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: 28.05). 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.


Available from: Santosh Kumar Maurya, Feb 24, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The brown adipocyte phenotype (BAP) in white adipose tissue (WAT) is transiently induced in adult mammals in response to reduced ambient temperature. Since it is unknown whether a cold challenge can permanently induce brown adipocytes (BAs), we reared C57BL/6J (B6) and AxB8/PgJ (AxB8) mice at 17 or 29°C from birth to weaning, to assess the BAP in young and adult mice. Energy balance measurements showed that 17°C reduced fat mass in the preweaning mice by increasing energy expenditure and suppressed diet-induced obesity in adults. Microarray analysis of global gene expression of inguinal fat (ING) from 10-day-old (D) mice indicates that expression at 17°C vs. 29°C was not different. Between 10 and 21 days of age, the BAP was induced coincident with morphologic remodeling of ING and marked changes in expression of neural development genes (e.g., Akap 12 and Ngfr). Analyses of Ucp1 mRNA and protein showed that 17°C transiently increased the BAP in ING from 21D mice; however, BAs were unexpectedly present in mice reared at 29°C. The involution of the BAP in WAT occurred after weaning in mice reared at 23°C. Therefore, the capacity to stimulate thermogenically competent BAs in WAT is set by a temperature-independent, genetically controlled program between birth and weaning.-Chabowska-Kita, A., Trabczynska, A., Korytko, A., Kaczmarek, M. M., Kozak, L. P. Low ambient temperature during early postnatal development fails to cause a permanent induction of brown adipocytes. © FASEB.
    The FASEB Journal 04/2015; DOI:10.1096/fj.15-271395 · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 (TRPM8) and vanilloid-4 (TRPV4). Since the endo-lysosomal two-pore channels (TPCs) have also been ascribed with metabolic functionality, we studied the effect of simultaneously knocking out TPC1 and TPC2 on body composition and energy balance in male mice fed a chow diet. Compared with wild-type (WT) mice, TPC1 and TPC2 double knockout (Tpcn1/2(-/-)) animals had a higher respiratory quotient and became obese between 6 and 9 months of age. While food intake was unaltered, interscapular brown adipose tissue (BAT) maximal temperature and lean-mass adjusted oxygen consumption were lower in Tpcn1/2(-/-) than in WT. Phosphorylated hormone-sensitive lipase expression and lipid density, and expression of beta-adrenergic receptors were also lower in Tpcn1/2(-/-) BAT, while mitochondrial respiratory chain function and uncoupling protein-1 expression remained intact. We conclude that Tpcn1/2(-/-) mice show mature-onset obesity due to reduced lipid availability and utilisation, and a defect in beta-adrenergic receptor signaling, leading to impaired thermogenic activity, in BAT.
    Endocrinology 12/2014; 156(3):en20141766. DOI:10.1210/en.2014-1766 · 4.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The sarcoplasmic reticulum calcium pump (SERCA) is regulated by small integral membrane proteins phospholamban (PLN) and sarcolipin (SLN). These regulators have homologous transmembrane regions, yet they differ in their cytoplasmic and luminal domains. While the sequences of PLN and SLN are practically invariant amongst mammals, they vary in fish. Zebrafish appear to harbor multiple PLN isoforms, one of which contains 18 sequence variations and a unique luminal extension. Characterization of this isoform (zfPLN) revealed that SERCA inhibition and reversal by phosphorylation were comparable to human PLN. To understand the sequence variations in zfPLN, chimeras were created by transferring the N-terminus, linker and C-terminus of zfPLN onto human PLN. A chimera containing the N-terminal domain resulted in mild loss of function, while a chimera containing the linker domain resulted in gain of function. This latter effect was due to changes in basic residues in the linker region of PLN. Removing the unique luminal domain of zfPLN (53SFHGM) resulted in loss of function, while adding this domain to human PLN had a minimal effect on SERCA inhibition. We conclude that the luminal extension contributes to SERCA inhibition, but only in the context of zfPLN. Although this domain is distinct from the SLN luminal tail, zfPLN appears to use a hybrid PLN-SLN inhibitory mechanism. Importantly, the different zebrafish PLN isoforms raises the interesting possibility that SR calcium handling and cardiac contractility may be regulated by the differential expression of PLN functional variants. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 01/2015; 290(11). DOI:10.1074/jbc.M114.585604 · 4.60 Impact Factor