Bruce M Spiegelman

Harvard University, Cambridge, Massachusetts, United States

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Publications (354)4990.03 Total impact

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    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.
    No preview · Article · Dec 2015 · Cell metabolism
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    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
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    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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    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
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    Paul Cohen · Bruce M Spiegelman
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    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.
    Preview · Article · Jun 2015 · Diabetes
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    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).
    No preview · Article · May 2015 · Diabetologia
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    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.
    No preview · Article · Apr 2015 · Cell metabolism
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    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

  • No preview · Article · Jan 2015 · Cell Metabolism
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    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."
    Preview · Article · Dec 2014 · Proceedings of the National Academy of Sciences
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    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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    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
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    ABSTRACT: Phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARγ when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPARγ. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPARγ in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.
    Preview · Article · Oct 2014 · Genes & Development
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    Bruce M Spiegelman · Christiane Wrann

    Preview · Article · Sep 2014 · Diabetes
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    ABSTRACT: Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.
    Full-text · Article · Jul 2014 · Nature
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    ABSTRACT: A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic β cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining β cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca(2+). Finally, we demonstrate that T2DM patients with β cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to β cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM.
    Full-text · Article · Jul 2014 · Cell
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    ABSTRACT: Brown fat can reduce obesity through the dissipation of calories as heat. Control of thermogenic gene expression occurs via the induction of various coactivators, most notably PGC-1α. In contrast, the transcription factor partner(s) of these cofactors are poorly described. Here, we identify interferon regulatory factor 4 (IRF4) as a dominant transcriptional effector of thermogenesis. IRF4 is induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance. Conversely, knockout of IRF4 in UCP1+ cells causes reduced thermogenic gene expression and energy expenditure, obesity, and cold intolerance. IRF4 also induces the expression of PGC-1α and PRDM16 and interacts with PGC-1α, driving Ucp1 expression. Finally, cold, β-agonists, or forced expression of PGC-1α are unable to cause thermogenic gene expression in the absence of IRF4. These studies establish IRF4 as a transcriptional driver of a program of thermogenic gene expression and energy expenditure.
    Full-text · Article · Jul 2014 · Cell
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    ABSTRACT: Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure and improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.
    Full-text · Article · Jun 2014 · Cell
  • Xingxing Kong · Alexander Banks · Tiemin Liu · Bruce Spiegelman · Evan Rosen

    No preview · Article · Jun 2014 · Diabetes
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    ABSTRACT: Thermogenic UCP1-positive cells, which include brown and beige adipocytes, transform chemical energy into heat and increase whole-body energy expenditure. Using a ribosomal profiling approach, we present a comprehensive molecular description of brown and beige gene expression from multiple fat depots in vivo. This UCP1-TRAP data set demonstrates striking similarities and important differences between these cell types, including a smooth muscle-like signature expressed by beige, but not classical brown, adipocytes. In vivo fate mapping using either a constitutive or an inducible Myh11-driven Cre demonstrates that at least a subset of beige cells arise from a smooth muscle-like origin. Finally, ectopic expression of PRDM16 converts bona fide vascular smooth muscle cells into Ucp1-positive adipocytes in vitro. These results establish a portrait of brown and beige adipocyte gene expression in vivo and identify a smooth muscle-like origin for beige cells.
    Full-text · Article · Apr 2014 · Cell metabolism

Publication Stats

95k Citations
4,990.03 Total Impact Points

Institutions

  • 1991-2015
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 1984-2014
    • Dana-Farber Cancer Institute
      • Department of Cancer Biology
      Boston, Massachusetts, United States
  • 1980-2014
    • Harvard Medical School
      • • Department of Cell Biology
      • • Department of Biological Chemistry and Molecular Pharmacology
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2007
    • Beth Israel Deaconess Medical Center
      • Division of Endocrinology, Diabetes and Metabolism
      Boston, MA, United States
    • Boston University
      Boston, Massachusetts, United States
  • 2004
    • University of California, Los Angeles
      • Department of Biological Chemistry
      Los Ángeles, California, United States
  • 2003
    • Duke University
      Durham, North Carolina, United States
  • 1990-2003
    • 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
  • 1996
    • Duke University Medical Center
      • Division of Medical Oncology
      Durham, North Carolina, United States
  • 1989-1995
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1992
    • American Heart Association
      Dallas, Texas, United States
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 1988
    • Tufts University
      Georgia, United States
    • Roche Institute of Molecular Biology
      Nutley, New Jersey, United States
  • 1981-1982
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1977-1979
    • Princeton University
      Princeton, New Jersey, United States