Article

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

ABSTRACT

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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    • "As animals acclimate to cold exposure and fasting, skeletal muscle also shows an increased capacity for non-shivering thermogenesis. A recently characterized protein, sarcolipin, reduces sarco/endoplasmic reticulum Ca 2+ - ATPase (SERCA) pump Ca 2+ affinity in skeletal muscle and results in increased ATP consumption and heat generation when mice are exposed to cold ambient temperatures (Bal et al., 2012). Increased expression of sarcolipin decreases sarcoplasmic reticulum uptake of Ca 2+ in cardiac atrial cells and skeletal muscle cells (Babu et al., 2007;Schneider et al., 2013), potentially altering the expression and activity of PPAR and PGC-1α with resulting alterations in slow fiber expression, mitochondrial biogenesis and endurance capacity (Sopariwala et al., 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.
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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.
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