Mitochondrial (Dys)function in Adipocyte (De)differentiation and Systemic Metabolic Alterations
2009; Elsevier BV; Volume: 175; Issue: 3 Linguagem: Inglês
10.2353/ajpath.2009.081155
ISSN1525-2191
AutoresAurélia De Pauw, Silvia Tejerina, Martine Raes, Jaap Keijer, Thierry Arnould,
Tópico(s)Mitochondrial Function and Pathology
ResumoIn mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria. In mammals, adipose tissue, composed of BAT and WAT, collaborates in energy partitioning and performs metabolic regulatory functions. It is the most flexible tissue in the body, because it is remodeled in size and shape by modifications in adipocyte cell size and/or number, depending on developmental status and energy fluxes. Although numerous reviews have focused on the differentiation program of both brown and white adipocytes as well as on the pathophysiological role of white adipose tissues, the importance of mitochondrial activity in the differentiation or the dedifferentiation programs of adipose cells and in systemic metabolic alterations has not been extensively reviewed previously. Here, we address the crucial role of mitochondrial functions during adipogenesis and in mature adipocytes and discuss the cellular responses of white adipocytes to mitochondrial activity impairment. In addition, we discuss the increase in scientific knowledge regarding mitochondrial functions in the last 10 years and the recent suspicion of mitochondrial dysfunction in several 21st century epidemics (ie, obesity and diabetes), as well as in lipodystrophy found in HIV-treated patients, which can contribute to the development of new therapeutic strategies targeting adipocyte mitochondria. Adipocytes and, more generally, the adipose tissues are major actors in both obesity and the emergence of a cluster of associated diseases such as insulin resistance and type 2 diabetes mellitus (T2DM), cardiovascular diseases, hypertension, dyslipidemia, and even some cancers. Obesity and diabetes are now recognized as worldwide epidemics,1Smyth S Heron A Diabetes and obesity: the twin epidemics.Nat Med. 2006; 12: 75-80Crossref PubMed Scopus (162) Google Scholar with 1.6 billion people being overweight, of which 400 million are obese (body mass index ≥30) (World Health Organization, Geneva 2006). Attention for adipocytes has increased ever since it has been found that these differentiated cells are not only able to store and release triglycerides (TGs) but also have an important endocrine activity. Indeed, adipocytes secrete “adipokines” (specific hormones and proinflammatory cytokines) to communicate systemically with other cell types and thus, importantly, contribute to the regulation of energy homeostasis.2Ahima RS Adipose tissue as an endocrine organ.Obesity. 2006; 14: 242S-249SCrossref PubMed Scopus (278) Google Scholar Adipose tissue is present in different interacting depots in the body. In addition to white adipose tissue (WAT), brown adipose tissue (BAT) can also be distinguished.3Rossmeisl M Barbatelli G Flachs P Brauner P Zingaretti MC Marelli M Janovska P Horakova M Syrovy I Cinti S Kopecky J Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in unilocular adipocytes in vivo.Eur J Biochem. 2002; 269: 19-28Crossref PubMed Scopus (50) Google Scholar Although BAT originates from the myogenic lineage,4Seale 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: 961-967Crossref PubMed Scopus (530) Google Scholar it shares many features of WAT that are discussed in this review. Because WAT is by far the largest depot in humans and, as a metabolically active, lipid storage and endocrine organ, its proper functioning is essential for health maintenance and is of primary importance for pharmaceutical and food industries. A better understanding of the mechanisms involved in adipocyte differentiation, dedifferentiation (defined as the acquisition of a more primitive phenotype and gain of cell proliferative ability)5Matsumoto T Kano K Kondo D Fukuda N Iribe Y Tanaka N Matsubara Y Sakuma T Satomi A Otaki M Ryu J Mugishima H Mature adipocyte-derived dedifferentiated fat cells exhibit multilineage potential.J Cell Physiol. 2008; 215: 210-222Crossref PubMed Scopus (88) Google Scholar and even trans-differentiation (a process related to reversion of one cell phenotype into another, ie, from white to brown adipocytes,6Cinti S Adipocyte differentiation and transdifferentiation: plasticity of the adipose organ.J Endocrinol Invest. 2002; 25: 823-835Crossref PubMed Google Scholar, 7Morroni M Giordano A Zingaretti MC Boiani R De Matteis R Kahn BB Nisoli E Tonello C Pisoschi C Luchetti MM Marelli M Cinti S Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland.Proc Natl Acad Sci USA. 2004; 101: 16801-16806Crossref PubMed Scopus (41) Google Scholar which is still poorly experimentally documented), is required to unravel mechanisms underlying obesity and its symptomatic cohort of associated pathologies. This understanding may be used to develop new, original, and more effective therapeutic approaches that directly target intracellular pathways in adipocytes. Although the adipocyte differentiation program,8Rosen ED Spiegelman BM Adipocytes as regulators of energy balance and glucose homeostasis.Nature. 2006; 444: 847-853Crossref PubMed Scopus (627) Google Scholar as well as the activity/function and dys/malfunction of the endoplasmic reticulum (which play an important role in the adipocyte physiology) have been recently reviewed,9Gregor MG Hotamisligil GS Thematic review series: Adipocyte Biology Adipocyte stress: the endoplasmic reticulum and metabolic disease.J Lipid Res. 2007; 48: 1905-1914Crossref PubMed Scopus (237) Google Scholar the role of mitochondrial activity or dysfunction during preadipocyte differentiation and its consequences in mature adipocytes has hardly been addressed. Subcutaneous and visceral WATs have a different metabolic activity, depending on their anatomical position and mitochondrial content: epididymal (in the visceral depot) adipocytes are richer in mitochondria than inguinal (s.c.) adipocytes.10Deveaud C Beauvoit B Salin B Schaeffer J Rigoulet M Regional differences in oxidative capacity of rat white adipose tissue are linked to the mitochondrial content of mature adipocytes.Mol Cell Biochem. 2004; 267: 157-166Crossref PubMed Scopus (27) Google Scholar In addition, mitochondria play a key role in physiological processes and are involved in the pathology of many diseases.11Duchen MR Mitochondria in health and disease: perspectives on a new mitochondrial biology.Mol Aspects Med. 2004; 25: 365-451Crossref PubMed Scopus (288) Google Scholar In compiling knowledge on mitochondria in the context of adipose tissue, we hope to stimulate thoughts in regards to the impact of mitochondrial activity in adipocyte biology, the effects of mitochondrial dysfunction/stress on adipocytes, and the subsequent alterations of systemic metabolic functions. Mitochondria are usually described as the “powerhouse unit” of the cell, because they contain the molecular machinery that governs many distinct metabolic pathways by which chemical energy (coming from carbohydrates, lipids, and proteins) is converted into ATP. Indeed, it is in this organelle that pyruvate oxidation, fatty acid β-oxidation, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation (OXPHOS) take place.12Goldenthal MJ Marin-Garcia J Mitochondrial signaling pathways: a receiver/integrator organelle.Mol Cell Biochem. 2004; 262: 1-16Crossref PubMed Scopus (103) Google Scholar The essential role of mitochondria in bioenergetic aspects of the cell is supported by the dynamics of this organelle, which is controlled by fusion and fission events.13Detmer SA Chan DC Functions and dysfunctions of mitochondrial dynamics.Nat Rev Mol Cell Biol. 2007; 8: 870-879Crossref PubMed Scopus (375) Google Scholar In addition, eukaryotic cells have the ability to initiate adaptative responses to different environmental stimuli, such as modifications in energy demands, cell growth, cell death/stress or cell differentiation, by altering the number of mitochondria (enhanced or reduced mitochondrial biogenesis), changing their morphology, or remodeling the organization and distribution of mitochondria within the cell.14Li P Zhu Z Lu Y Granneman JG Metabolic and cellular plasticity in white adipose tissue II: role of peroxisome proliferator-activated receptor α.Am J Physiol Endocrinol Metab. 2005; 289: E617-E626Crossref PubMed Scopus (57) Google Scholar It is thus understandable that the “mitochondrion” (a word referring to the network and the ultrastructure of the organelle) is also dramatically affected during adipocyte differentiation. Indeed, undifferentiated adipoblasts undergo numerous and radical events, and the acquisition of the adipocyte phenotype is characterized by chronological and sequential changes in the activity of several transcription factors such as cAMP responsive element-binding protein (CREB), CCAAT/enhancer-binding protein (C/EBP) family members, and peroxisome proliferator-activated receptor γ (PPARγ), which control the expression of numerous genes encoding proteins and effectors involved in TG accumulation and other characteristics of differentiated adipocytes.15Rosen ED Spiegelman BM Molecular regulation of adipogenesis.Annu Rev Cell Dev Biol. 2000; 16: 145-171Crossref PubMed Scopus (666) Google Scholar The activity of the different transcription factors is sequentially turned on, and their transcriptional activation usually requires the participation of PPARγ coactivator 1 (PGC-1) and related proteins, major coactivators of nuclear receptors that regulate several components of energy metabolism involved in both adipogenesis and mitochondrial biogenesis.16Spiegelman BM Puigserver P Wu Z Regulation of adipogenesis and energy balance by PPARγ and PGC-1.Int J Obes Relat Metab Disord. 2000; 24: S8-S10Crossref PubMed Google Scholar The fact that the transcription factors PPARγ, C/EBPα, CREB, and estrogen-related receptor α (ERRα)17Ijichi N Ikeda K Horie-Inoue K Yagi K Okazaki Y Inoue S Estrogen-related receptor α modulates the expression of adipogenesis-related genes during adipocyte differentiation.Biochem Biophys Res Commun. 2007; 358: 813-818Crossref PubMed Scopus (26) Google Scholar and the gene expression coactivator PGC-1α16Spiegelman BM Puigserver P Wu Z Regulation of adipogenesis and energy balance by PPARγ and PGC-1.Int J Obes Relat Metab Disord. 2000; 24: S8-S10Crossref PubMed Google Scholar are induced in the control of both adipogenesis and mitochondrial biogenesis is a strong argument that supports coordination between the biogenesis of the organelle and energetic balance (Figure 1). In addition, a huge increase in the expression and/or abundance of numerous mitochondrial proteins is detectable in vitro in differentiating 3T3-L1 adipocytes within 4 days after induction of the differentiation program, and the enhanced biogenesis of the organelle is sustained up to 10 days postdifferentiation. The de novo mitochondrial biogenesis found during 3T3-L1 adipogenesis is accompanied by the remodeling of mitochondrion, ie, qualitative changes in mitochondrial composition as pyuvate carboxylase, aconitase, and enzymes involved in fatty acid metabolism, such as acyl-CoA synthetase and various forms of acyl-CoA dehydrogenase, are only expressed in adipocyte mitochondria.18Wilson-Fritch L Burkart A Bell G Mendelson K Leszyk J Nicoloro S Czech M Corvera S Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone.Mol Cell Biol. 2003; 23: 1085-1094Crossref PubMed Scopus (196) Google Scholar Besides, the increase in the basal rate of oxygen consumption in adipocytes compared with preadipocytes is a clear manifestation of an increased mitochondrial biogenesis during the adipogenic process.18Wilson-Fritch L Burkart A Bell G Mendelson K Leszyk J Nicoloro S Czech M Corvera S Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone.Mol Cell Biol. 2003; 23: 1085-1094Crossref PubMed Scopus (196) Google Scholar, 19Leonardsson G Steel JH Christian M Pocock V Milligan S Bell J So PW Medina-Gomez G Vidal-Puig A White R Parker MG Nuclear receptor corepressor RIP140 regulates fat accumulation.Proc Natl Acad Sci USA. 2004; 101: 8437-8442Crossref PubMed Scopus (199) Google Scholar, 20Powelka AM Seth A Virbasius JV Kiskinis E Nicoloro SM Guilherme A Tang X Straubhaar J Cherniack AD Parker MG Czech MP Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes.J Clin Invest. 2006; 116: 125-136Crossref PubMed Scopus (134) Google Scholar, 21Si 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: 826-836Crossref PubMed Scopus (19) Google Scholar, 22Wilson-Fritch L Nicoloro S Chouinard M Lazar MA Chui PC Leszyk J Straubhaar J Czech MP Corvera S Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone.J Clin Invest. 2004; 114: 1281-1289Crossref PubMed Scopus (253) Google Scholar Moreover, mitochondrial biogenesis during adipogenesis is thought to be a necessary adjustment, because the adipocyte differentiation program requires large amount of ATP when cells become fully metabolically active. More specifically, although biogenesis of mitochondria is stimulated during the differentiation program, ATP content decreases as a negative balance between production and consumption by high ATP-consuming processes such as lipogenesis.18Wilson-Fritch L Burkart A Bell G Mendelson K Leszyk J Nicoloro S Czech M Corvera S Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone.Mol Cell Biol. 2003; 23: 1085-1094Crossref PubMed Scopus (196) Google Scholar Furthermore, the connection between mitochondrial biogenesis, organelle function and adipocyte differentiation is best supported by treatment of adipocytes with rosiglitazone, a potent PPARγ agonist that causes significant alterations in mitochondrial density and morphology, suggesting that nucleus-encoded mitochondrial genes may be under the control of the adipogenic transcription factor PPARγ.22Wilson-Fritch L Nicoloro S Chouinard M Lazar MA Chui PC Leszyk J Straubhaar J Czech MP Corvera S Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone.J Clin Invest. 2004; 114: 1281-1289Crossref PubMed Scopus (253) Google Scholar The mitochondria might play a critical role in lipogenesis by providing key intermediates for the synthesis of TGs. More particularly, adipocytes must generate glycerol 3-phosphate at a sufficient rate to sustain TG synthesis; this generation is covered by a glyceroneogenic pathway and mitochondrial anaplerosis.23Franckhauser S Munoz S Pujol A Casellas A Riu E Otaegui P Su B Bosch F Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance.Diabetes. 2002; 51: 624-630Crossref PubMed Google Scholar, 24Olswang Y Cohen H Papo O Cassuto H Croniger CM Hakimi P Tilghman SM Hanson RW Reshef L A mutation in the peroxisome proliferator-activated receptor γ-binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice.Proc Natl Acad Sci USA. 2002; 99: 625-630Crossref PubMed Scopus (82) Google Scholar In addition, the generation of acetyl-CoA for fatty acid activation and synthesis before their esterification into TGs also requires an abundant mitochondrial population. Indeed, whereas the activation of long-chain fatty acids is shared with the endoplasmic reticulum, the mitochondrial matrix is the only place where medium-chain fatty acid activation occurs. Moreover, the outer mitochondrial membrane is also a site for phospholipid synthesis.25Bremer J Bjerve KS Borrebaek B Christiansen R The glycerophosphateacyltransferases and their function in the metabolism of fatty acids.Mol Cell Biochem. 1976; 12: 113-125Crossref PubMed Google Scholar Besides its role in lipogenesis, mitochondria of WAT also seem to be involved in the regulation of lipolysis. Indeed, in numerous cell types including adipocytes, fatty acids resulting from lipolysis are oxidized by the fatty acid β-oxidation cycle into the mitochondrial matrix compartment. This fatty acid oxidation constitutes an important source of energy for ATP production when energy needs increase. On the other hand, it has been long known that a decrease in intracellular ATP in white adipocytes induced by uncouplers or inhibitors of the mitochondrial respiratory chain can inhibit the lipolysis stimulated by catecholamines.26Fassina G Dorigo P Gaion RM Equilibrium between metabolic pathways producing energy: a key factor in regulating lipolysis.Pharmacol Res Commun. 1974; 6: 1-21Crossref PubMed Google Scholar Furthermore, lipolysis is now accepted to be a metabolic pathway that depends on the energy status of adipocytes as the activation of AMP-activated protein kinase, a central intracellular molecular sensor of energetic stress, can decrease the lipolysis stimulated by agonists of β-adrenoreceptors.27Daval M Diot-Dupuy F Bazin R Hainault I Viollet B Vaulont S Hajduch E Ferre P Foufelle F Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes.J Biol Chem. 2005; 280: 25250-25257Crossref PubMed Scopus (131) Google Scholar These data sets clearly show a direct link between lipolysis and the functional state of mitochondrial OXPHOS system in white adipocytes. Taken together, these data support the thesis that a reorganization of the mitochondrial population, its morphology, and abundance occurs during adipogenesis and is necessary to cover energy needs and lipid metabolism during the differentiation program. Consequently, because of numerous and key functions played by mitochondria during adipogenesis, impaired mitochondrial activity within preadipocytes and/or mature adipocytes could alter the physiology of WAT and thus might be reflected at the system level by affecting the molecular communication between adipocytes and other tissues such as muscle, liver, and brain.28Maasen JA Mitochondria, body fat and type 2 diabetes: what is the connection?.Minerva Med. 2008; 99: 241-251PubMed Google Scholar Mitochondrial dysfunction could result in acute cellular or systemic disruption, leading to the development of pathologies. Since mitochondrial proteins are encoded by both the mitochondrial DNA (mtDNA) and the nuclear DNA, mitochondrial diseases may thus result from mutations in both nuclear and mitochondrial genomes.29Wallace DC Mitochondrial diseases in man and mouse.Science. 1999; 283: 1482-1488Crossref PubMed Scopus (1858) Google Scholar It is well established that the mitochondrial genome displays a very high mutation rate (10 to 20 times higher than nuclear genome) because of the proximity of sites of reactive oxygen species (ROS) production, a histone-free packaging of DNA in nucleoids, and a less active and lower diversity in DNA repair enzymes.30Kujoth GC Bradshaw PC Haroon S Prolla TA The role of mitochondrial DNA mutations in mammalian aging.PLoS Genet. 2007; 3: e24Crossref PubMed Scopus (47) Google Scholar The major tissues affected by mitochondrial dysfunction are tissues with a high energy demand such as the brain, heart, muscles, and endocrine glands.31Chan DC Mitochondria: dynamic organelles in disease, aging, and development.Cell. 2006; 125: 1241-1252Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar In the past few years, it has been shown that reduced mitochondrial density and oxidative metabolism in various tissues is an early event in the complications that are associated with obesity,32Crunkhorn S Dearie F Mantzoros C Gami H da Silva WS Espinoza D Faucette R Barry K Bianco AC Patti ME Peroxisome proliferator activator receptor γ coactivator-1 expression is reduced in obesity: potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation.J Biol Chem. 2007; 282: 15439-15450Crossref PubMed Scopus (111) Google Scholar, 33Heilbronn LK Gan SK Turner N Campbell LV Chisholm DJ Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects.J Clin Endocrinol Metab. 2007; 92: 1467-1473Crossref PubMed Scopus (62) Google Scholar, 34Mootha VK Lindgren CM Eriksson KF Subramanian A Sihag S Lehar J Puigserver P Carlsson E Ridderstrale M Laurila E Houstis N Daly MJ Patterson N Mesirov JP Golub TR Tamayo P Spiegelman B Lander ES Hirschhorn JN Altshuler D Groop LC PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately down-regulated in human diabetes.Nat Genet. 2003; 34: 267-273Crossref PubMed Scopus (2065) Google Scholar, 35Semple RK Crowley VC Sewter CP Laudes M Christodoulides C Considine RV Vidal-Puig A O'Rahilly S Expression of the thermogenic nuclear hormone receptor coactivator PGC-1α is reduced in the adipose tissue of morbidly obese subjects.Int J Obes Relat Metab Disord. 2004; 28: 176-179Crossref PubMed Scopus (79) Google Scholar a phenomenon observed in both humans and rodents. Besides mitochondrial involvement in energy state deficiency-associated diseases, the malfunction of the organelle might also play a major role in pathologies that show modifications of lipid metabolism and/or energy partitioning. Indeed, a clear link between mitochondrial dysfunction and type I diabetes has been established; patients with mitochondrial diabetes often harbor mutations or deletions in mtDNA of pancreatic β-cells that lead to a defective insulin secretion, cell apoptosis, and eventually, a decrease in β-cell mass.36Lowell BB Shulman GI Mitochondrial dysfunction and type 2 diabetes.Science. 2005; 307: 384-387Crossref PubMed Scopus (823) Google Scholar A strong argument supporting a crucial role of mitochondrial dysfunction in T2DM in vivo is the fact that insulin resistance is often observed in elderly people with reduced OXPHOS activity as well as in obese individuals with increased risk for T2DM, which is supposed to be caused by high plasma free fatty acid concentrations.37Petersen KF Befroy D Dufour S Dziura J Ariyan C Rothman DL DiPietro L Cline GW Shulman GI Mitochondrial dysfunction in the elderly: possible role in insulin resistance.Science. 2003; 300: 1140-1142Crossref PubMed Scopus (973) Google Scholar Indeed, in adipocytes as in skeletal muscle, mitochondrial activity impairment is usually associated with reduced fatty acid β-oxidation, leading to an increase in cytosolic free fatty acid that alters glucose uptake.28Maasen JA Mitochondria, body fat and type 2 diabetes: what is the connection?.Minerva Med. 2008; 99: 241-251PubMed Google Scholar, 36Lowell BB Shulman GI Mitochondrial dysfunction and type 2 diabetes.Science. 2005; 307: 384-387Crossref PubMed Scopus (823) Google Scholar Central obesity accompanied by diabetes and hypertriglyceridemia with insulin resistance are also common features found in patients with nonalcoholic steatohepatitis, who suffer from mitochondrial injury characterized by increased lipid peroxidation, alterations in the mitochondrial ultrastructure, depletion in mtDNA, and low OXPHOS activity.38Pessayre D Fromenty B Mansouri A Mitochondrial injury in steatohepatitis.Eur J Gastroenterol Hepatol. 2004; 16: 1095-1105Crossref PubMed Scopus (84) Google Scholar Moreover, impaired mitochondrial activity has been reported for HIV-treated patients with highly active antiretroviral therapy (HAART) leading to lipodystrophy (ectopic fat storage). These metabolic complications induced by HAART are brought together in lipodystrophy syndrome, which is associated with peripheral lipoatrophy and an increase in the amount of visceral WAT and often accompanied by glucose homeostasis abnormalities and insulin resistance.39Falutz J Therapy insight: body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy.Nat Clin Pract Endocrinol Metab. 2007; 3: 651-661Crossref PubMed Scopus (23) Google Scholar A similar phenotype is also observed in old age. Of interest, engineered mice carrying a proof-reading-deficient version of POLγA, the nucleus-encoded catalytic subunit of mtDNA polymerase, develop a mtDNA mutator phenotype associated with reduced lifespan and premature onset of aging-related phenotypes, such as reduced s.c. fat and increased lipid accumulation in nonlipid tissues.40Trifunovic A Wredenberg A Falkenberg M Spelbrink JN Rovio AT Bruder CE Bohlooly YM Gidlof S Oldfors A Wibom R Tornell J Jacobs HT Larsson NG Premature ageing in mice expressing defective mitochondrial DNA polymerase.Nature. 2004; 429: 417-423Crossref PubMed Scopus (983) Google Scholar Interestingly, CREB, an ubiquitous transcription factor involved in numerous cellular functions such as cell survival, proliferation, and differentiation as well as glucose and lipid metabolism,41Reusch JE Klemm DJ Inhibition of cAMP-response element-binding protein activity decreases protein kinase B/Akt expression in 3T3-L1 adipocytes and induces apoptosis.J Biol Chem. 2002; 277: 1426-1432Crossref PubMed Scopus (51) Google Scholar, 42Zhou XY Shibusawa N Naik K Porras D Temple K Ou H Kaihara K Roe MW Brady MJ Wondisford FE Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.Nat Med. 2004; 10: 633-637Crossref PubMed Scopus (70) Google Scholar is a gene expression regulator that is activated in response to impaired mitochondrial activity in different cell lines such as L929, 143B, and PC12 cells.43Arnould T Vankoningsloo S Renard P Houbion A Ninane N Demazy C Remacle J Raes M CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation.EMBO J. 2002; 21: 53-63Crossref PubMed Scopus (108) Google Scholar, 44Beitner-Johnson D Millhorn DE Hypoxia induces phosphorylation of the cyclic AMP response element-binding protein by a novel signaling mechanism.J Biol Chem. 1998; 273: 19834-19839Crossref PubMed Scopus (102) Google Scholar, 45Beitner-Johnson D Rust RT Hsieh T Millhorn DE Regulation of CREB by moderate hypoxia in PC12 cells.Adv Exp Med Biol. 2000; 475: 143-152Crossref PubMed Google Scholar In 3T3-L1 preadipocytes, mitochondrial OXPHOS inhibitors as well as mitochondrial protein synthesis inhibitors impair respiration, leading to TG accumulation.46Vankoningsloo S Piens M Lecocq C Gilson A De Pauw A Renard P Demazy C Houbion A Raes M Arnould T Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid β-oxidation and glucose.J Lipid Res. 2005; 46: 1133-1149Crossref PubMed Scopus (58) Google Scholar Surprisingly, mitochondrial uncouplers such as FCCP (carbonyl cyanide p-trifluoromethoxy phenylhydrazone) do not induce TG accumulation in these cells, suggesting that different signaling pathways or second messengers are activated, depending on the type of mitochondrial alterations. Although TGs accumulate in preadipocytes treated with OXPHOS inhibitors, a process that might be induced by free fatty acid (re)esterification into TGs in the cytosol of cells that display impaired mitochondrial activity, they maintain a fibroblast phenotype and do not acquire adipogenic markers46Vankoningsloo S Piens M Lecocq C Gilson A De Pauw A Renard P Demazy C Houbion A Raes M Arnould T Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid β-oxidation and glucose.J Lipid Res. 2005; 46: 1133-1149Crossref PubMed Scopus (58) Google Scholar, 47Vankoningsloo S De Pauw A Houbion A Tejerina S Demazy C de Longueville F Bertholet V Renard P Remacle J Holvoet P Raes M Arnould T CREB activation induced by mitochondrial dysfunction triggers triglyceride accumulation in 3T3-L1 preadipocytes.J Cell Sci. 2006; 119: 1266-1282Crossref PubMed Scopus (47) Google Scholar(Figure 2). 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