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Energy metabolism is the process by which nutrients are metabolized for storage or the generation of ATP. For example, the adipose tissue stores the bulk of energy in our body as fats, whereas mitochondrion is the major site of fuel oxidation and energy production. It is very clear now that modulation of energy metabolism underlies many biological processes, and this is essential for normal cell and tissue functions within an organism. We use integrated approaches to study transcriptional networks that control metabolic programs at the level of genes, cells and organisms, and to understand their roles in the pathogenesis of metabolic diseases and neurodegeneration.
Although t he biochemical nature of enzymatic reactions that connect metabolic pathways has been extensively studied for decades, the current challenge is to understand how these metabolic programs are dynamically regulated in response to physiological signals. A major point of metabolic control occurs at the level of gene transcription. The basic question that we address is how transcription factors and their coactivators coordinate the construction of complex metabolic programs, and how these factors transduce metabolic signals to allow close coupling of metabolism to unique cellular functions. For example, stimulation of mitochondrial oxidative metabolism is integral to the physiological response to muscle contraction, neuronal activity, and adaptive thermogenesis. We focus our analysis on liver, muscle, brain and fat to identify pathways that are conserved in different cell types and those that operate in a tissue-specific manner. Our overall goal is to understand the fundamental mechanisms that control cellular and systemic energy metabolism, and to gain insight into the pathogenesis of obesity, type 2 diabetes, hyperlipidemia and neurodegeneration.
- Handschin, C., Lin, J., Wu, P., Rhee, J., Peyer, A., Meyer, U.A., Spiegelman, B.M. (2005). Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha. Cell 122:505-515
- Lin, J. , Yang, R., Tarr, P.T., Wu, P., Handschin, C., Yang, W., Pei, L., Uldry, M., Tontonoz, P., Newgard, C.B., Spiegelman, B.M. (2005). Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell, 120:261-273
- Arany, Z.*, He, H.*, Lin, J. *, Hoyer, K., Handschin, C., Doka, O., Chin, S., Wu, P., Rybkin, I.I., Shelton, J.M., Manieri, M., Cinti, S., Schoen, F.J., Bassel-Duby, R., Ingwall, J., Spiegelman, B.M. (2005). Transcriptional coactivator PGC-1alpha controls the energy state and contractile function of cardiac muscle. Cell Metabolism, 1:259-271 (*Equal contribution).
- Lin, J. , Wu, P., Tarr, P.T., Lindenberg, K.S., St-Pierre, J., Zhang, C.Y., Mootha, V.K., Jäger, S., Vianna, C.R., Reznick, R.M., Cui, L., Manieri, M., Donovan, M.X., Wu, Z., Cooper, M.P., Fan, M.C., Rohas, L.M., Zavacki, A., Cinti, S., Shulman, G.I., Lowell, B.B., Krainc, D., Spiegelman, B.M. (2004). Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119:121-135
- Lin, J. , Tarr, P.T., Yang, R., Rhee, J., Puigserver, P., Newgard, C.B., Spiegelman, B.M. (2003). PGC-1beta in the regulation of hepatic glucose and energy metabolism. J Biol Chem 278:30843-30848
- Handschin, C., Rhee, J., Lin, J., Tarr, P.T., Spiegelman, B.M. (2003). An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Proc Natl Acad Sci USA 100:7111-7116
- Lin, J. , Wu, H., Tarr, P.T., Zhang, C.Y., Wu, Z., Boss, O., Michael, L.F., Puigserver, P., Isotani, E., Olson, E.N., Lowell, B.B., Bassel-Duby, R., Spiegelman, B.M. (2002). Transcriptional co-activator PGC-1alpha drives the formation of slow-twitch muscle fibres. Nature 418: 797-801
- Lin, J. , Puigserver, P., Donovan, J., Tarr, P.T., Spiegelman, B.M. (2002). Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1 b ), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 277: 1645-1648
- Puigserver, P., Rhee J, Lin, J., Wu, Z., Yoon, J.C., Zhang, C.Y., Krauss, S., Mootha, V.K., Lowell, B.B., Spiegelman, B.M. (2001). Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell 8: 971-982
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