A PGC1α-dependent myokine that drives browning of white fat and thermogenesis

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional coactivator PGC1α Here we show that PGC1α expression in muscle stimulates an increase in expression of Fndc5, a membrane protein that is cleaved and secreted as a new hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be a protein therapeutic for human metabolic disease and other disorders that are improved with exercise.

Related collections

Most cited references 19

Record: found
Abstract: found
Article: not found

The role of exercise and PGC1alpha in inflammation and chronic disease.

Christoph Handschin, Bruce M Spiegelman (2008)

Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1alpha has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise.

0 comments Cited 336 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.

Yu-Hua Tseng, Efi Kokkotou, Tim Schulz … (2008)

Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1alpha (peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARgamma and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.

0 comments Cited 335 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals.

Christoph Handschin, Sherry Chin, Ping Li … (2007)

The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a key integrator of neuromuscular activity in skeletal muscle. Ectopic expression of PGC-1alpha in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue-resistant muscle fibers. Whole body PGC-1alpha knock-out mice have a very complex phenotype but do not have a marked skeletal muscle phenotype. We thus analyzed skeletal muscle-specific PGC-1alpha knock-out mice to identify a specific role for PGC-1alpha in skeletal muscle function. These mice exhibit a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal muscle-specific PGC-1alpha knock-out animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running. Our data demonstrate a critical role for PGC-1alpha in maintenance of normal fiber type composition and of muscle fiber integrity following exertion.

0 comments Cited 187 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 7 June 2012

Publication date (Electronic): 11 January 2012

Publication date PMC-release: 14 December 2012

Volume: 481

Issue: 7382

Pages: 463-468

Affiliations

[1 ]Dana-Farber Cancer Institute and Harvard Medical School, 3 Blackfan Circle, CLS Building, floor 11, Boston, MA, 02115, USA

[2 ]Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA

[3 ]Renal Division, Brigham and Women’s Hospital, Harvard Medical School

[4 ]UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco

[5 ]Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Electron Microscopy Unit-Azienda Ospedali Riuniti, Ancona 60020, Italy

[6 ]Diabetes Research Center, Department of Endocrinology, Odense University Hospital, Denmark

[7 ]LakePharma, Inc. 530 Harbor Blvd, Belmont CA 94002

Author notes

Corresponding author: bruce_spiegelman@ 123456dfci.harvard.edu , Tel: 617-632-3567

Article

Manuscript ID: NIHMS383119

DOI: 10.1038/nature10777

PMC ID: 3522098

PubMed ID: 22237023

SO-VID: bfe00ac8-2880-4207-81f9-22119ec7ca5a

License:

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

History

Funding

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

Award ID: R37 DK031405 || DK

Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK

A PGC1α-dependent myokine that drives browning of white fat and thermogenesis

Read this article at

Abstract

Related collections

GLUT4 biology

Most cited references 19

The role of exercise and PGC1alpha in inflammation and chronic disease.

New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure.

Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals.

Author and article information

Journal

Affiliations

Author notes

Article

History

Funding

Categories

Comments

Comment on this article

Similar content 126

Cited by 1,548

Most referenced authors 338