OBJECTIVE: Non-shivering thermogenesis (NST) mediated by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) can be activated via the adrenergic system in response to cold or diet, contributing to both thermal and energy homeostasis. Other mechanisms, including metabolism of skeletal muscle, may also be involved in NST. However, relative contribution of these energy dissipating pathways and their adaptability remain a matter of long-standing controversy. METHODS: We used warm-acclimated (30 °C) mice to characterize the effect of an up to 7-day cold acclimation (6 °C; CA) on thermoregulatory thermogenesis, comparing inbred mice with a genetic background conferring resistance (A/J) or susceptibility (C57BL/6 J) to obesity. RESULTS: Both warm-acclimated C57BL/6 J and A/J mice exhibited similar cold endurance, assessed as a capability to maintain core body temperature during acute exposure to cold, which improved in response to CA, resulting in comparable cold endurance and similar induction of UCP1 protein in BAT of mice of both genotypes. Despite this, adrenergic NST in BAT was induced only in C57BL/6 J, not in A/J mice subjected to CA. Cold tolerance phenotype of A/J mice subjected to CA was not based on increased shivering, improved insulation, or changes in physical activity. On the contrary, lipidomic, proteomic and gene expression analyses along with palmitoyl carnitine oxidation and cytochrome c oxidase activity revealed induction of lipid oxidation exclusively in skeletal muscle of A/J mice subjected to CA. These changes appear to be related to skeletal muscle NST, mediated by sarcolipin-induced uncoupling of sarco(endo)plasmic reticulum calcium ATPase pump activity and accentuated by changes in mitochondrial respiratory chain supercomplexes assembly. CONCLUSIONS: Our results suggest that NST in skeletal muscle could be adaptively augmented in the face of insufficient adrenergic NST in BAT, depending on the genetic background of the mice. It may provide both protection from cold and resistance to obesity, more effectively than BAT.

Laboratory of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic

Laboratory of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 00 Prague Czech Republic; Department of Physiology Faculty of Science Charles University Prague Vinicna 7 128 44 Prague Czech Republic

Laboratory of Bioenergetics Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Laboratory of Developmental Epileptology Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Laboratory of Translational Metabolism and Laboratory of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Section for Pharmacology and Pharmaceutical Biosciences Department of Pharmacy University of Oslo Sem Sælands vei 3 0371 Oslo Norway

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Cannon B., Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84(1):277–359. PubMed

Rohm M., Zeigerer A., Machado J., Herzig S. Energy metabolism in cachexia. EMBO Rep. 2019;20(4) PubMed PMC

Jansky I. Humoral thermogenesis and its role in maintaining energy balance. Physiol Rev. 1995;75(2):237–259. PubMed

Silva J.E. Thermogenic mechanisms and their hormonal regulation. Physiol Rev. 2006;86(2):435–464. PubMed

Flachs P., Rossmeisl M., Kuda O., Kopecky J. Stimulation of mitochondrial oxidative capacity in white fat independent of UCP1: a key to lean phenotype. Biochim Biophys Acta. 2013;1831(5):986–1003. PubMed

Kozak L.P. Brown fat and the myth of diet-induced thermogenesis. Cell Metabol. 2010;11(4):263–267. PubMed PMC

Granneman J.G., Burnazi M., Zhu Z., Schwamb L.A. White adipose tissue contributes to UCP1-independent thermogenesis. Am J Physiol Endocrinol Metab. 2003;285(6):E1230–E1236. PubMed

Blondin D.P., Haman F. Shivering and nonshivering thermogenesis in skeletal muscles. Handb Clin Neurol. 2018;156:153–173. PubMed

Bal N.C., Periasamy M. Uncoupling of sarcoendoplasmic reticulum calcium ATPase pump activity by sarcolipin as the basis for muscle non-shivering thermogenesis. Philos Trans R Soc Lond B Biol Sci. 2020;375(1793) PubMed PMC

Liu X., Rossmeisl M., McClaine J., Kozak L.P. Paradoxical resistance to diet-induced obesity in UCP1-deficient mice1. J Clin Invest. 2003;111(3):399–407. PubMed PMC

Blondin D.P., Daoud A., Taylor T., Tingelstad H.C., Bezaire V., Richard D., et al. Four-week cold acclimation in adult humans shifts uncoupling thermogenesis from skeletal muscles to brown adipose tissue. J Physiol. 2017;595(6):2099–2113. PubMed PMC

Rothwell N.J., Stock M.J. Similarities between cold-induced and diet-induced thermogenesis in the rat. Can J Physiol Pharmacol. 1980;58(7):842–848.

Wijers S.L., Saris W.H., Marken Lichtenbelt W.D. Individual thermogenic responses to mild cold and overfeeding are closely related. J Clin Endocrinol Metab. 2007;92(11):4299–4305. PubMed

von Essen G., Lindsund E., Cannon B., Nedergaard J. Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice. Am J Physiol Endocrinol Metab. 2017;313(5):E515–E527. PubMed

Guerra C., Koza R.A., Yamashita H., King K.W., Kozak L.P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest. 1998;102(2):412–420. PubMed PMC

Petrovic N., Walden T.B., Shabalina I.G., Timmons J.A., Cannon B., Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem. 2010;285(10):7153–7164. PubMed PMC

Wu J., Bostrom P., Sparks L.M., Ye L., Choi J.H., Giang A.H., et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366–376. PubMed PMC

Collins S., Daniel K.W., Petro A.E., Surwit R.S. Strain-specific response to beta3-adrenergic receptor agonist treatment of diet-induced obesity in mice. Endocrinology. 1997;138:405–413. PubMed

Kopecky J., Clarke G., Enerback S., Spiegelman B., Kozak L.P. Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity. J Clin Invest. 1995;96(6):2914–2923. PubMed PMC

Zheng Q., Lin J., Huang J., Zhang H., Zhang R., Zhang X., et al. Reconstitution of UCP1 using CRISPR/Cas9 in the white adipose tissue of pigs decreases fat deposition and improves thermogenic capacity. Proc Natl Acad Sci U S A. 2017;114(45):E9474–E9482. PubMed PMC

Finlin B.S., Memetimin H., Confides A.L., Kasza I., Zhu B., Vekaria H.J., et al. Human adipose beiging in response to cold and mirabegron. JCI Insight. 2018;3(15) PubMed PMC

Oeckl J., Janovska P., Adamcova K., Bardova K., Brunner S., Dieckmann S., et al. Loss of UCP1 function augments recruitment of futile lipid cycling for thermogenesis in murine brown fat. Mol Metabol. 2022;61 PubMed PMC

Kazak L., Rahbani J.F., Samborska B., Lu G.Z., Jedrychowski M.P., Lajoie M., et al. Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity. Nature Metab. 2019;1(3):360–370. PubMed PMC

Zurlo F., Larson K., Bogardus C., Ravussin E. Skeletal muscle metabolism is a major determinant of resting energy expenditure. J Clin Invest. 1990;86(5):1423–1427. PubMed PMC

Smith T.J., Edelman I.S. The role of sodium transport in thyroid thermogenesis. Fed Proc. 1979;38(8):2150–2153. PubMed

Clarke R.J., Catauro M., Rasmussen H.H., Apell H.J. Quantitative calculation of the role of the Na(+),K(+)-ATPase in thermogenesis. Biochim Biophys Acta. 2013;1827(10):1205–1212. PubMed

Fernandez-Vizarra E., Lopez-Calcerrada S., Sierra-Magro A., Perez-Perez R., Formosa L.E., Hock D.H., et al. Two independent respiratory chains adapt OXPHOS performance to glycolytic switch. Cell Metabol. 2022;34(11):1792–1808. PubMed

Frank V., Kadenbach B. Regulation of the H+/e- stoichiometry of cytochrome c oxidase from bovine heart by intramitochondrial ATP/ADP ratios. FEBS Lett. 1996;382(1–2):121–124. PubMed

Wyckelsma V.L., Venckunas T., Houweling P.J., Schlittler M., Lauschke V.M., Tiong C.F., et al. Loss of alpha-actinin-3 during human evolution provides superior cold resilience and muscle heat generation. Am J Hum Genet. 2021;108(3):446–457. PubMed PMC

Dulloo A.G., Miles-Chan J.L., Montani J.P., Schutz Y. Isometric thermogenesis at rest and during movement: a neglected variable in energy expenditure and obesity predisposition. Obes Rev. 2017;18(Suppl 1):56–64. PubMed

Ukropec J., Anunciado R.V., Ravussin Y., Kozak L.P. Leptin is required for uncoupling protein-1-independent thermogenesis during cold stress. Endocrinology. 2006;147(5):2468–2480. PubMed

Solinas G., Summermatter S., Mainieri D., Gubler M., Pirola L., Wymann M.P., et al. The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation. FEBS Lett. 2004;577(3):539–544. PubMed

Kus V., Prazak T., Brauner P., Hensler M., Kuda O., Flachs P., et al. Induction of muscle thermogenesis by high-fat diet in mice: association with obesity-resistance. Am J Physiol Endocrinol Metab. 2008;295(2):E356–E367. PubMed

Minokoshi Y., Kim Y.B., Peroni O.D., Fryer L.G., Muller C., Carling D., et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415(6869):339–343. PubMed

Campbell K.L., Dicke A.A. Sarcolipin makes heat, but is it adaptive thermogenesis? Front Physiol. 2018;9:714. PubMed PMC

Ukropec J., Anunciado R.P., Ravussin Y., Hulver M.W., Kozak L.P. UCP1-independent thermogenesis in white adipose tissue of cold-acclimated Ucp1-/- mice. J Biol Chem. 2006;281(42):31894–31908. PubMed

Nowack J., Vetter S.G., Stalder G., Painer J., Kral M., Smith S., et al. Muscle nonshivering thermogenesis in a feral mammal. Sci Rep. 2019;9(1):6378. PubMed PMC

Rowland L.A., Bal N.C., Kozak L.P., Periasamy M. Uncoupling protein 1 and sarcolipin are required to maintain optimal thermogenesis, and loss of both systems compromises survival of mice under cold stress. J Biol Chem. 2015;290(19):12282–12289. PubMed PMC

Bal N.C., Maurya S.K., Sopariwala D.H., Sahoo S.K., Gupta S.C., Shaikh S.A., et al. Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med. 2012;18(10):1575–1579. PubMed PMC

Maurya S.K., Bal N.C., Sopariwala D.H., Pant M., Rowland L.A., Shaikh S.A., et al. Sarcolipin is a key determinant of the basal metabolic rate, and its overexpression enhances energy expenditure and resistance against diet-induced obesity. J Biol Chem. 2015;290(17):10840–10849. PubMed PMC

Bal N.C., Maurya S.K., Singh S., Wehrens X.H., Periasamy M. Increased reliance on muscle-based thermogenesis upon acute minimization of Brown adipose tissue function. J Biol Chem. 2016;291(33):17247–17257. PubMed PMC

Bal N.C., Singh S., Reis F.C.G., Maurya S.K., Pani S., Rowland L.A., et al. Both brown adipose tissue and skeletal muscle thermogenesis processes are activated during mild to severe cold adaptation in mice. J Biol Chem. 2017;292(40):16616–16625. PubMed PMC

Golozoubova V., Hohtola E., Matthias A., Jacobsson A., Cannon B., Nedergaard J. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. Faseb J. 2001;15(9):2048–2050. PubMed

Vybiral S., Lesna I., Jansky L., Zeman V. Thermoregulation in winter swimmers and physiological significance of human catecholamine thermogenesis. Exp Physiol. 2000;85(3):321–326. PubMed

Golozoubova V., Cannon B., Nedergaard J. UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. Am J Physiol Endocrinol Metab. 2006;291(2):E350–E357. PubMed

Goldsmith R., Joanisse D.R., Gallagher D., Pavlovich K., Shamoon E., Leibel R.L., et al. Effects of experimental weight perturbation on skeletal muscle work efficiency, fuel utilization, and biochemistry in human subjects. Am J Physiol Regul Integr Comp Physiol. 2010;298(1):R79–R88. PubMed PMC

Rosenbaum M., Goldsmith R., Bloomfield D., Magnano A., Weimer L., Heymsfield S., et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005;115(12):3579–3586. PubMed PMC

Kaspari R.R., Reyna-Neyra A., Jung L., Torres-Manzo A.P., Hirabara S.M., Carrasco N. The paradoxical lean phenotype of hypothyroid mice is marked by increased adaptive thermogenesis in the skeletal muscle. Proc Natl Acad Sci U S A. 2020;117(36):22544–22551. PubMed PMC

Nicolaisen T.S., Klein A.B., Dmytriyeva O., Lund J., Ingerslev L.R., Fritzen A.M., et al. Thyroid hormone receptor alpha in skeletal muscle is essential for T3-mediated increase in energy expenditure. Faseb J. 2020;34(11):15480–15491. PubMed PMC

Keipert S., Lutter D., Schroeder B.O., Brandt D., Stahlman M., Schwarzmayr T., et al. Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice. Nat Commun. 2020;11(1):624. PubMed PMC

Grimpo K., Volker M.N., Heppe E.N., Braun S., Heverhagen J.T., Heldmaier G. Brown adipose tissue dynamics in wild-type and UCP1-knockout mice: in vivo insights with magnetic resonance. J Lipid Res. 2014;55(3):398–409. PubMed PMC

Flachs P., Adamcova K., Zouhar P., Marques C., Janovska P., Viegas I., et al. Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype. Int J Obes. 2017;41(3):372–380. PubMed

Shin H., Ma Y., Chanturiya T., Cao Q., Wang Y., Kadegowda A.K.G., et al. Lipolysis in Brown adipocytes is not essential for cold-induced thermogenesis in mice. Cell Metabol. 2017;26:1–14. PubMed PMC

Surwit R.S., Wang S., Petro A.E., Sanchis D., Raimbault S., Ricquier D., et al. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci U S A. 1998;95(7):4061–4065. PubMed PMC

Surwit R.S., Feinglos M.N., Rodin J., Sutherland A., Petro A.E., Opara E.C., et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metabolism. 1995;44(5):645–651. PubMed

Barreau C., Labit E., Guissard C., Rouquette J., Boizeau M.L., Gani Koumassi S., et al. Regionalization of browning revealed by whole subcutaneous adipose tissue imaging. Obesity. 2016;24(5):1081–1089. PubMed

Riachi M., Himms-Hagen J., Harper M.E. Percent relative cumulative frequency analysis in indirect calorimetry: application to studies of transgenic mice. Can J Physiol Pharmacol. 2004;82(12):1075–1083. PubMed

Meyer C.W., Willershauser M., Jastroch M., Rourke B.C., Fromme T., Oelkrug R., et al. Adaptive thermogenesis and thermal conductance in wild-type and UCP1-KO mice. Am J Physiol Regul Integr Comp Physiol. 2010;299(5):R1396–R1406. PubMed PMC

Weir J.B. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol. 1949;109(1–2):1–9. PubMed PMC

Abreu-Vieira G., Xiao C., Gavrilova O., Reitman M.L. Integration of body temperature into the analysis of energy expenditure in the mouse. Mol Metabol. 2015;4(6):461–470. PubMed PMC

Teodoro J.S., Zouhar P., Flachs P., Bardova K., Janovska P., Gomes A.P., et al. Enhancement of brown fat thermogenesis using chenodeoxycholic acid in mice. Int J Obes. 2014;38(8):1027–1034. PubMed

Zouhar P., Janovska P., Stanic S., Bardova K., Funda J., Haberlova B., et al. A pyrexic effect of FGF21 independent of energy expenditure and UCP1. Mol Metabol. 2021 PubMed PMC

Pecinova A., Drahota Z., Nuskova H., Pecina P., Houstek J. Evaluation of basic mitochondrial functions using rat tissue homogenates. Mitochondrion. 2011;11(5):722–728. PubMed

Wittig I., Braun H.P., Schagger H. Blue native PAGE. Nat Protoc. 2006;1(1):418–428. PubMed

Park J.W., Jung K.H., Lee J.H., Quach C.H., Moon S.H., Cho Y.S., et al. 18F-FDG PET/CT monitoring of beta3 agonist-stimulated brown adipocyte recruitment in white adipose tissue. J Nucl Med. 2015;56(1):153–158. PubMed

Hartmannova H., Piherova L., Tauchmannova K., Kidd K., Acott P.D., Crocker J.F., et al. Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6. Hum Mol Genet. 2016;25(18):4062–4079. PubMed

Cervinkova Z., Rauchova H., Krivakova P., Drahota Z. Inhibition of palmityl carnitine oxidation in rat liver mitochondria by tert-butyl hydroperoxide. Physiol Res. 2008;57(1):133–136. PubMed

Drahota Z., Milerova M., Stieglerova A., Skarka L., Houstek J., Ostadal B. Development of cytochrome-c oxidase activity in rat heart: downregulation in newborn rats. Cell Biochem Biophys. 2005;43(1):87–94. PubMed

Smith P.K., Krohn R.I., Hermanson G.T., Mallia A.K., Gartner F.H., Provenzano M.D., et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150(1):76–85. PubMed

Chong J., Soufan O., Li C., Caraus I., Li S., Bourque G., et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018;46(W1):W486–W494. PubMed PMC

Sustarsic E.G., Ma T., Lynes M.D., Larsen M., Karavaeva I., Havelund J.F., et al. Cardiolipin synthesis in Brown and beige fat mitochondria is essential for systemic energy homeostasis. Cell Metabol. 2018;28(1):159–174 e111. PubMed PMC

Shabalina I.G., Vrbacky M., Pecinova A., Kalinovich A.V., Drahota Z., Houstek J., et al. ROS production in brown adipose tissue mitochondria: the question of UCP1-dependence. Biochim Biophys Acta. 2014;1837(12):2017–2030. PubMed

Olsen J.M., Csikasz R.I., Dehvari N., Lu L., Sandstrom A., Oberg A.I., et al. beta3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: mediation through the mTOR pathway. Mol Metabol. 2017;6(6):611–619. PubMed PMC

Chen Y., Ikeda K., Yoneshiro T., Scaramozza A., Tajima K., Wang Q., et al. Thermal stress induces glycolytic beige fat formation via a myogenic state. Nature. 2019;565(7738):180–185. PubMed PMC

Westerberg R., Mansson J.E., Golozoubova V., Shabalina I.G., Backlund E.C., Tvrdik P., et al. ELOVL3 is an important component for early onset of lipid recruitment in brown adipose tissue. J Biol Chem. 2006;281(8):4958–4968. PubMed

McKay W.P., Vargo M., Chilibeck P.D., Daku B.L. Effects of ambient temperature on mechanomyography of resting quadriceps muscle. Appl Physiol Nutr Metabol. 2013;38(3):227–233. PubMed

Lenhardt R. The effect of anesthesia on body temperature control. Front Biosci. 2010;2(3):1145–1154. PubMed

Diaz M., Becker D.E. Thermoregulation: physiological and clinical considerations during sedation and general anesthesia. Anesth Prog. 2010;57(1):25–32. quiz 33-24. PubMed PMC

Lomo T., Eken T., Bekkestad Rein E., Nja A. Body temperature control in rats by muscle tone during rest or sleep. Acta Physiol. 2020;228(2) PubMed

Haman F., Legault S.R., Rakobowchuk M., Ducharme M.B., Weber J.M. Effects of carbohydrate availability on sustained shivering II. Relating muscle recruitment to fuel selection. J Appl Physiol. 2004;96(1):41–49. (1985) PubMed

Davoudi M., Kotarsky H., Hansson E., Kallijarvi J., Fellman V. COX7A2L/SCAFI and pre-complex III modify respiratory chain supercomplex formation in different mouse strains with a Bcs1l mutation. PLoS One. 2016;11(12) PubMed PMC

Lapuente-Brun E., Moreno-Loshuertos R., Acin-Perez R., Latorre-Pellicer A., Colas C., Balsa E., et al. Supercomplex assembly determines electron flux in the mitochondrial electron transport chain. Science. 2013;340(6140):1567–1570. PubMed

Ikeda K., Shiba S., Horie-Inoue K., Shimokata K., Inoue S. A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle. Nat Commun. 2013;4:2147. PubMed

Radzyukevich T.L., Neumann J.C., Rindler T.N., Oshiro N., Goldhamer D.J., Lingrel J.B., et al. Tissue-specific role of the Na,K-ATPase alpha2 isozyme in skeletal muscle. J Biol Chem. 2013;288(2):1226–1237. PubMed PMC

Koves T.R., Ussher J.R., Noland R.C., Slentz D., Mosedale M., Ilkayeva O., et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metabol. 2008;7(1):45–56. PubMed

Muoio D.M., Noland R.C., Kovalik J.P., Seiler S.E., Davies M.N., DeBalsi K.L., et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metabol. 2012;15(5):764–777. PubMed PMC

Buresova J., Janovska P., Kuda O., Krizova J., der Stelt I.R., Keijer J., et al. Postnatal induction of muscle fatty acid oxidation in mice differing in propensity to obesity: a role of pyruvate dehydrogenase. Int J Obes. 2020;44(1):235–244. PubMed

Vercellino I., Sazanov L.A. The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol. 2021;23(2):141–161. PubMed

Calvo E., Cogliati S., Hernansanz-Agustin P., Loureiro-Lopez M., Guaras A., Casuso R.A., et al. Functional role of respiratory supercomplexes in mice: SCAF1 relevance and segmentation of the Qpool. Sci Adv. 2020;6(26) PubMed PMC

Perez-Perez R., Lobo-Jarne T., Milenkovic D., Mourier A., Bratic A., Garcia-Bartolome A., et al. COX7A2L is a mitochondrial complex III binding protein that stabilizes the III2+IV supercomplex without affecting respirasome formation. Cell Rep. 2016;16(9):2387–2398. PubMed PMC

Liu J., Hiser C., Ferguson-Miller S. Role of conformational change and K-path ligands in controlling cytochrome c oxidase activity. Biochem Soc Trans. 2017;45(5):1087–1095. PubMed PMC

Cunatova K., Reguera D.P., Houstek J., Mracek T., Pecina P. Role of cytochrome c oxidase nuclear-encoded subunits in health and disease. Physiol Res. 2020;69(6):947–965. PubMed PMC

Benegiamo G., Bou Sleiman M., Wohlwend M., Rodriguez-Lopez S., Goeminne L.J.E., Laurila P.P., et al. COX7A2L genetic variants determine cardiorespiratory fitness in mice and human. Nat Metab. 2022;4(10):1336–1351. PubMed PMC

Garcia-Poyatos C., Cogliati S., Calvo E., Hernansanz-Agustin P., Lagarrigue S., Magni R., et al. Scaf1 promotes respiratory supercomplexes and metabolic efficiency in zebrafish. EMBO Rep. 2020;21(7) PubMed PMC

Shiba S., Ikeda K., Horie-Inoue K., Nakayama A., Tanaka T., Inoue S. Deficiency of COX7RP, a mitochondrial supercomplex assembly promoting factor, lowers blood glucose level in mice. Sci Rep. 2017;7(1):7606. PubMed PMC

Sepa-Kishi D.M., Sotoudeh-Nia Y., Iqbal A., Bikopoulos G., Ceddia R.B. Cold acclimation causes fiber type-specific responses in glucose and fat metabolism in rat skeletal muscles. Sci Rep. 2017;7(1) PubMed PMC

Jequier E. In: Obesity. J.B. Bjorntorp P., Brodoff B.N., editors. . Lippincott Company; Philadelphia: 1992. Regulation of thermogenesis and nutrient metabolism in the human: relevance for obesity; pp. 130–135.

Filozof C.M., Murua C., Sanchez M.P., Brailovsky C., Perman M., Gonzalez C.D., et al. Low plasma leptin concentration and low rates of fat oxidation in weight-stable post-obese subjects. Obes Res. 2000;8(3):205–210. PubMed

West D.B., Boozer C.N., Moody D.L., Atkinson R.L. Dietary obesity in nine inbred mouse strains. Am J Physiol. 1992;262(6 Pt 2):R1025–R1032. PubMed

Hofmann W.E., Liu X., Bearden C.M., Harper M.E., Kozak L.P. Effects of genetic background on thermoregulation and fatty acid- induced uncoupling of mitochondria in UCP1-deficient mice. J Biol Chem. 2001;276(15):12460–12465. PubMed

Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity