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Showing papers by "Bruce M. Spiegelman published in 2014"


Journal ArticleDOI
16 Jan 2014-Cell
TL;DR: New perspective is gained on the roles played by adipocyte in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues and how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health.

1,746 citations


Journal ArticleDOI
16 Jan 2014-Cell
TL;DR: It is shown that adipocyte-specific deletion of the coregulatory protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or β3-agonist treatment, indicating that PRDM 16 and beige fat cells are required for the "browning" of white fat and the healthful effects of sub cutaneous adipose tissue.

716 citations


Journal ArticleDOI
05 Jun 2014-Cell
TL;DR: The identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure, which links host-adaptive responses to the regulation of energy homeostasis and tissue inflammation and has therapeutic potential for metabolic and inflammatory diseases.

680 citations


Journal ArticleDOI
04 Sep 2014-Nature
TL;DR: It is demonstrated 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, and mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia.
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

485 citations



Journal ArticleDOI
TL;DR: 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.

375 citations


Journal ArticleDOI
03 Jul 2014-Cell
TL;DR: 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.

277 citations


Journal ArticleDOI
03 Jul 2014-Cell
TL;DR: Interferon regulatory factor 4 is identified as a dominant transcriptional effector of thermogenesis and induced by cold and cAMP in adipocytes and is sufficient to promote increased thermogenic gene expression, energy expenditure, and cold tolerance.

224 citations


Journal ArticleDOI
TL;DR: It is shown that G protein-coupled receptor 56 (GPR56) is a transcriptional target of PGC-1α4 and is induced in humans by resistance exercise, which elucidates a previously unknown mechanism of muscle anabolism and gives another target of investigation for therapies against the loss of muscle mass seen with aging and various wasting diseases.
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.

86 citations


Journal ArticleDOI
TL;DR: Reduced expression of Thrap3 in fat tissue by antisense oligonucleotides 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.
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.

47 citations


Journal ArticleDOI
01 Feb 2014-Diabetes
TL;DR: It is shown that in vivo treatments of this recombinant protein in mice show strong anti-obesity effects and improve systematic glucose homeostasis and could represent part of the longer-lasting benefits of exercise.
Abstract: Increasing energy expenditure is an attractive approach to fighting the worldwide epidemic in obesity and type 2 diabetes. Exercise is an important component of good health and represents the first line of therapy for humans with a variety of metabolic disorders: obesity, diabetes, and nonalcoholic hepatic steatosis. Recent data has shown that exercise, besides using calories to do physical work, also causes an increase in energy expenditure through augmentation in brown fat and the browning of white fat (Fig. 1) (1,2). Indeed, these effects on brown fat could represent part of the longer-lasting benefits of exercise. Figure 1 Recombinant irisin regulates the thermogenic program in fat through ERK and p38 pathways. Recombinant irisin produced in yeast is glycosylated and active. It induces the thermogenic gene program in 3T3-L1 cells and primary subcutaneous adipocytes. In vivo treatments of this recombinant protein in mice show strong anti-obesity effects and improve systematic glucose homeostasis. That brown fat, in all of its dimensions, can improve type 2 diabetes and metabolic health seems to be settled science, at least in experimental animals (3). These cells express UCP1 and have a high mitochondrial content, thereby dissipating chemical energy …


Journal ArticleDOI
01 Sep 2014-Diabetes
TL;DR: Despite the claims of Elsen et al. (1), there are now over 45 articles that have measured human irisin, using a variety of immunoassays with independently derived irisin levels, according to a database of articles published in refereed journals.
Abstract: Despite the claims of Elsen et al. (1), there are now over 45 articles that have measured human irisin, using a variety of immunoassays with independently derived …

Patent
21 Jan 2014
TL;DR: In this paper, compositions and methods for regulating thermogenesis and muscle inflammation through modulation of Metrnl and/or Metrn activity and or expression are provided. But none of these methods are suitable for treating metabolic disorders.
Abstract: The invention provides compositions and methods for regulating thermogenesis and muscle inflammation through modulation of Metrnl and/or Metrn activity and/or expression. Also provided are methods for preventing or treating metabolic disorders and muscle inflammation disorders in a subject through modulation of Metrnl and/or Metrn activity and/or expression. Further provided are methods for identifying compounds that are capable of treating metabolic disorders and muscle inflammation disorders by modulating Metrnl and/or Metrn activity and/or expression.

Patent
01 Oct 2014
TL;DR: In this article, the authors proposed methods for identifying, assessing, preventing, and treating neurological disorders and diseases using Fndc5 and modulators of FndC5 expression or activity.
Abstract: The invention provides methods for identifying, assessing, preventing, and treating neurological disorders and diseases using Fndc5 and modulators of Fndc5 expression or activity.

Patent
30 Jul 2014
TL;DR: In this article, compositions and methods for modulating thermogenesis and related activities by modulating ΡΤΉ-related and EGF-related expression and activity were provided.
Abstract: The present invention provides compositions and methods for modulating thermogenesis and related activities by modulating ΡΤΉ-related and EGF-related expression and activity. Also provided are methods for preventing or treating metabolic disorders in a subject through modulation of PTH-related and EGF-related expression and activity.

Patent
01 Oct 2014
TL;DR: In this paper, the authors proposed methods for identifying, assessing, preventing, and treating neurological disorders and diseases using Fndc5 and modulators of FndC5 expression or activity.
Abstract: The invention provides methods for identifying, assessing, preventing, and treating neurological disorders and diseases using Fndc5 and modulators of Fndc5 expression or activity