The overall theme of our lab is the regulation of energy homeostasis in mammalian systems, with special reference to adipose and muscle tissues. While we have long been interested in diabetes and obesity, our current interests extend to muscle disorders, neurodegeneration and cancer cell metabolism. We are particularly interested in mitochondrial metabolism and dynamics in these disorders and in the development of novel therapeutic approaches. We work at both the biochemical and physiological levels, employing cultured cells and in vivo murine models. The lab welcomes applications from qualified Ph.D. students and those looking for post-doctoral positions.
The following are major current research areas:
PGC1a and the control of energy homeostasis
We discovered the transcriptional coactivator PGC1a in 1998. Work from our lab and others have demonstrated that this molecule is the dominant regulator of mitochondrial biogenesis in most tissues and is conserved from humans to flies. We are currently focused on the new modes of regulation of this critical molecule, including regulation of mRNA translation and post-translational modifications of the protein itself.
We are also interested in how PGC1a particularly in muscle, talks to other tissues beyond where its expressed. PGC1a in muscle is induced in exercise as part of the adaptation to endurance exercise. We are now trying to identify comprehensively all of the secreted proteins expressed by muscle cells under the influence of elevated PGC1a. We are testing these for their effects on tissues known to experience benefits of exercise in humans: muscle itself, adipose tissues, liver, kidney and brain.
Development and function of brown and beige adipose tissues
We have a long-standing interest in adipose cells and tissues. Most recently we have been focused on how thermogenic fat cells, brown and beige, form and function. We are especially focused on the bioenergetics pathways in mitochondria that lead to energy expenditure. How these same pathways can be used to combat obesity and diabetes has been under study. We are also interested in how thermogenic fat cells become much more highly innervated by the sympathetic nervous systems compared to other kinds of fat cells.
Protein factors secreted from muscle, fat and other tissues are being examined for their ability to stimulate “browning” of adipose tissues. These include Slit2-C, irisin and meteorin-like. Preclinical studies are preparing the way for what we hope will be clinical studies, as will identification of their cognate receptors.
PPARg and its role in cancer biology and cancer treatment
There is increasing interest in the metabolism of cancer cells and this has led to interest in whether treatments for metabolic diseases have a place in cancer therapy. We have shown, over many years, that drugs that activate PPARg can slow down the growth of tumor cells and be used on models of cancer in mice. More recently we have shown that PPARg ligands can synergize with DNA damaging agents to inhibit tumor cell growth. We are trying to understand whether these striking effects are through actions on DNA damage/repair processes and how this can be leveraged in the human cancer clinic.
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Puigserver P, Wu Z, Park CW, Graves R, Wright M and Spiegelman BM. A cold inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92:829-839.
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Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang A, Khandekar M, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt WD, Hoeks J, Enerbäck S, Schrauwen P and Spiegelman BM. Beige Adipocytes are a Distinct Type of Thermogenic Fat Cell in Mouse and Human. Cell 2012; 150(2):366-376.
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Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, Lo JC, Zeng X, Ye L, Khandekar MJ, Wu J, Gunawardana SC, Banks AS, Camporez JP, Jurczak MJ, Kajimura S, Piston DW, Mathis D, Cinti S, Shulman GI, Seale P, Spiegelman BM. Ablation of PRDM16 and Beige Fat Causes Metabolic Dysfunction and a Subcutaneous to Visceral Adipose Switch. Cell 2014; 156(1-2):304-316.
Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, Vetrivelan R, Lu GZ, Laznik-Bogoslavski D, Hasenfuss SC, Kajimura S, Gygi SP, Spiegelman BM. A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat. Cell 2015; 163(3):643-655.
Svensson KJ, Long JZ, Jedrychowski MP, Cohen P, Lo JC, Serag S, Kir S, Shinoda K, Tartaglia JA, Rao RR, Chedotal A, Kajimura S, Gygi SP, Spiegelman BM. A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function. Cell Metab. 2016; 23(3):454-466.
Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, Lou J, Rao RR, Chang MR, Jedrychowski MP, Paulo JA, Gygi SP, Griffin PR, Nomura DK, Spiegelman BM. PM20D1 secretion by thermogenic adipocytes regulates lipidated amino acid uncouplers of mitochondrial respiration. Cell 2016; 166(2):424-435.
Zeng, X, Jedrychowski MP, Chen Y, Serag S, Lavery GG, Gygi SP, Spiegelman BM. Lysine-Specific Demethylase 1 Promotes Brown Adipose Tissue Thermogenesis via Repressing Glucocorticoid Activation. Genes & Dev. 2016; 30(16):1822-1836.
Chouchani ET, Kazak L, Jedrychowski MP, Lu GZ, Erickson BK, Szpyt J, Pierce KA, Laznik-Bogoslavski D, Vetrivelan R, Clish CB, Robinson AJ, Gygi SP and Spiegelman BM. Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 2016; 532(7597):112-116.
Kazak L, Chouchani ET, Lu GZ, Jedrychowski MP, Bare CJ, Mina AI, Kumari M, Zhang S, Vuckovic I, Laznik-Bogoslavski D, Dzeja P, Banks AS, Rosen ED, Spiegelman BM. Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metab. 2017; 26(4):660-671.
Chen Y, Zeng X, Huang X, Serag S, Woolf CJ and Spiegelman BM. Crosstalk between Kcnk3-mediated ion current and adrenergic signaling regulates adipose thermogenesis and obesity. Cell 2017; 171(4):836-848.