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

ABSTRACT 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.

Download full-text


Available from: Peter Gluckman, Feb 02, 2015
33 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular clock is intimately linked with metabolic regulation and brown adipose tissue plays a key role in energy homeostasis. However, whether the cell-intrinsic clock machinery participates in brown adipocyte development is unknown. Here we show that Bmal1, the essential clock transcription activator, inhibits brown adipogenesis to adversely impact brown fat formation and thermogenic capacity. Global ablation of Bmal1 in mice increases brown fat mass and cold tolerance, while adipocyte-selective inactivation of Bmal1 recapitulates these effects and demonstrates its cell-autonomous role in brown adipocyte formation. Further loss- and gain-of function studies in mesenchymal precursors and committed brown progenitors reveal that Bmal1 inhibits brown adipocyte lineage commitment and terminal differentiation. Mechanistically, Bmal1 inhibits brown adipogenesis through direct transcriptional control of key components of the TGF-β pathway together with reciprocally altered BMP signaling, and activation of TGF-β, or blockade of BMP pathways, suppresses enhanced differentiation in Bmal1-deficient brown adipocytes. Collectively, our study demonstrates a novel temporal regulatory mechanism in fine-tuning brown adipocyte lineage progression to impact brown fat formation and thermogenic regulation, which may be targeted therapeutically to combat obesity.
    Journal of Cell Science 03/2015; · 5.43 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity, a major concern for equine welfare, is highly prevalent in the leisure horse population. Skeletal-muscle and adipose tissues are important determinants of maintenance energy requirements. The myostatin and perilipin pathways play key roles in the regulation of muscle mass and lipolysis respectively and have both been associated with obesity predisposition in other mammalian species. High quality samples, suitable for molecular biology, are an essential prerequisite for detailed investigations of gene and protein expression. Hence, this study has evaluated a) the post-mortem stability of RNA extracted from skeletal-muscle and adipose-tissues collected under commercial conditions and b) the tissue-specific presence of myostatin, the moystatin receptor (activin receptor IIB, ActRIIB), follistatin and perilipin, genes and proteins across a range of equine tissues. Objectives were addressed using tissues from 7 Thoroughbred horses presented for slaughter at a commercial abattoir; a) samples were collected at 7 time-points from Masseter muscle and perirenal adipose from 5 minutes to 6 hours post-mortem. Extracted RN was appraised by Optical Density analysis and agarose-gel electrophoresis. b) Quantitative real time PCR and Western Blotting were used to evaluate gene and protein expression in anatomically-defined samples collected from 17 tissues (6 organs, 4 skeletal muscles and 7 discrete adipose depots). The results indicate that, under the present collection conditions, intact, good quality RNA could be extracted from skeletal-muscle for up to 2 hours post-mortem. However, RNA from adipose tissue may be more susceptible to degradation/contamination and samples should be collected no later than 30 minutes post-mortem. The data also show that myostatin and ActRIIB genes and proteins were almost exclusively expressed in skeletal muscle. The follistatin gene showed a more diverse gene expression profile, with expression evident in several organs, adipose tissue depots and skeletal muscles. Perilipin gene and protein were almost exclusively expressed by adipose tissue.
    PLoS ONE 06/2014; 9(6):e100810. DOI:10.1371/journal.pone.0100810 · 3.23 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although myostatin functions primarily as a negative regulator of skeletal muscle growth and development, accumulating biological and epidemiological evidence indicates an important contributing role in liver disease. In this study we demonstrate that myostatin suppresses the proliferation of Hepa-1C1c7 murine-derived liver cells (50%; P < 0.001) in part by reducing the expression of the cyclins and cyclin-dependent kinases that elicit G1-S phase transition of the cell cycle (P < 0.001). Furthermore, RT-PCR based quantification of the long noncoding RNA Malat1, recently identified as a myostatin-responsive transcript in skeletal muscle, revealed a significant down-regulation (25% and 50% respectively, P < 0.05) in the livers of myostatin-treated mice and liver cells. The importance of Malat1 in liver cell proliferation was confirmed via arrested liver cell proliferation (P < 0.05) in response to partial Malat1 siRNA-mediated knockdown. Myostatin also significantly blunted insulin-stimulated glucose uptake and Akt phosphorylation in liver cells while increasing the phosphorylation of Myristoylated Alanine-Rich Kinase C Substrate (MARCKS), a protein that is essential for cancer cell proliferation and insulin-stimulated glucose transport. Together, these findings reveal a plausible mechanism by which circulating myostatin contributes to the diminished regenerative capacity of the liver and diseases characterized by liver insulin resistance.
    Biochemistry and Cell Biology 04/2014; bcb-2014-0004. DOI:10.1139/bcb-2014-0004#.U1pzJeZdVq5 · 2.15 Impact Factor
Show more