The complementary and divergent roles of uncoupling proteins 1 and 3 in thermoregulation

Riley, Christopher L.; Dao, Christine Ky Linh; Kenaston, M. Alexander; Muto, Luigina; Kohno, Shohei; Nowinski, Sara M.; Solmonson, Ashley; Pfeiffer, Matthew; Sack, Michael N.; Lu, Zhongping; Fiermonte, Giuseppe; Sprague, Jon E.; Mills, Edward

doi:10.1113/jp272971

Cited by 57 publications

(53 citation statements)

References 41 publications

(79 reference statements)

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“…It is possible that in the absence of UCP1 in pigs, UCP3 in beige adipocytes might have acquired a novel function. However, the primary function of UCP3 is to reduce reactive oxygen species in the mitochondria and not thermogenesis, at least in mice [116][117][118][119][120]. It is also pertinent to note here that while UCP3 expression in the skeletal muscle is reduced in humans, it was upregulated in UCP1-KO mice after cold adaptation [121,122].…”

Section: (B) Sarcolipin-based Thermogenesis In Mammals Lacking Brown mentioning

confidence: 85%

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Bal

Periasamy

2020

Phil. Trans. R. Soc. B

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Thermogenesis in endotherms relies on both shivering and non-shivering thermogenesis (NST). The role of brown adipose tissue (BAT) in NST is well recognized, but the role of muscle-based NST has been contested. However, recent studies have provided substantial evidence for the importance of muscle-based NST in mammals. This review focuses primarily on the role of sarcoplasmic reticulum (SR) Ca 2+ -cycling in muscle NST; specifically, it will discuss recent data showing how uncoupling of sarcoendoplasmic reticulum calcium ATPase (SERCA) (inhibition of Ca 2+ transport but not ATP hydrolysis) by sarcolipin (SLN) results in futile SERCA pump activity, increased ATP hydrolysis and heat production contributing to muscle NST. It will also critically examine how activation of muscle NST can be an important factor in regulating metabolic rate and whole-body energy homeostasis. In this regard, SLN has emerged as a powerful signalling molecule to promote mitochondrial biogenesis and oxidative metabolism in muscle. Furthermore, we will discuss the functional interplay between BAT and muscle, especially with respect to how reduced BAT function in mammals could be compensated by muscle-based NST. Based on the existing data, we argue that SLN-mediated thermogenesis is an integral part of muscle NST and that muscle NST potentially contributed to the evolution of endothermy within the vertebrate clade. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

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Section: (B) Sarcolipin-based Thermogenesis In Mammals Lacking Brown mentioning

confidence: 85%

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Bal

Periasamy

2020

Phil. Trans. R. Soc. B

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“…This would be an interesting avenue to explore as others have shown that transplantation of iWAT from trained into sedentary mice preserves body temperature upon exposure to cold, 9 and that UCP-1 may be involved in the thermogenic response to LPS. 48 Overall, we demonstrate that habitual physical activity, in the form of VWR, is able to protect against acute inflammation in adipose tissue of C57BL/J mice. This effect occurs with modest depot specificity, such that the effects are greater in iWAT vs. eWAT.…”

Section: Discussionmentioning

confidence: 96%

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

et al. 2016

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Sepsis is a systemic inflammatory response to infection, with no preventative strategies. In this study, we identify a role for habitual physical activity in the prevention of adipose tissue inflammation induced by a model of sepsis, lipopolysaccharide (LPS). Male C57BL/6J mice (8 weeks old) were housed with access to voluntary wheel running (VWR) or sedentary (SED) for 10 weeks. Mice were then injected with LPS (2 mg/kg) or saline (SAL), and tissues were removed 6 hours postinjection. VWR attenuated body, epididymal adipose tissue (eWAT), and subcutaneous inguinal adipose tissue (iWAT) mass gain, improved glucose tolerance, increased markers of mitochondrial biogenesis in iWAT and eWAT, and increased UCP-1 protein content in iWAT. In iWAT, VWR attenuated the LPS induced increase in mRNA expression of TNF-a, MCP-1, and follistatin, along with phosphorylation of STAT3. In addition, VWR had a main effect for reducing iWAT mRNA expression of IL-1b, IL-6, and SOCS3. In eWAT, VWR had a main effect for reducing mRNA expression of IL-1b, MCP-1, IL-6, and follistatin. Further, VWR increased SOCS3 mRNA expression and phosphorylation of STAT3 in SAL mice, thus the relative change in response to LPS for these markers was attenuated. The protective effect of prior physical activity occurred in conjunction with increases in the protein content of a component of the LPS binding complex, MyD88. Overall, the results from this study demonstrate that habitual physical activity can attenuate the LPS induced inflammatory response in adipose tissue and this occurs to a greater extent in iWAT compare with eWAT.

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“…Sharing ∼60% homology with UCP1, uncoupling protein 3 (UCP3) gene and protein expression are high in skeletal muscle, and UCP3 is also expressed in brown adipose tissue and heart (3, 4). UCP3 is the only uncoupling protein to be expressed at the protein level in skeletal muscle, and although it does not appear to contribute to cold‐induced thermogenesis, it has recently been shown to be essential for normal thermogenic responses induced by the sympathomimetic methamphetamine and by the endotoxin lipopolysaccharide (5). It remains unclear what molecule or molecules are transported across the mitochondrial inner membrane, although there is strong evidence that UCP3 plays a role in modifying mitochondrial membrane electrochemical potential.…”

mentioning

confidence: 99%

A novel amino acid and metabolomics signature in mice overexpressing muscle uncoupling protein 3

et al. 2016

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Uncoupling protein 3 (UCP3) is highly selectively expressed in skeletal muscle and is known to lower mitochondrial reactive oxygen species and promote fatty acid oxidation; however, the global impact of UCP3 activity on skeletal muscle and whole-body metabolism have not been extensively studied. We utilized untargeted metabolomics to identify novel metabolites that distinguish mice overexpressing UCP3 in muscle, both at rest and after exercise regimens that challenged muscle metabolism, to potentially unmask subtle phenotypes. Male wild-type (WT) and muscle-specific UCP3-overexpressing transgenic (UCP3 Tg) C57BL/6J mice were compared with or without a 5 wk endurance training protocol at rest or after an acute exercise bout (EB). Skeletal muscle, liver, and plasma samples were analyzed by gas chromatography time-of-flight mass spectrometry. Discriminant metabolites were considered if within the top 99th percentile of variable importance measurements obtained from partial least-squares discriminant analysis models. A total of 80 metabolites accurately discriminated UCP3 Tg mice from WT when modeled within a specific exercise condition (i.e., untrained/rested, endurance trained/rested, untrained/EB, and endurance trained/EB). Results revealed that several amino acids and amino acid derivatives in skeletal muscle and plasma of UCP3 Tg mice (e.g., Asp, Glu, Lys, Tyr, Ser, Met) were significantly reduced after an EB; that metabolites associated with skeletal muscle glutathione/Met/Cys metabolism (2-hydroxybutanoic acid, oxoproline, Gly, and Glu) were altered in UCP3 Tg mice across all training and exercise conditions; and that muscle metabolite indices of dehydrogenase activity were increased in UCP3 Tg mice, suggestive of a shift in tissue NADH/NAD ratio. The results indicate that mitochondrial UCP3 activity affects metabolism well beyond fatty acid oxidation, regulating biochemical pathways associated with amino acid metabolism and redox status. That select metabolites were altered in liver of UCP3 Tg mice highlights that changes in muscle UCP3 activity can also affect other organ systems, presumably through changes in systemic metabolite trafficking.-Aguer, C., Piccolo, B. D., Fiehn, O., Adams, S. H., Harper, M.-E. A novel amino acid and metabolomics signature in mice overexpressing muscle uncoupling protein 3.

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The complementary and divergent roles of uncoupling proteins 1 and 3 in thermoregulation

Cited by 57 publications

References 41 publications

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

A novel amino acid and metabolomics signature in mice overexpressing muscle uncoupling protein 3

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