Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals

Department of Physiology and Cell Biology, Ohio State University, College of Medicine, Columbus, Ohio, USA.
Nature medicine (Impact Factor: 27.36). 09/2012; 18(10):1575-9. DOI: 10.1038/nm.2897
Source: PubMed


The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca(2+), which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.

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Available from: Santosh Kumar Maurya, Feb 24, 2014
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    • "Glyc- erol-3-phosphate shuttle activation and lipid turnover (Flachs et al., 2011; Grimpo et al., 2014) have been posited to act independently of UCP1. Calcium cycling has been proposed to be an additional source of thermogenesis in BAT (Ukropec et al., 2006) and is a well-established thermogenic mechanism in the extraocular heater muscle cells of certain fish and in mammalian skeletal muscle (Bal et al., 2012; Block et al., 1994). Interestingly, large reductions in creatine levels have previously been linked to deregulated thermal homeostasis in rats (Wakatsuki et al., 1996; Yamashita et al., 1995), through unknown mechanisms. "
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    ABSTRACT: Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a β3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PAPERCLIP.
    Cell 10/2015; 163(3):643-655. DOI:10.1016/j.cell.2015.09.035 · 32.24 Impact Factor
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    • "The lack of an effect of VWR on visceral adiposity in the current study, in both WT and Sln À/À animals, is likely reflective of the low caloric demand of the voluntary running completed relative to that taken in from high-fat feeding. Additionally, these models have altered signaling of pathways involving regulation of energy intake, and obesity is a function of hyperphagia, whereas the development of obesity in Sln À/À mice is the result of an inability to recruit diet-induced thermogenesis in response to calorie excess (Bal et al. 2012; Bombardier et al. 2013a). "
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    ABSTRACT: Several rodent models of obesity have been shown to develop excessive adiposity only when voluntary cage ambulation is restricted. We have previously shown that mice lacking the sarco(endo)plasmic reticulum Ca2+-ATPase pump regulatory protein sarcolipin (Sln−/−), an uncoupler of Ca2+ uptake, develop excessive diet-induced obesity under standard housing conditions. However, it is unclear whether this phenotype is due, in part, to the sedentary housing environment in which these animals are kept. To address this, we allowed wild-type and Sln−/− animals ad libitum access to voluntary wheel running while consuming a standard chow or high-fat diet for 8 weeks. During this period, wheel revolutions were monitored along with weekly mass gain. Postdiet glucose tolerance and visceral adiposity were also taken. The volume of wheel running completed was similar between genotype, regardless of diet. Although voluntary activity reduced mass gain relative to sedentary controls within each diet (P < 0.05), visceral adiposity was surprisingly unaltered with activity. However, Sln−/− mice developed excessive obesity (P < 0.05) and glucose intolerance (P < 0.05) with high-fat feeding relative to wild-type controls. These findings indicate that the excessive diet-induced obese phenotype previously observed in Sln−/− mice is not the result of severely restricted daily ambulation, but in fact the inability to recruit uncoupling of the Ca2+-ATPase pump.
    09/2015; 3(9). DOI:10.14814/phy2.12549
    • "SLN is a small single transmembrane peptide composed of 31 amino acids localized in the SR membrane and its expression is tightly regulated and predominantly restricted to striated muscles (Odermatt et al., 1998). Our studies showed that mice lacking SLN were sensitive to cold challenge when BAT function was minimized and that reintroduction of SLN rescued the cold-sensitive phenotype, indicating thermogenic function of SLN (Bal et al., 2012). "
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    ABSTRACT: Neonatal mice have a greater thermogenic need and may require additional means of heat production, other than the established mechanism of brown adipose tissue (BAT). Others and we recently discovered a novel mediator of skeletal muscle-based thermogenesis called sarcolipin (SLN) that acts by uncoupling sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA). In addition, we have shown that SLN expression is downregulated during neonatal development in rats. In this study we probed two questions; 1) whether SLN expression is developmentally regulated in neonatal mice 2) if yes, will cold adaptation override developmental regulation of SLN expression. Our data shows that SLN expression is higher during early neonatal stages and is gradually downregulated in fast twitch skeletal muscles. Interestingly, we demonstrate that cold acclimatization of neonatal mice can prevent downregulation of SLN expression. This observation suggests that SLN-mediated thermogenesis can be recruited to a greater extent during extreme physiological need, in addition to BAT. © 2015. Published by The Company of Biologists Ltd.
    Journal of Experimental Biology 05/2015; 218(Pt 15). DOI:10.1242/jeb.119164 · 2.90 Impact Factor
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