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Diabetologia

Erschienen in:

01.01.2012 | Article

Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice

verfasst von: C. Zhang, C. McFarlane, S. Lokireddy, S. Masuda, X. Ge, P. D. Gluckman, M. Sharma, R. Kambadur

Erschienen in: Diabetologia | Ausgabe 1/2012

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Abstract

Aims/hypothesis

Although myostatin-null (Mstn ^−/−) mice fail to accumulate fat in adipose tissue when fed a high-fat diet (HFD), little is known about the molecular mechanism(s) behind this phenomenon. We therefore sought to identify the signalling pathways through which myostatin regulates accumulation and/or utilisation of fat.

Methods

Wild-type, Mstn ^−/− and wild-type mice treated with soluble activin type IIB receptor (sActRIIB) were fed a control chow diet or an HFD for 12 weeks. Changes in gene expression were measured by microarray and quantitative PCR. Histological changes in white adipose tissue were assessed together with peripheral tissue fatty acid oxidation and changes in circulating hormones following HFD feeding.

Results

Our results demonstrate that inactivation of myostatin results in reduced fat accumulation in mice on an HFD. Molecular analysis revealed that metabolic benefits, due to lack of myostatin, are mediated through at least two independent mechanisms. First, lack of myostatin increased fatty acid oxidation in peripheral tissues through induction of enzymes involved in lipolysis and in fatty acid oxidation in mitochondria. Second, inactivation of myostatin also enhanced brown adipose formation in white adipose tissue of Mstn ^−/− mice. Consistent with the above, treatment of HFD-fed wild-type mice with the myostatin antagonist, sActRIIB, reduced the obesity phenotype.

Conclusions/interpretation

We conclude that absence of myostatin results in enhanced peripheral tissue fatty acid oxidation and increased thermogenesis, culminating in increased fat utilisation and reduced adipose tissue mass. Taken together, our data suggest that anti-myostatin therapeutics could be beneficial in alleviating obesity.

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McPherron AC, Lawler AM, Lee SJ (1997) Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387:83–90PubMedCrossRef

Sharma M, Kambadur R, Matthews KG et al (1999) Myostatin, a transforming growth factor-beta superfamily member, is expressed in heart muscle and is upregulated in cardiomyocytes after infarct. J Cell Physiol 180:1–9PubMedCrossRef

McPherron AC, Lee SJ (1997) Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA 94:12457–12461PubMedCrossRef

Kambadur R, Sharma M, Smith TP, Bass JJ (1997) Mutations in myostatin (GDF8) in double-muscled Belgian Blue and Piedmontese cattle. Genome Res 7:910–916PubMed

Clop A, Marcq F, Takeda H et al (2006) A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Nat Genet 38:813–818PubMedCrossRef

Schuelke M, Wagner KR, Stolz LE et al (2004) Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med 350:2682–2688PubMedCrossRef

McPherron AC, Lee SJ (2002) Suppression of body fat accumulation in myostatin-deficient mice. J Clin Invest 109:595–601PubMed

Zhao B, Wall RJ, Yang J (2005) Transgenic expression of myostatin propeptide prevents diet-induced obesity and insulin resistance. Biochem Biophys Res Commun 337:248–255PubMedCrossRef

Feldman BJ, Streeper RS, Farese RV Jr, Yamamoto KR (2006) Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc Natl Acad Sci USA 103:15675–15680PubMedCrossRef

10.

Cigolini M, Cinti S, Bosello O, Brunetti L, Bjorntorp P (1986) Isolation and ultrastructural features of brown adipocytes in culture. J Anat 145:207–216PubMed

11.

Guerra C, Koza RA, Walsh K, Kurtz DM, Wood PA, Kozak LP (1998) Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation. J Clin Invest 102:1724–1731PubMedCrossRef

12.

Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP (1998) Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 102:412–420PubMedCrossRef

13.

Vegiopoulos A, Muller-Decker K, Strzoda D et al (2010) Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328:1158–1161PubMedCrossRef

14.

Zhang C, McFarlane C, Lokireddy S et al (2011) Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway. Diabetologia 54:1491–1501PubMedCrossRef

15.

Denton RM, Randle PJ (1967) Concentrations of glycerides and phospholipids in rat heart and gastrocnemius muscles. Effects of alloxan-diabetes and perfusion. Biochem J 104:416–422PubMed

16.

Frayn KN, Maycock PF (1980) Skeletal muscle triacylglycerol in the rat: methods for sampling and measurement, and studies of biological variability. J Lipid Res 21:139–144PubMed

17.

Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC (2009) Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity. PLoS One 4:e4937PubMedCrossRef

18.

Hirschey MD, Shimazu T, Goetzman E et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121–125PubMedCrossRef

19.

Wensaas AJ, Rustan AC, Lovstedt K et al (2007) Cell-based multiwell assays for the detection of substrate accumulation and oxidation. J Lipid Res 48:961–967PubMedCrossRef

20.

Dilger AC, Spurlock ME, Grant AL, Gerrard DE (2010) Myostatin null mice respond differently to dietary-induced and genetic obesity. Anim Sci J 81:586–593PubMedCrossRef

21.

Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B, Nedergaard J (2001) Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J 15:2048–2050PubMed

22.

Bernardo BL, Wachtmann TS, Cosgrove PG et al (2010) Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice. PLoS One 5:e11307PubMedCrossRef

23.

Choi SJ, Yablonka-Reuveni Z, Kaiyala KJ, Ogimoto K, Schwartz MW, Wisse BE (2011) Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. Am J Physiol Endocrinol Metab 300:E1031–E1037PubMedCrossRef

24.

Li ZB, Kollias HD, Wagner KR (2008) Myostatin directly regulates skeletal muscle fibrosis. J Biol Chem 283:19371–19378PubMedCrossRef

25.

Ruderman NB, Dean D (1998) Malonyl CoA, long chain fatty acyl CoA and insulin resistance in skeletal muscle. J Basic Clin Physiol Pharmacol 9:295–308PubMedCrossRef

26.

Canto C, Gerhart-Hines Z, Feige JN et al (2009) AMPK regulates energy expenditure by modulating NAD⁺ metabolism and SIRT1 activity. Nature 458:1056–1060PubMedCrossRef

27.

Wang YX, Lee CH, Tiep S et al (2003) Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113:159–170PubMedCrossRef

28.

Hennebry A, Berry C, Siriett V et al (2009) Myostatin regulates fiber-type composition of skeletal muscle by regulating MEF2 and MyoD gene expression. Am J Physiol Cell Physiol 296:C525–C534PubMedCrossRef

29.

Wilkes JJ, Lloyd DJ, Gekakis N (2009) Loss-of-function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity-induced insulin resistance. Diabetes 58:1133–1143PubMedCrossRef

30.

Izumiya Y, Hopkins T, Morris C et al (2008) Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice. Cell Metab 7:159–172PubMedCrossRef

31.

Cousin B, Cinti S, Morroni M et al (1992) Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci 103:931–942PubMed

32.

Cypess AM, Lehman S, Williams G et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517PubMedCrossRef

33.

Lee SJ, Reed LA, Davies MV et al (2005) Regulation of muscle growth by multiple ligands signaling through activin type II receptors. Proc Natl Acad Sci U S A 102:18117–18122PubMedCrossRef

34.

Morine KJ, Bish LT, Selsby JT et al (2010) Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophy. Muscle Nerve 42:722–730PubMedCrossRef

35.

Akpan I, Goncalves MD, Dhir R et al (2009) The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int J Obes (Lond) 33:1265–1273CrossRef

36.

Zhou X, Wang JL, Lu J et al (2010) Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142:531–543PubMedCrossRef

37.

Sako D, Grinberg AV, Liu J et al (2010) Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIb. J Biol Chem 285:21037–21048PubMedCrossRef

38.

Souza TA, Chen X, Guo Y et al (2008) Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators. Mol Endocrinol 22:2689–2702PubMedCrossRef

Titel: Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice
verfasst von: C. Zhang
C. McFarlane
S. Lokireddy
S. Masuda
X. Ge
P. D. Gluckman
M. Sharma
R. Kambadur
Publikationsdatum: 01.01.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 1/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2304-4

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Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice

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