catabolism (GAPDH) and anabolism (PHGDH)53. Restoring serine supply negates the suppressive effects of lactate on T cell proliferation54. These data support redox manipulation of a potential mechanism for rewiring T cell activity to mitigate Type I diabetes.
Changes in NAD metabolism during aging and caloric restriction. Steady state NAD concentration declines with age. Whether these changes in NAD concentration are driven by effects on synthesis or consumption is not known, and cannot be determined through steady state measurements. In tight collaboration with the Regional Metabolomics and Fluxomics Core, we have performed tracer studies to look at NAD synthesis and breakdown fluxes in vivo across the lifespan and during interventions including caloric restriction. These studies reveal that NAD synthesis is intact in aged animals and the decline in NAD is attributable to increased consumer activity. The manuscript has been submitted. Going forward, we plan to examine the contributions of specific consumers using knockout mice. In addition, we plan to take advantage of the new imaging mass spectrometry capabilities of the core to provide spatial information about the distribution of NAD metabolites and turnover within tissues, and how this relates to increased diabetes risk with aging.