OPA1 in Lipid Metabolism: Function of OPA1 in Lipolysis and Thermogenesis of Adipocytes

Abstract

OPA1 (Optic Atrophy 1) is a mitochondrial GTPase known to regulate fission of mitochondria. It was recently also shown to locate on lipid droplets in adipocytes where it functions as an A-kinase anchoring protein (AKAP) that mediates adrenergic control of lipolysis by facilitating PKA phosphorylation of perilipin (Plin1). In brown adipocytes indirect evidence support the notion that OPA1 regulation of fission serves to increase thermogenesis, which thereby contributes to dissipation of energy. In white adipocytes, OPA1 located on lipid droplets serves as a gatekeeper to control lipolysis induced by adrenergic agonists. However, the function of OPA1 in lipolysis and thermogenesis in inducible brown adipocytes (brite/beige cells) remains elusive. Here we discuss the role of OPA1 in lipid metabolism.

Key words

OPA1 - AKAP - cAMP - lipid metabolism - brown adipocyte - white adipocyte

Publication History

Received: 22 August 2016

Accepted: 21 December 2016

Article published online:
20 April 2017

• References

• 1 Wilting R, Yanover E, Heideman M, Jacobs H, Horner J, van der Torre J, DePinho R, Dannenberg J. Overlapping functions of Hdac1 and Hdac2 in cell cycle regulation and haematopoiesis. EMBO J 2010; 29: 2586-2597
• 2 Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiological Reviews 2004; 84: 277-359
• 3 Atit R, Sgaier SK, Mohamed OA, Taketo MM, Dufort D, Joyner AL, Niswander L, Conlon RA. β-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Develop Biol 2006; 296: 164-176
• 4 Timmons JA, Wennmalm K, Larsson O, Walden TB, Lassmann T, Petrovic N, Hamilton DL, Gimeno RE, Wahlestedt C, Baar K, Nedergaard J, Cannon B. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl Acad Sci USA 2007; 104: 4401-4406
• 5 Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor γ (pparγ) 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: 7153-7164
• 6 Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008; 454: 961-967
• 7 Rosenwald M, Wolfrum C. The origin and definition of brite versus white and classical brown adipocytes. Adipocyte 2014; 3: 4-9
• 8 Gesta S, Tseng Y-H, Kahn CR. Developmental origin of fat: tracking obesity to its source. Cell 2007; 131: 242-256
• 9 Bjørndal B, Burri L, Staalesen V, Skorve J, Berge RK. Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. J Obes 2011; 490650 doi:10.1155/2011/490650 [Epub 2011 Feb 15]
• 10 Koza RA, Nikonova L, Hogan J, Rim J-S, Mendoza T, Faulk C, Skaf J, Kozak LP. Changes in gene expression foreshadow diet-induced obesity in genetically identical mice. PLoS Genet 2006; 2: e81
• 11 Nikonova L, Koza RA, Mendoza T, Chao P-M, Curley JP, Kozak LP. Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance. The FASEB J 2008; 22: 3925-3937
• 12 Kozak LP, Newman S, Chao P-M, Mendoza T, Koza RA. The early nutritional environment of mice determines the capacity for adipose tissue expansion by modulating genes of caveolae structure. PLoS One 2010; 5: e11015
• 13 Mori H, Prestwich TC, Reid MA, Longo KA, Gerin I, Cawthorn WP, Susulic VS, Krishnan V, Greenfield A, MacDougald OA. Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition. J Clin Invest 2012; 122: 2405-2416
• 14 Jura M, Jarosławska J, Chu DT, Kozak LP. Mest and Sfrp5 are biomarkers for healthy adipose tissue. Biochimie 2016; 124: 124-133
• 15 Chu D-T, Malinowska E, Gawronska-Kozak B, Kozak LP. Expression of adipocyte biomarkers in a primary cell culture models reflects preweaning adipobiology. J Biol Chem 2014; 289: 18478-18488
• 16 Kozak LP. Brown Fat and the myth of diet-induced thermogenesis. Cell Metab 2010; 11: 263-267
• 17 Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng Y-H, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Eng J Med 2009; 360: 1509-1517
• 18 Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold Exposure and Adiposity. Diabetes 2009; 58: 1526-1531
• 19 van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJJ. Cold-activated brown adipose tissue in healthy men. N Eng J Med 2009; 360: 1500-1508
• 20 Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto N-J, Enerbäck S, Nuutila P. Functional brown adipose tissue in healthy adults. N Eng J Med 2009; 360: 1518-1525
• 21 Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009; 23: 3113-3120
• 22 Nagano G, Ohno H, Oki K, Kobuke K, Shiwa T, Yoneda M, Kohno N. Activation of classical brown adipocytes in the adult human perirenal depot is highly correlated with prdm16–ehmt1 complex expression. PLoS One 2015; 10: e0122584
• 23 Lidell ME, Betz MJ, Leinhard OD, Heglind M, Elander L, Slawik M, Mussack T, Nilsson D, Romu T, Nuutila P, Virtanen KA, Beuschlein F, Persson A, Borga M, Enerback S. Evidence for two types of brown adipose tissue in humans. Nat Med 2013; 19: 631-634
• 24 Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med 2013; 19: 1252-1263
• 25 Heaton JM. The distribution of brown adipose tissue in the human. J Anat 1972; 112: 35-39
• 26 Jespersen Naja Z, Larsen Therese J, Peijs L, Daugaard S, Homøe P, Loft A, de Jong J, Mathur N, Cannon B, Nedergaard J, Pedersen Bente K, Møller K, Scheele C. A classical brown adipose tissue mrna signature partly overlaps with brite in the supraclavicular region of adult humans. Cell Metab 2013; 17: 798-805
• 27 Shabalina IG, Jacobsson A, Cannon B, Nedergaard J. Native UCP1 displays simple competitive kinetics between the regulators purine nucleotides and fatty acids. J Biol Chem 2004; 279: 38236-38248
• 28 Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS One 2012; 7: e49452
• 29 Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab 2011; 302: E19-E31
• 30 Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: Is beige the new brown?. Gen Develop 2013; 27: 234-250
• 31 Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Gen Develop 2012; 26: 271-281
• 32 Shinoda K, Ohyama K, Hasegawa Y, Chang H-Y, Ogura M, Sato A, Hong H, Hosono T, Sharp Louis Z, Scheel David W, Graham M, Ishihama Y, Kajimura S. Phosphoproteomics identifies CK2 as a negative regulator of beige adipocyte thermogenesis and energy expenditure. Cell Metab 2015; 22: 997-1008
• 33 Lonçar D, Afzelius BA, Cannon B. Epididymal white adipose tissue after cold stress in rats I. Nonmitochondrial changes. J Ultrastruct Mol Struct Res 1988; 101: 109-122
• 34 Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest 1998; 102: 412-420
• 35 Himms-Hagen J, Cui J, Danforth Jr. E, Taatjes DA, Lang SS, Waters BL, Claus TH. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol 1994; 266: R1371-R1382
• 36 Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, Zhang C, Seki T, Hosaka K, Wahlberg E, Yang J, Zhang L, Länne T, Sun B, Li X, Liu Y, Zhang Y, Cao Y. Cold exposure promotes atherosclerotic plaque growth and instability via ucp1-dependent lipolysis. Cell Metab 2013; 18: 118-129
• 37 Elabd C, Chiellini C, Carmona M, Galitzky J, Cochet O, Petersen R, Pénicaud L, Kristiansen K, Bouloumié A, Casteilla L, Dani C, Ailhaud G, Amri E-Z. Human multipotent adipose-derived. Stem Cells Differentiate into Functional Brown Adipocytes. Stem Cells 2009; 27: 2753-2760
• 38 Pardo R, Enguix N, Lasheras J, Feliu JE, Kralli A, Villena JA. Rosiglitazone-induced mitochondrial biogenesis in white adipose tissue is independent of peroxisome proliferator-activated receptor γ coactivator-1α. PLoS One 2011; 6: e26989
• 39 Kozak UC, Kozak LP. Norepinephrine-dependent selection of brown adipocyte cell lines. Endocrinology 1994; 134: 906-913
• 40 Tvrdik P, Asadi A, Kozak LP, Nedergaard J, Cannon B, Jacobsson A. Cig30, a mouse member of a novel membrane protein gene family, is involved in the recruitment of brown adipose tissue. J Biol Chem 1997; 272: 31738-31746
• 41 Bengtsson T, Redegren K, Strosberg AD, Nedergaard J, Cannon B. Down-regulation of β3 adrenoreceptor gene expression in brown fat cells is transient and recovery is dependent upon a short-lived protein factor. J Biol Chem 1996; 271: 33366-33375
• 42 Boon MR, van den Berg SAA, Wang Y, van den Bossche J, Karkampouna S, Bauwens M, De Saint-Hubert M, van der Horst G, Vukicevic S, de Winther MPJ, Havekes LM, Jukema JW, Tamsma JT, van der Pluijm G, van Dijk KW, Rensen PCN. BMP7 activates brown adipose tissue and reduces diet-induced obesity only at subthermoneutrality. PLoS One 2013; 8: e74083
• 43 Schulz TJ, Huang TL, Tran TT, Zhang H, Townsend KL, Shadrach JL, Cerletti M, McDougall LE, Giorgadze N, Tchkonia T, Schrier D, Falb D, Kirkland JL, Wagers AJ, Tseng Y-H. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci USA 2011; 108: 143-148
• 44 Zhang H, Schulz TJ, Espinoza DO, Huang TL, Emanuelli B, Kristiansen K, Tseng Y-H. Cross talk between insulin and bone morphogenetic protein signaling systems in brown adipogenesis. Mol Cell Biol 2010; 30: 4224-4233
• 45 Lee P, Linderman Joyce D, Smith S, Brychta Robert J, Wang J, Idelson C, Perron Rachel M, Werner Charlotte D, Phan Giao Q, Kammula Udai S, Kebebew E, Pacak K, Chen Kong Y, Celi Francesco S. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 19: 302-309
• 46 Wu J, Spiegelman BM. Irisin ERKs the Fat. Diabetes 2014; 63: 381-383
• 47 Bayindir I, Babaeikelishomi R, Kocanova S, Sousa IS, Lerch S, Hardt O, Wild S, Bosio A, Bystricky K, Herzig S, Vegiopoulos A. Transcriptional pathways in cPGI2-induced adipocyte progenitor activation for browning. Front Endocrinol 2015; 6: 129
• 48 Wu J, Boström P, Sparks Lauren M, Ye L, Choi Jang H, Giang A-H, Khandekar M, Virtanen Kirsi A, Nuutila P, Schaart G, Huang K, Tu H, van Marken Lichtenbelt Wouter D, Hoeks J, Enerbäck S, Schrauwen P, Spiegelman Bruce M. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012; 150: 366-376
• 49 Giralt M, Villarroya F. White, brown, beige/brite: different adipose cells for different functions?. Endocrinology 2013; 154: 2992-3000
• 50 Li Y, Bolze F, Fromme T, Klingenspor M. Intrinsic differences in BRITE adipogenesis of primary adipocytes from two different mouse strains. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 2014; 1841: 1345-1352
• 51 Chu-Dinh T, Chu DT. 4-1BB and the Epigenetic regulations of this molecule. Med Epigenet 2014; 2: 80-85
• 52 Long Jonathan Z, Svensson Katrin J, Tsai L, Zeng X, Roh Hyun C, Kong X, Rao Rajesh R, Lou J, Lokurkar I, Baur W, Castellot John Jr. J, Rosen Evan D, Spiegelman Bruce M. A smooth muscle-like origin for beige adipocytes. Cell Metab 2014; 19: 810-820
• 53 Pidoux G, Witczak O, Jarnæss E, Myrvold L, Urlaub H, Stokka AJ, Küntziger T, Taskén K. Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis. EMBO J 2011; 30: 4371-4386
• 54 Quirós PM, Ramsay AJ, Sala D, Fernández-Vizarra E, Rodríguez F, Peinado JR, Fernández-García MS, Vega JA, Enríquez JA, Zorzano A, López-Otín C. Loss of mitochondrial protease OMA1 alters processing of the GTPase OPA1 and causes obesity and defective thermogenesis in mice. EMBO J 2012; 31: 2117-2133
• 55 Grant RW, Vester Boler BM, Ridge TK, Graves TK, Swanson KS. Adipose tissue transcriptome changes during obesity development in female dogs. Physiol Genom 2011; 43: 295-307
• 56 Cederberg A, Grønning LM, Ahrén B, Taskén K, Carlsson P, Enerbäck S. FOXC2 Is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 2001; 106: 563-573
• 57 Lidell ME, Seifert EL, Westergren R, Heglind M, Gowing A, Sukonina V, Arani Z, Itkonen P, Wallin S, Westberg F, Fernandez-Rodriguez J, Laakso M, Nilsson T, Peng X-R, Harper M-E, Enerbäck S. The adipocyte-expressed forkhead transcription factor foxc2 regulates metabolism through altered mitochondrial function. Diabetes 2011; 60: 427-435
• 58 Rong JX, Klein J-LD, Qiu Y, Xie M, Johnson JH, Waters KM, Zhang V, Kashatus JA, Remlinger KS, Bing N, Crosby RM, Jackson TK, Witherspoon SM, Moore JT, Ryan TE, Neill SD, Strum JC. Rosiglitazone induces mitochondrial biogenesis in differentiated murine 3T3-L1 and C3H/10T1/2 adipocytes. PPAR Res 2011; 1-11
• 59 Capllonch-Amer G, Lladó I, Proenza AM, García-Palmer FJ, Gianotti M. Opposite effects of 17β-estradiol and testosterone on mitochondrial biogenesis and adiponectin synthesis in white adipocytes. Journal of Molecular Endocrinology 2014; 52: 203-214
• 60 Miegueu St P, Pierre D, Broglio F, Cianflone K. Effect of desacyl ghrelin, obestatin and related peptides on triglyceride storage, metabolism and GHSR signaling in 3T3-L1 adipocytes. J Cell Biochem 2011; 112: 704-714
• 61 Wang Y, Katayama A, Terami T, Han X, Nunoue T, Zhang D, Teshigawara S, Eguchi J, Nakatsuka A, Murakami K, Ogawa D, Furuta Y, Makino H, Wada J. Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes. Metabolism 2015; 64: 677-688
• 62 Anusree SS, Nisha VM, Priyanka A, Raghu KG. Insulin resistance by TNF-α is associated with mitochondrial dysfunction in 3T3-L1 adipocytes and is ameliorated by punicic acid, a PPARγ agonist. Mol Cell Endocrinol 2015; 413: 120-128
• 63 Kita T, Nishida H, Shibata H, Niimi S, Higuti T, Arakaki N. Possible role of mitochondrial remodelling on cellular triacylglycerol accumulation. J Biochem 2009; 146: 787-796
• 64 Wikstrom JD, Mahdaviani K, Liesa M, Sereda SB, Si Y, Las G, Twig G, Petrovic N, Zingaretti C, Graham A, Cinti S, Corkey BE, Cannon B, Nedergaard J, Shirihai OS. Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure. EMBO J 2014; 33: 418-436
• 65 Hahn WS, Kuzmicic J, Burrill JS, Donoghue MA, Foncea R, Jensen MD, Lavandero S, Arriaga EA, Bernlohr DA. Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Am J Physiol 2014; 306: E1033-E1045
• 66 Tanaka K, Masaki Y, Tanaka M, Miyazaki M, Enjoji M, Nakamuta M, Kato M, Nomura M, Inoguchi T, Kotoh K, Takayanagi R. Exenatide improves hepatic steatosis by enhancing lipid use in adipose tissue in nondiabetic rats. World J Gastroenterol 2014; 20: 2653-2663
• 67 Derecka M, Gornicka A, Koralov Sergei B, Szczepanek K, Morgan M, Raje V, Sisler J, Zhang Q, Otero D, Cichy J, Rajewsky K, Shimoda K, Poli V, Strobl B, Pellegrini S, Harris Thurl E, Seale P, Russell Aaron P, McAinch Andrew J, O’Brien Paul E, Keller Susanna R, Croniger CM, Kordula T, Larner AC. Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity. Cell Metab 2012; 16: 814-824
• 68 Lin L, Lee JH, Bongmba OYN, Ma X, Zhu X, Sheikh-Hamad D, Sun Y. The suppression of ghrelin signaling mitigates age-associated thermogenic impairment. AGING 2014; Vol 6: 1019-1032
• 69 Dali-Youcef N, Mataki C, Coste A, Messaddeq N, Giroud S, Blanc S, Koehl C, Champy M-F, Chambon P, Fajas L, Metzger D, Schoonjans K, Auwerx J. Adipose tissue-specific inactivation of the retinoblastoma protein protects against diabesity because of increased energy expenditure. Proc Natl Acad Sci USA 2007; 104: 10703-10708
• 70 Hontecillas R, O’Shea M, Einerhand A, Diguardo M, Bassaganya-Riera J. Activation of PPAR γ and α by punicic acid ameliorates glucose tolerance and suppresses obesity-related inflammation. J Am College Nutr 2009; 28: 184-195
• 71 Bassaganya-Riera J, DiGuardo M, Climent M, Vives C, Carbo A, Jouni ZE, Einerhand AWC, O’Shea M, Hontecillas R. Activation of PPARγ and δ by dietary punicic acid ameliorates intestinal inflammation in mice. British Journal of Nutrition 2011; 106: 878-886
• 72 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-660
• 73 Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908-913
• 74 Shimbara T, Mondal MS, Kawagoe T, Toshinai K, Koda S, Yamaguchi H, Date Y, Nakazato M. Central administration of ghrelin preferentially enhances fat ingestion. Neurosci Lett 2004; 369: 75-79
• 75 Rodriguez A, Gomez-Ambrosi J, Catalan V, Gil MJ, Becerril S, Sainz N, Silva C, Salvador J, Colina I, Fruhbeck G. Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes 2009; 33: 541-552
• 76 Mano-Otagiri A, Ohata H, Iwasaki-Sekino A, Nemoto T, Shibasaki T. Ghrelin suppresses noradrenaline release in the brown adipose tissue of rats. J Endocrinol 2009; 201: 341-349
• 77 Maeda H, Hosokawa M, Sashima T, Funayama K, Miyashita K. Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues. Biochemical and Biophysical Research Communications 2005; 332: 392-397
• 78 Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Fernø J, Salvador J, Escalada J, Dieguez C, Lopez M, Frühbeck G, Nogueiras R. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 2014; 63: 3346-3358
• 79 Wu M-T, Chou H-N, Huang C-J. Dietary fucoxanthin increases metabolic rate and upregulated mrna expressions of the pgc-1alpha network, mitochondrial biogenesis and fusion genes in white adipose tissues of mice. Marine Drugs 2014; 12: 964-982
• 80 Ahmadian M, Wang Y, Sul HS. Lipolysis in adipocytes. Int J Biochem Cell Biol 2010; 42: 555-559
• 81 Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annual Review of Nutrition 2007; 27: 79-101
• 82 Collins S. β-Adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front Endocrinol 2011; 2: 102
• 83 McTernan PG, Harte AL, Anderson LA, Green A, Smith SA, Holder JC, Barnett AH, Eggo MC, Kumar S. Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. Diabetes 2002; 51: 1493-1498
• 84 Greenberg AS, Kraemer FB, Soni KG, Jedrychowski MP, Yan QW, Graham CE, Bowman TA, Mansur A. Lipid droplet meets a mitochondrial protein to regulate adipocyte lipolysis. EMBO J 2011; 30: 4337-4339
• 85 Olichon A, Guillou E, Delettre C, Landes T, Arnauné-Pelloquin L, Emorine LJ, Mils V, Daloyau M, Hamel C, Amati-Bonneau P, Bonneau D, Reynier P, Lenaers G, Belenguer P. Mitochondrial dynamics and disease, OPA1. Biochim Biophys Acta 2006; 1763: 500-509
• 86 Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 2007; 178: 749-755
• 87 Lee Y-j, Jeong S-Y, Karbowski M, Smith CL, Youle RJ. Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in Apoptosis. Mol Biol Cell 2004; 15: 5001-5011
• 88 Chen H, Chan DC. Emerging functions of mammalian mitochondrial fusion and fission. Human Mol Genet 2005; 14: R283-R289
• 89 Si Y, Palani S, Jayaraman A, Lee K. Effects of forced uncoupling protein 1 expression in 3T3-L1 cells on mitochondrial function and lipid metabolism. J Lipid Res 2007; 48: 826-836
• 90 Hofmann WE, Liu X, Bearden CM, Harper M-E, Kozak LP. Effects of genetic background on thermoregulation and fatty acid-induced uncoupling of mitochondria in UCP1-deficient Mice. J Biol Chem 2001; 276: 12460-12465
• 91 Xue B, Rim J-S, Hogan JC, Coulter AA, Koza RA, Kozak LP. Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat. J Lipid Res 2007; 48: 41-51
• 92 Fedorenko A, Lishko Polina V, Kirichok Y. Mechanism of fatty-acid-dependent ucp1 uncoupling in brown fat mitochondria. Cell 2012; 151: 400-413
• 93 Fink BD, Herlein JA, Almind K, Cinti S, Kahn CR, Sivitz WI. Mitochondrial proton leak in obesity-resistant and obesity-prone mice. Am J Physiol 2007; 293: R1773-R1780
• 94 Marette A, Bukowiecki LJ. Noradrenaline stimulates glucose-transport in rat brown adipocytes by activating thermogenesis - evidence that fatty-acid activation of mitochondrial respiration enhances glucose-transport. Biochem J 1991; 277: 119-124
• 95 Alvarez R, de Andrés J, Yubero P, Viñas O, Mampel T, Iglesias R, Giralt M, Villarroya F. A Novel Regulatory Pathway of Brown Fat Thermogenesis: Retinoic acid is a Transcriptional Activator of the Mitochondrial Uncoupling Protein Gene. J Biol Chem 1995; 270: 5666-5673
• 96 Müller TD, Lee SJ, Jastroch M, Kabra D, Stemmer K, Aichler M, Abplanalp B, Ananthakrishnan G, Bhardwaj N, Collins S, Divanovic S, Endele M, Finan B, Gao Y, Habegger KM, Hembree J, Heppner KM, Hofmann S, Holland J, Küchler D, Kutschke M, Krishna R, Lehti M, Oelkrug R, Ottaway N, Perez-Tilve D, Raver C, Walch AK, Schriever SC, Speakman J, Tseng Y-H, Diaz-Meco M, Pfluger PT, Moscat J, Tschöp MH. p62 Links β-adrenergic input to mitochondrial function and thermogenesis. J Clin Invest 2013; 123: 469-478
• 97 Lee J-Y, Takahashi N, Yasubuchi M, Kim Y-I, Hashizaki H, Kim M-J, Sakamoto T, Goto T, Kawada T. Triiodothyronine induces UCP-1 expression and mitochondrial biogenesis in human adipocytes. Am J Physiol 2012; 302: C463-C472
• 98 Ye L, Wu J, Cohen P, Kazak L, Khandekar MJ, Jedrychowski MP, Zeng X, Gygi SP, Spiegelman BM. Fat cells directly sense temperature to activate thermogenesis. Proc Natl Acad Sci USA 2013; 110: 12480-12485
• 99 Himms-Hagen J. Nonshivering thermogenesis. Brain Research Bulletin 1984; 12: 151-160
• 100 Calvani R, Leeuwenburgh C, Marzetti E. Brown adipose tissue and the cold war against obesity. Diabetes 2014; 63: 3998-4000
• 101 Lee J, Ellis Jessica M, Wolfgang Michael J. Adipose fatty acid oxidation is required for thermogenesis and potentiates oxidative stress-induced inflammation. Cell Rep 2015; 10: 266-279
• 102 Souza SC, Christoffolete MA, Ribeiro MO, Miyoshi H, Strissel KJ, Stancheva ZS, Rogers NH, D’Eon TM, Perfield JW, Imachi H, Obin MS, Bianco AC, Greenberg AS. Perilipin regulates the thermogenic actions of norepinephrine in brown adipose tissue. J Lipid Res 2007; 48: 1273-1279
• 103 Wang H, Sreenivasan U, Hu H, Saladino A, Polster BM, Lund LM, Gong D-w Stanley WC, Sztalryd C. Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. J Lipid Res 2011; 52: 2159-2168
• 104 Sawada T, Miyoshi H, Shimada K, Suzuki A, Okamatsu-Ogura Y, Perfield II JW, Kondo T, Nagai S, Shimizu C, Yoshioka N, Greenberg AS, Kimura K, Koike T. Perilipin overexpression in white adipose tissue induces a brown fat-like phenotype. PLoS One 2010; 5: e14006
• 105 Miyoshi H, Souza SC, Endo M, Sawada T, Perfield JW, Shimizu C, Stancheva Z, Nagai S, Strissel KJ, Yoshioka N, Obin MS, Koike T, Greenberg AS. Perilipin overexpression in mice protects against diet-induced obesity. J Lipid Res 2010; 51: 975–982