Cell and Developmental Biology University of Michigan

Transcriptional control of energy metabolism

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.

Publications

Representative Publications

• Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN, Lowell BB, Bassel-Duby R, Spiegelman BM (2002) Transcriptional co-activator PGC-1a drives the formation of slow-twitch muscle fibres.  Nature 418: 797-801
• Lin J, Wu P, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, Mootha VK, Jäger S, Vianna CR, Reznick RM, Cui L, Manieri M, Donovan MX, Wu Z, Cooper MP, Fan MC, Rohas LM, Zavacki A, Cinti S, Shulman GI, Lowell BB, Krainc D, Spiegelman BM (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1a null mice.  Cell 119:121-135
• Lin J, Yang R, Tarr PT, Wu P, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard CB, Spiegelman BM (2005) Hyperlipidemic effects of dietary saturated fats mediated through PGC-1b coactivation of SREBP.  Cell 120:261-273
• Liu C, Li S, Liu T, Borjigin J, Lin JD (2007) Transcriptional coactivator PGC-1a integrates mammalian clock and energy metabolism.  Nature, 447:477-481. 
• Li S, Liu C, Li N, Hao T, Han T, Hill DE, Vidal M, Lin JD (2008) Genome-wide coactivation analysis of PGC-1a identifies BAF60a as a regulator of hepatic lipid metabolism.  Cell Metabolism, 8:105-117.  
• Li S, Arland E, Liu C, Vitvitsky V, Hernandez C, Banerjee R, Bottiglieri T, Lin JD (2009) Regulation of homocysteine homeostasis through the transcriptional coactivator PGC-1a.  Am. J. Physiol. Endo. Metab. 296:E543-548.  
• Lin JD (2009) The PGC-1 coactivator networks: chromatin-remodeling and mitochondrial energy metabolism.  Mol Endocrinol, 23:2-10.