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.

Download full-text


Available from: Peter Gluckman, Feb 02, 2015
    • "However, several studies have shown an increased glucose transport when incubating various cell types with recombinant myostatin (Mitchell et al. 2006, Chen et al. 2010, Liu et al. 2013). Lastly, myostatin may also have metabolic effects on adipose tissue by inhibiting the differentiation of pre-adipocytes and thereby lipid accumulation (Feldman et al. 2006, Stolz et al. 2008, Li et al. 2011, Zhu et al. 2015), and myostatin deficiency may promote browning of adipocytes (Zhang et al. 2012, Braga et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Some health benefits of exercise may be explained by altered secretion of myokines. Because previous focus has been on upregulated myokines, we screened for downregulated myokines, and identified myostatin. We studied the expression of myostatin in relation to exercise and dysglycemia in skeletal muscle, adipose tissue and plasma. We further examined some effects of myostatin on energy metabolism in primary human muscle cells and SGBS adipocytes. Methods: Sedentary men with or without dysglycemia underwent a 45 min acute bicycle test before and after 12 weeks of combined endurance and strength training. Blood samples and biopsies from m. vastus lateralis and adipose tissue were collected. Results: Myostatin mRNA expression was reduced in skeletal muscle after acute as well as long-term exercise, and was even further downregulated by acute exercise on top of 12 weeks training. Furthermore, the expression of myostatin at baseline correlated negatively with insulin sensitivity. Myostatin expression in adipose tissue increased after 12 weeks of training and correlated positively with insulin sensitivity markers. In cultured muscle cells but not in SGBS cells, myostatin promoted an insulin-independent increase in glucose uptake. Furthermore, muscle cells incubated with myostatin had enhanced rate of glucose oxidation and lactate production. Conclusion: Myostatin was differentially expressed in muscle and adipose tissue in relation to physical activity and dysglycemia. Recombinant myostatin increased the consumption of glucose in human skeletal muscle cells, suggesting a complex regulatory role of myostatin in skeletal muscle homeostasis. This article is protected by copyright. All rights reserved.
    No preview · Article · Nov 2015 · Acta Physiologica
  • 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.
    Full-text · Article · Mar 2015 · Journal of Cell Science
  • 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.
    Full-text · Article · Jun 2014 · PLoS ONE
Show more