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

Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Brenner Centre for Molecular Medicine, Singapore, Republic of Singapore.
Diabetologia (Impact Factor: 6.67). 09/2011; 55(1):183-93. DOI: 10.1007/s00125-011-2304-4
Source: PubMed


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.
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.
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.
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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Available from: Peter Gluckman, Feb 02, 2015
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    • "In contrast, TGF-b signaling exerts inhibitory effects on BAT development, with ablation of Smad3, the ultimate signal transducer of the TGF-b pathway, resulting in selective induction of brown-adipocyte-specific marker genes and enhanced mitochondrial function (Yadav et al., 2011). In addition, inhibition of activin receptor IIB and myostatin, both signaling through Smad3 (Fournier et al., 2012; Kim et al., 2012; Koncarevic et al., 2012; Zhang et al., 2012), were recently reported to promote brown adipogenesis. We have previously shown that Bmal1 suppresses white adipocyte differentiation (Guo et al., 2012). "
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    Journal of Cell Science 03/2015; · 5.43 Impact Factor
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    • "Furthermore, actions of this circulating growth factor are not restricted to muscle alone. Murine and human studies have clearly implicated myostatin in the development of obesity [16]–[18]. The myostatin protein has been detected in skeletal muscle from Thoroughbred and Kiso-uma horses [19] and polymorphisms in the equine myostatin gene have also been linked with optimal race distance in Thoroughbred horses [20]. "
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    PLoS ONE 06/2014; 9(6):e100810. DOI:10.1371/journal.pone.0100810 · 3.23 Impact Factor
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    • "Whereas the antagonism or inhibition of myostatin signaling induces striking skeletal muscle hypertrophy (McCroskery et al. 2005; Siriett et al. 2007), systemic over-expression leads to dramatic losses in both skeletal muscle and adipose tissue mass (Zimmers et al. 2002). Myostatin-deficient mice also exhibit reduced adiposity and resistance to dietary-induced obesity (McPherron and Lee 2002) due to increased muscle mass and increased thermogenesis through the activation of brown adipose tissue (Zhang et al. 2012). "
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