Bruce M Spiegelman

Dana-Farber Cancer Institute, Boston, Massachusetts, United States

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Publications (390)

  • Xing Zeng · Mark P Jedrychowski · Yi Chen · [...] · Bruce M Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways. On the one hand, LSD1 associates with PRDM16 to repress expression of white fat-selective genes. On the other hand, LSD1 represses HSD11B1 (hydroxysteroid 11-β-dehydrogenase isozyme 1), a key glucocorticoid-activating enzyme, independently from PRDM16. Adipose-specific ablation of LSD1 impaired mitochondrial fatty acid oxidation capacity of the brown adipose tissue, reduced whole-body energy expenditure, and increased fat deposition, which can be significantly alleviated by simultaneously deleting HSD11B1. These findings establish a novel regulatory pathway connecting histone modification and hormone activation with mitochondrial oxidative capacity and whole-body energy homeostasis.
    Article · Aug 2016 · Genes & development
  • Serkan Kir · Bruce M. Spiegelman
    Article · Aug 2016
  • [Show abstract] [Hide abstract] ABSTRACT: The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.
    Article · Jun 2016
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    Jonathan Z. Long · Katrin J. Svensson · Leslie A. Bateman · [...] · Bruce M. Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1+ versus UCP1− adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders.
    Full-text Article · Jun 2016 · Cell
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    Edward T. Chouchani · Lawrence Kazak · Mark P. Jedrychowski · [...] · Bruce M. Spiegelman
    Full-text Article · May 2016 · Nature
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction: Exercise performed with blood flow restriction simultaneously enhances the acute responses to both myogenic and mitochondrial pathways with roles in training adaptation. We investigated isoform-specific gene expression of the peroxisome proliferator-activated receptor gamma (PPARG) coactivator 1 and selected target genes and proteins regulating skeletal muscle training adaptation. Methods: 9 healthy, untrained males participated in a randomized, counter-balanced, cross-over design in which each subject completed a bout of low-intensity endurance exercise performed with blood flow restriction (15 min cycling at 40% of VO2peak, BFR-EE), endurance exercise (30 min cycling at 70% of VO2peak, EE) or resistance exercise (4 x 10 repetitions of leg press at 70% of 1-repetition maximum, RE) separated by at least one-week recovery. A single resting muscle biopsy (vastus lateralis) was obtained two weeks before the first exercise trial (rest) and 3 h after each boat. Results: Total PGC-1α mRNA abundance, along with all four isoforms, increased above rest with EE only (P<0.05) being higher than BFR-EE (P<0.05). PGC-1α1, 2 and 4 were higher after EE compared to RE (P<0.05). EE also increased VEGF, Hif-1α and MuRF-1 mRNA abundance above rest (P<0.05) while COXIV mRNA expression increased with EE compared to BFR-EE (P<0.05). Conclusion: The attenuated expression of all four PGC-1α isoforms when endurance exercise is performed with blood flow restriction suggests this type of exercise provides an insufficient stimulus to activate the signaling pathways governing mitochondrial and angiogenesis responses observed with moderate- to high intensity endurance exercise.
    Article · Apr 2016 · Medicine and science in sports and exercise
  • Edward T. Chouchani · Lawrence Kazak · Mark P. Jedrychowski · [...] · Bruce M. Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.
    Article · Mar 2016 · Nature
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    Katrin J. Svensson · Jonathan Z. Long · Mark P. Jedrychowski · [...] · Bruce M. Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Activation of brown and beige fat can reduce obesity and improve glucose homeostasis through nonshivering thermogenesis. Whether brown or beige fat also secretes paracrine or endocrine factors to promote and amplify adaptive thermogenesis is not fully explored. Here we identify Slit2, a 180 kDa member of the Slit extracellular protein family, as a PRDM16-regulated secreted factor from beige fat cells. In isolated cells and in mice, full-length Slit2 is cleaved to generate several smaller fragments, and we identify an active thermogenic moiety as the C-terminal fragment. This Slit2-C fragment of 50 kDa promotes adipose thermogenesis, augments energy expenditure, and improves glucose homeostasis in vivo. Mechanistically, Slit2 induces a robust activation of PKA signaling, which is required for its prothermogenic activity. Our findings establish a previously unknown peripheral role for Slit2 as a beige fat secreted factor that has therapeutic potential for the treatment of obesity and related metabolic disorders.
    Full-text Article · Feb 2016 · Cell metabolism
  • Serkan Kir · Hirotaka Komaba · Ana P. Garcia · [...] · Bruce M. Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. Our recent work demonstrated that tumor-derived PTHrP drives adipose tissue browning and cachexia. Here, we show that PTH is involved in stimulating a thermogenic gene program in 5/6 nephrectomized mice that suffer from cachexia. Fat-specific knockout of PTHR blocked adipose browning and wasting. Surprisingly, loss of PTHR in fat tissue also preserved muscle mass and improved muscle strength. Similarly, PTHR knockout mice were resistant to cachexia driven by tumors. Our results demonstrate that PTHrP and PTH mediate wasting through a common mechanism involving PTHR, and there exists an unexpected crosstalk mechanism between wasting of fat tissue and skeletal muscle. Targeting the PTH/PTHrP pathway may have therapeutic uses in humans with cachexia.
    Article · Dec 2015 · Cell metabolism
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    Lawrence Kazak · Edward T Chouchani · Mark P Jedrychowski · [...] · Bruce M Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a β3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PAPERCLIP.
    Full-text Article · Oct 2015 · Cell
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    Shingo Kajimura · Bruce M Spiegelman · Patrick Seale
    [Show abstract] [Hide abstract] ABSTRACT: Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
    Full-text Article · Oct 2015 · Cell metabolism
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    Mark P. Jedrychowski · Christiane D. Wrann · Joao A. Paulo · [...] · Bruce M. Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Exercise provides many health benefits, including improved metabolism, cardiovascular health, and cognition. We have shown previously that FNDC5, a type I transmembrane protein, and its circulating form, irisin, convey some of these benefits in mice. However, recent reports questioned the existence of circulating human irisin both because human FNDC5 has a non-canonical ATA translation start and because of claims that many human irisin antibodies used in commercial ELISA kits lack required specificity. In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. This precise state-of-the-art method shows that human irisin is mainly translated from its non-canonical start codon and circulates at ∼3.6 ng/ml in sedentary individuals; this level is increased to ∼4.3 ng/ml in individuals undergoing aerobic interval training. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text Article · Aug 2015 · Cell metabolism
  • Paul Cohen · Bruce M Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can increase energy expenditure through the dissipation of chemical energy in the form of heat, using mitochondrial uncoupling and perhaps other pathways. We discuss here some of the thermodynamic and cellular aspects of recent progress in brown fat research. This includes studies of developmental lineages of UCP1(+) adipocytes, including the discovery of beige fat cells, a new thermogenic cell type. We also discuss the physiology and transcriptional control of brown and beige cells in rodents and the state of current knowledge about human brown fat. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Article · Jun 2015 · Diabetes
  • [Show abstract] [Hide abstract] ABSTRACT: The recent recognition that humans possess active depots of brown adipose tissue has boosted the interest in this tissue as a potential target for the prevention and treatment of obesity and related metabolic disorders. Furthermore, it was also revealed that brown adipose tissue (BAT) in humans may consist of so-called beige or brite adipocytes. So far, cold exposure is recognised as the strongest activator of BAT in humans, but there is much ongoing research focused on finding alternative activators of BAT. The consequences of long-term BAT activation and/or cold exposure on metabolic health are still unknown, and this represents an area of intensive research. This is one of a series of commentaries under the banner '50 years forward', giving personal opinions on future perspectives in diabetes, to celebrate the 50th anniversary of Diabetologia (1965-2015).
    Article · May 2015 · Diabetologia
  • [Show abstract] [Hide abstract] ABSTRACT: Exercise induces physiological cardiac growth and protects the heart against pathological remodeling. Recent work suggests exercise also enhances the heart's capacity for repair, which could be important for regenerative therapies. While microRNAs are important in certain cardiac pathologies, less is known about their functional roles in exercise-induced cardiac phenotypes. We profiled cardiac microRNA expression in two distinct models of exercise and found microRNA-222 (miR-222) was upregulated in both. Downstream miR-222 targets modulating cardiomyocyte phenotypes were identified, including HIPK1 and HMBOX1. Inhibition of miR-222 in vivo completely blocked cardiac and cardiomyocyte growth in response to exercise while reducing markers of cardiomyocyte proliferation. Importantly, mice with inducible cardiomyocyte miR-222 expression were resistant to adverse cardiac remodeling and dysfunction after ischemic injury. These studies implicate miR-222 as necessary for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart and show that it is sufficient to protect the heart against adverse remodeling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Apr 2015 · Cell metabolism
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    [Show abstract] [Hide abstract] ABSTRACT: Context: Skeletal muscle from sedentary older adults exhibits reduced mitochondrial abundance and oxidative capacity (OXPHOS). Objective: The primary objective was to determine whether eight weeks of combined training (CT) has more robust effect than, endurance training (ET) or resistance training (RT) on mitochondrial physiology in healthy young (18-30 y) and older (≥65 y) adults. Intervention: Thirty-four young and 31 older adults were randomized to eight weeks of ET, RT, control/CT. Control subjects completed eight weeks of no exercise (control) followed by eight weeks of CT. Body composition, skeletal muscle strength, and peak oxygen uptake were measured before and after the intervention. Vastus lateralis muscle biopsies were obtained before and 48 h after the intervention. Mitochondrial physiology was evaluated by high-resolution respirometry, and expression of mitochondrial proteins and transcription factors by quantitative PCR and immunoblotting. Results: ET and CT significantly increased oxidative capacity and expression of mitochondrial proteins and transcription factors. All training modalities improved body composition, cardiorespiratory fitness, and skeletal muscle strength. CT induced the most robust improvements in mitochondrial related outcomes and physical characteristics despite lower training volumes for the ET and RT components. Importantly, most of the adaptations to training occurred independent of age. Conclusion: Collectively, these results demonstrate that both ET and CT increase muscle mitochondrial abundance and capacity. Although CT induced the most robust improvements in the outcomes measured. In conclusion, CT provides a robust exercise regimen to improve muscle mitochondrial outcomes and physical characteristics independent of age.
    Full-text Article · Jan 2015 · Journal of Clinical Endocrinology & Metabolism
  • Jeffrey M. Friedman · Bruce Spiegelman · Jeffrey Flier · [...] · C. Ronald Kahn
    Article · Jan 2015 · Cell Metabolism
  • Daniela Cipolletta · Paul Cohen · Bruce M Spiegelman · [...] · Diane Mathis
    [Show abstract] [Hide abstract] ABSTRACT: A unique population of Foxp3(+)CD4(+) regulatory T (Treg) cells resides in visceral adipose tissue (VAT) of lean mice, especially in the epididymal fat depot. VAT Tregs are unusual in their very high representation within the CD4(+) T-cell compartment, their transcriptome, and their repertoire of antigen-specific T-cell receptors. They are important regulators of local and systemic inflammation and metabolism. The overall goal of this study was to learn how the VAT Treg transcriptome adapts to different stimuli; in particular, its response to aging in lean mice, to metabolic perturbations associated with obesity, and to certain signaling events routed through PPARγ, the "master-regulator" of adipocyte differentiation. We show that the VAT Treg signature is imposed early in life, well before age-dependent expansion of the adipose-tissue Treg population. VAT Tregs in obese mice lose the signature typical of lean individuals but gain an additional set of over- and underrepresented transcripts. This obese mouse VAT Treg signature depends on phosphorylation of the serine residue at position 273 of PPARγ, in striking parallel to a pathway recently elucidated in adipocytes. These findings are important to consider in designing drugs to target type 2 diabetes and other features of the "metabolic syndrome."
    Article · Dec 2014 · Proceedings of the National Academy of Sciences
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    Alexander S Banks · Fiona E McAllister · João Paulo G Camporez · [...] · Bruce M Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
    Full-text Article · Nov 2014 · Nature
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    James P White · Christiane D Wrann · Rajesh R Rao · [...] · Bruce M Spiegelman
    [Show abstract] [Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha 4 (PGC-1α4) is a protein isoform derived by alternative splicing of the PGC1α mRNA and has been shown to promote muscle hypertrophy. We show here that G protein-coupled receptor 56 (GPR56) is a transcriptional target of PGC-1α4 and is induced in humans by resistance exercise. Furthermore, the anabolic effects of PGC-1α4 in cultured murine muscle cells are dependent on GPR56 signaling, because knockdown of GPR56 attenuates PGC-1α4-induced muscle hypertrophy in vitro. Forced expression of GPR56 results in myotube hypertrophy through the expression of insulin-like growth factor 1, which is dependent on Gα12/13 signaling. A murine model of overload-induced muscle hypertrophy is associated with increased expression of both GPR56 and its ligand collagen type III, whereas genetic ablation of GPR56 expression attenuates overload-induced muscle hypertrophy and associated anabolic signaling. These data illustrate a signaling pathway through GPR56 which regulates muscle hypertrophy associated with resistance/loading-type exercise.
    Full-text Article · Oct 2014 · Proceedings of the National Academy of Sciences

Publication Stats

102k Citations

Institutions

  • 1994-2014
    • Dana-Farber Cancer Institute
      • Department of Cancer Biology
      Boston, Massachusetts, United States
  • 1991-2008
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 2007
    • Boston University
      Boston, Massachusetts, United States
    • Beth Israel Deaconess Medical Center
      • Division of Endocrinology, Diabetes and Metabolism
      Boston, MA, United States
  • 1999-2005
    • Harvard Medical School
      • Department of Cell Biology
      Boston, MA, United States
  • 2003
    • Duke University
      Durham, North Carolina, United States
    • The Rockefeller University
      • Laboratory of Biochemistry and Molecular Biology
      New York City, NY, United States
  • 1995-1997
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1992
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
    • American Heart Association
      Dallas, Texas, United States
  • 1988
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
  • 1979
    • Princeton University
      Princeton, New Jersey, United States