BADERC-Zhijun Luo

Vamsi Mootha, M.D.

Systems Approaches to Metabolism and Mitochondrial Biology

The research program is aimed at utilizing the new tools of genomics and computational biology to understand mitochondrial biology and metabolism. We are particularly interested in the rare mitochondrial disorders – collectively the largest class of inborn errors of metabolism. Major efforts in the group are aimed at identifying all of the protein components of mitochondria, discovering the regulatory networks that control their expression and assembly, and discovering genetic variants that disrupt these proteins and networks in human disease. We are also interested in type 2 diabetes and have several ongoing projects focused in this area:

1) Oxidative phosphorylation and human diabetes
Working in collaboration with Drs. David Altshuler and Leif Groop, we previously discovered that the nuclear genes encoding the oxidative phosphorylation (OXPHOS) machinery are reduced in prediabetic and diabetic muscle. This conclusion was reached independently by the research group of M.E. Patti and C.R. Kahn. At present, whether these gene expression changes are causally related to the development of diabetes, or secondary to the diabetic milieu, is not clear. We are working to systematically dissect the transcriptional program underlying these changes, and have discovered a critical role for the orphan nuclear receptor ESRRA in controlling OXPHOS gene expresssion in muscle. We are currently working to identify additional transcriptional regulators of this program, and are also using chemical biology approaches to manipulate this pathway.

2) Role of TXNIP in human diabetes
Working in collaboration with Dr. Leif Groop, we used microarrays to discover that three genes, G0S2, BCL6, and TXNIP, are strongly regulated by insulin in humans in vivo. We have performed follow-up analysis on TXNIP to discover that insulin strongly suppresses its expression, while glucose strongly upregulates it. Moreover, we have shown using gain of function and loss of function experiments that TXNIP is a negative regulator of glucose uptake. Hence, it appears to be a sensor and regulator of glucose homeostasis in fat and muscle. Our results suggest that agents that downregulate the expression of TXNIP may promote peripheral glucose uptake and insulin sensitivity. Interestingly, research from other groups have shown that elevations in TXNIP in the pancreatic beta cell are associated with beta cell apoptosis. Hence, in beta cells, muscle, and in fat, it appears that reducing TXNIP gene expression levels could suppress beta cell apoptosis and promote peripheral glucose uptake. Current research is focused on understanding the transcriptional control of TXNIP, and identifying small molecule modulators of its expression.

3) Metabolomic approaches to diabetes
We have worked with the Broad Institute to establish a metabolomics platform with which to study metabolism in humans. Our platform is capable of monitoring the relative abundance of over 200 metabolites in plasma. In an initial study of healthy college students, we characterized the human response to an oral glucose challenge. One of our unexpected findings is that a variety of bile acids exhibit a pronounced and sustained elevation following an oral glucose challenge. We also found metabolite changes reflective of insulin’s suppression of proteolysis, lipolysis, ketogenesis. We have also performed similar measurements in individuals with prediabetes. We have found that alterations in branched chain amino acids and glycerol are strongly correlated to insulin levels and are currently working with Dr. Robert Gerszten’s group to determine if any of these metabolomic changes may have value in predicting diabetes complications or treatment response.

References:

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman BM, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 2003;34(3):267-73.
Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proceedings of the National Academy of Sciences U.S.A. 2004;101(17):6570-5.
Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, Poulsen P, Saxena R, Ladd C, Schulze PC, Mazzini MJ, Jensen CB, Krook A, Björnholm M, Tornqvist H, Zierath JR, Ridderstråle M, Altshuler D, Lee RT, Vaag A, Groop LC, Mootha VK. TXNIP regulates peripheral glucose metabolism in humans. PLoS Medicine 2007;4(5)e158.
Wagner BK, Kitami T, Gilbert TJ, Peck D, Ramanathan A, Schreiber SL, Golub TR, Mootha VK. Large-scale chemical dissection of mitochondrial function. Nature Biotechnology 2008;26(3):343-51.
Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Ramachandran V, Carr SA, Thadhani R, Gerszten RE, Mootha VK. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Molecular Systems Biology 2008, doi:10.1038/msb.2008.50.






			Vamsi Mootha, M.D. Systems Approaches to Metabolism and Mitochondrial Biology The research program is aimed at utilizing the new tools of genomics and computational biology to understand mitochondrial biology and metabolism. We are particularly interested in the rare mitochondrial disorders – collectively the largest class of inborn errors of metabolism. Major efforts in the group are aimed at identifying all of the protein components of mitochondria, discovering the regulatory networks that control their expression and assembly, and discovering genetic variants that disrupt these proteins and networks in human disease. We are also interested in type 2 diabetes and have several ongoing projects focused in this area: 1) Oxidative phosphorylation and human diabetes Working in collaboration with Drs. David Altshuler and Leif Groop, we previously discovered that the nuclear genes encoding the oxidative phosphorylation (OXPHOS) machinery are reduced in prediabetic and diabetic muscle. This conclusion was reached independently by the research group of M.E. Patti and C.R. Kahn. At present, whether these gene expression changes are causally related to the development of diabetes, or secondary to the diabetic milieu, is not clear. We are working to systematically dissect the transcriptional program underlying these changes, and have discovered a critical role for the orphan nuclear receptor ESRRA in controlling OXPHOS gene expresssion in muscle. We are currently working to identify additional transcriptional regulators of this program, and are also using chemical biology approaches to manipulate this pathway. 2) Role of TXNIP in human diabetes Working in collaboration with Dr. Leif Groop, we used microarrays to discover that three genes, G0S2, BCL6, and TXNIP, are strongly regulated by insulin in humans in vivo. We have performed follow-up analysis on TXNIP to discover that insulin strongly suppresses its expression, while glucose strongly upregulates it. Moreover, we have shown using gain of function and loss of function experiments that TXNIP is a negative regulator of glucose uptake. Hence, it appears to be a sensor and regulator of glucose homeostasis in fat and muscle. Our results suggest that agents that downregulate the expression of TXNIP may promote peripheral glucose uptake and insulin sensitivity. Interestingly, research from other groups have shown that elevations in TXNIP in the pancreatic beta cell are associated with beta cell apoptosis. Hence, in beta cells, muscle, and in fat, it appears that reducing TXNIP gene expression levels could suppress beta cell apoptosis and promote peripheral glucose uptake. Current research is focused on understanding the transcriptional control of TXNIP, and identifying small molecule modulators of its expression. 3) Metabolomic approaches to diabetes We have worked with the Broad Institute to establish a metabolomics platform with which to study metabolism in humans. Our platform is capable of monitoring the relative abundance of over 200 metabolites in plasma. In an initial study of healthy college students, we characterized the human response to an oral glucose challenge. One of our unexpected findings is that a variety of bile acids exhibit a pronounced and sustained elevation following an oral glucose challenge. We also found metabolite changes reflective of insulin’s suppression of proteolysis, lipolysis, ketogenesis. We have also performed similar measurements in individuals with prediabetes. We have found that alterations in branched chain amino acids and glycerol are strongly correlated to insulin levels and are currently working with Dr. Robert Gerszten’s group to determine if any of these metabolomic changes may have value in predicting diabetes complications or treatment response. References: Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman BM, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature Genetics 2003;34(3):267-73. Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle. Proceedings of the National Academy of Sciences U.S.A. 2004;101(17):6570-5. Parikh H, Carlsson E, Chutkow WA, Johansson LE, Storgaard H, Poulsen P, Saxena R, Ladd C, Schulze PC, Mazzini MJ, Jensen CB, Krook A, Björnholm M, Tornqvist H, Zierath JR, Ridderstråle M, Altshuler D, Lee RT, Vaag A, Groop LC, Mootha VK. TXNIP regulates peripheral glucose metabolism in humans. PLoS Medicine 2007;4(5)e158. Wagner BK, Kitami T, Gilbert TJ, Peck D, Ramanathan A, Schreiber SL, Golub TR, Mootha VK. Large-scale chemical dissection of mitochondrial function. Nature Biotechnology 2008;26(3):343-51. Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Ramachandran V, Carr SA, Thadhani R, Gerszten RE, Mootha VK. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Molecular Systems Biology 2008, doi:10.1038/msb.2008.50.