Hostname: page-component-745bb68f8f-cphqk Total loading time: 0 Render date: 2025-01-30T01:24:48.011Z Has data issue: false hasContentIssue false
  • English
  • Français

Molecular mechanisms controlling human adipose tissue development: insights from monogenic lipodystrophies

Published online by Cambridge University Press:  02 August 2010

Justin J. Rochford
Justin J. Rochford
Affiliation:
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Addenbrookes Hospital, Hills Road Cambridge, Cambridge CB2 0QQ, UK. E-mail: jjr30@cam.ac.uk
Get access Rights & Permissions [Opens in a new window]

Abstract

Appropriately functioning adipose tissue is essential for human health, a fact most clearly illustrated by individuals with lipodystrophy, who have impaired adipose development and often suffer severe metabolic disease as a result. Humans with obesity display a similar array of metabolic problems. This reflects failures in fat tissue function in obesity, which results in consequences similar to those seen when insufficient adipose tissue is present. Thus a better understanding of the molecules that regulate the development of fat tissue is likely to aid the generation of novel therapeutic strategies for the treatment of all disorders of altered fat mass. Single gene disruptions causing lipodystrophy can give unique insights into the importance of the proteins they encode in human adipose tissue development. Moreover, the mechanisms via which they cause lipodystrophy can reveal new molecules and pathways important for adipose tissue development and function as well as confirming the importance of molecules identified from studies of cellular and animal models.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e24
Copyright
Copyright © Cambridge University Press 2010

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Garg, A. and Agarwal, A.K. (2009) Lipodystrophies: disorders of adipose tissue biology. Biochimica et Biophysica Acta 1791, 507-513CrossRefGoogle ScholarPubMed
2Hayashi, Y.K. et al. (2009) Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. The Journal of Clinical Investigation 119, 2623-2633CrossRefGoogle ScholarPubMed
3Hegele, R.A. et al. (2007) Thematic review series: adipocyte biology. Lipodystrophies: windows on adipose biology and metabolism. Journal of Lipid Research 48, 1433-1444CrossRefGoogle ScholarPubMed
4Rubio-Cabezas, O. et al. (2009) Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Molecular Medicine 1, 280-287Google Scholar
5Agarwal, A.K. and Garg, A. (2006) Genetic disorders of adipose tissue development, differentiation, and death. Annual Review of Genomics and Human Genetics 7, 175-199CrossRefGoogle ScholarPubMed
6Mallewa, J.E. et al. (2008) HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. The Journal of Antimicrobial Chemotherapy 62, 648-660CrossRefGoogle ScholarPubMed
7Villarroya, F., Domingo, P. and Giralt, M. (2007) Lipodystrophy in HIV 1-infected patients: lessons for obesity research. International Journal of Obesity 31, 1763-1776CrossRefGoogle ScholarPubMed
8Waki, H. and Tontonoz, P. (2007) Endocrine functions of adipose tissue. Annual Review of Pathology 2, 31-56Google Scholar
9Guo, Y. et al. (2009) Lipid droplets at a glance. Journal of Cell Science 122, 749-752CrossRefGoogle ScholarPubMed
10Brasaemle, D.L. (2007) Thematic review series: adipocyte biology. The perilipin family of structural lipid droplet proteins: stabilization of lipid droplets and control of lipolysis. Journal of Lipid Research 48, 2547-2559Google Scholar
11Ducharme, N.A. and Bickel, P.E. (2008) Lipid droplets in lipogenesis and lipolysis. Endocrinology 149, 942-949CrossRefGoogle ScholarPubMed
12Lefterova, M.I. and Lazar, M.A. (2009) New developments in adipogenesis. Trends in Endocrinology and Metabolism 20, 107-114Google Scholar
13Rosen, E.D. and MacDougald, O.A. (2006) Adipocyte differentiation from the inside out. Nature Reviews. Molecular Cell Biology 7, 885-896Google Scholar
14White, U.A. and Stephens, J.M. (2010) Transcriptional factors that promote formation of white adipose tissue. Molecular and Cellular Endocrinology 318, 10-14CrossRefGoogle ScholarPubMed
15Savage, D.B. (2009) Mouse models of inherited lipodystrophy. Disease Models and Mechanisms 2, 554-562CrossRefGoogle ScholarPubMed
16Savage, D.B., Petersen, K.F. and Shulman, G.I. (2007) Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiological Reviews 87, 507-520CrossRefGoogle ScholarPubMed
17Unger, R.H. and Scherer, P.E. (2010) Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends in Endocrinology and Metabolism 21, 345-352CrossRefGoogle ScholarPubMed
18Virtue, S. and Vidal-Puig, A. (2010) Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome – an allostatic perspective. Biochimica et Biophysica Acta 1801, 338-349CrossRefGoogle ScholarPubMed
19Spalding, K.L. et al. (2008) Dynamics of fat cell turnover in humans. Nature 453, 783-787CrossRefGoogle ScholarPubMed
20Kissebah, A.H. and Krakower, G.R. (1994) Regional adiposity and morbidity. Physiological Reviews 74, 761-811CrossRefGoogle ScholarPubMed
21Snijder, M.B. et al. (2003) Associations of hip and thigh circumferences independent of waist circumference with the incidence of type 2 diabetes: the Hoorn Study. The American Journal of Clinical Nutrition 77, 1192-1197CrossRefGoogle ScholarPubMed
22Tran, T.T. et al. (2008) Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metabolism 7, 410-420Google Scholar
23Tchkonia, T. et al. (2006) Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes 55, 2571-2578CrossRefGoogle ScholarPubMed
24Tran, T.T. and Kahn, C.R. (2010) Transplantation of adipose tissue and stem cells: role in metabolism and disease. Nature Reviews. Endocrinology 6, 195-213Google Scholar
25Simha, V. and Garg, A. (2003) Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes. The Journal of Clinical Endocrinology and Metabolism 88, 5433-5437CrossRefGoogle ScholarPubMed
26Kim, C.A. et al. (2008) Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. The Journal of Clinical Endocrinology and Metabolism 93, 1129-1134CrossRefGoogle ScholarPubMed
27Pearce, L.R., Komander, D. and Alessi, D.R. (2010) The nuts and bolts of AGC protein kinases. Nature Reviews. Molecular Cell Biology 11, 9-22Google Scholar
28Tontonoz, P. and Spiegelman, B.M. (2008) Fat and beyond: the diverse biology of PPARgamma. Annual Review of Biochemistry 77, 289-312CrossRefGoogle ScholarPubMed
29Shackleton, S. et al. (2000) LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature Genetics 24, 153-156Google Scholar
30Hegele, R.A. et al. (2000) Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Research 10, 652-658Google Scholar
31Hegele, R.A. et al. (2000) Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy. The Journal of Clinical Endocrinology and Metabolism 85, 3431-3435Google ScholarPubMed
32Cao, H. and Hegele, R.A. (2000) Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Human Molecular Genetics 9, 109-112CrossRefGoogle ScholarPubMed
33Worman, H.J. and Bonne, G. (2007) “Laminopathies”: a wide spectrum of human diseases. Experimental Cell Research 313, 2121-2133CrossRefGoogle ScholarPubMed
34Dechat, T. et al. (2008) Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes and Development 22, 832-853CrossRefGoogle ScholarPubMed
35Agarwal, A.K. et al. (2003) Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Human Molecular Genetics 12, 1995-2001CrossRefGoogle ScholarPubMed
36Pendas, A.M. et al. (2002) Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nature Genetics 31, 94-99CrossRefGoogle ScholarPubMed
37Lloyd, D.J., Trembath, R.C. and Shackleton, S. (2002) A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies. Human Molecular Genetics 11, 769-777CrossRefGoogle ScholarPubMed
38Kim, J.B. and Spiegelman, B.M. (1996) ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes and Development 10, 1096-1107CrossRefGoogle ScholarPubMed
39Kim, J.B. et al. (1998) ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proceedings of the National Academy of Sciences of the United States of America 95, 4333-4337Google Scholar
40Bengoechea-Alonso, M.T. and Ericsson, J. (2007) SREBP in signal transduction: cholesterol metabolism and beyond. Current Opinion in Cell Biology 19, 215-222Google Scholar
41Capanni, C. et al. (2003) Failure of lamin A/C to functionally assemble in R482L mutated familial partial lipodystrophy fibroblasts: altered intermolecular interaction with emerin and implications for gene transcription. Experimental Cell Research 291, 122-134Google Scholar
42Capanni, C. et al. (2005) Altered pre-lamin A processing is a common mechanism leading to lipodystrophy. Human Molecular Genetics 14, 1489-1502Google Scholar
43Boguslavsky, R.L., Stewart, C.L. and Worman, H.J. (2006) Nuclear lamin A inhibits adipocyte differentiation: implications for Dunnigan-type familial partial lipodystrophy. Human Molecular Genetics 15, 653-663CrossRefGoogle ScholarPubMed
44Classon, M. et al. (2000) Opposing roles of pRB and p107 in adipocyte differentiation. Proceedings of the National Academy of Sciences of the United States of America 97, 10826-10831Google Scholar
45Barak, Y. et al. (1999) PPAR gamma is required for placental, cardiac, and adipose tissue development. Molecular Cell 4, 585-595CrossRefGoogle ScholarPubMed
46Rosen, E.D. et al. (1999) PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Molecular Cell 4, 611-617CrossRefGoogle ScholarPubMed
47Jeninga, E.H., Gurnell, M. and Kalkhoven, E. (2009) Functional implications of genetic variation in human PPARgamma. Trends in Endocrinology and Metabolism 20, 380-387CrossRefGoogle ScholarPubMed
48Lefterova, M.I. et al. (2008) PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes and Development 22, 2941-2952CrossRefGoogle Scholar
49Nielsen, R. et al. (2008) Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. Genes and Development 22, 2953-2967Google Scholar
50Semple, R.K., Chatterjee, V.K. and O'Rahilly, S. (2006) PPAR gamma and human metabolic disease. The Journal of Clinical Investigation 116, 581-589Google Scholar
51Chao, L. et al. (2000) Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. The Journal of Clinical Investigation 106, 1221-1228CrossRefGoogle Scholar
52He, W. et al. (2003) Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences of the United States of America 100, 15712-15717Google Scholar
53Hevener, A.L. et al. (2003) Muscle-specific Pparg deletion causes insulin resistance. Nature Medicine 9, 1491-1497Google Scholar
54Guan, H.P. et al. (2002) A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nature Medicine 8, 1122-1128Google Scholar
55Medina-Gomez, G., Gray, S. and Vidal-Puig, A. (2007) Adipogenesis and lipotoxicity: role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1). Public Health Nutrition 10, 1132-1137Google Scholar
56Yamauchi, T. et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 7, 941-946CrossRefGoogle ScholarPubMed
57Yamauchi, T. et al. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Medicine 8, 1288-1285Google Scholar
58Kawai, T. et al. (1999) Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 48, 1102-1107Google Scholar
59Kelly, I.E. et al. (1999) Effects of a thiazolidinedione compound on body fat and fat distribution of patients with type 2 diabetes. Diabetes Care 22, 288-293CrossRefGoogle ScholarPubMed
60Mori, Y. et al. (1999) Effect of troglitazone on body fat distribution in type 2 diabetic patients. Diabetes Care 22, 908-1012Google Scholar
61George, S. et al. (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325-1328Google Scholar
62Johnson, L.N., Noble, M.E. and Owen, D.J. (1996) Active and inactive protein kinases: structural basis for regulation. Cell 85, 149-158CrossRefGoogle ScholarPubMed
63Yang, J. et al. (2002) Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Natural Structural Biology 9, 940-944CrossRefGoogle ScholarPubMed
64Cho, H. et al. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728-1731Google Scholar
65Garofalo, R.S. et al. (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. The Journal of Clinical Investigation 112, 197-208Google Scholar
66Peng, X.D. et al. (2003) Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes and Development 17, 1352-1365Google Scholar
67Yun, S.J. et al. (2008) Isoform-specific regulation of adipocyte differentiation by Akt/protein kinase Balpha. Biochemical and Biophysical Research Communications 371, 138-143Google Scholar
68Bouzakri, K. et al. (2006) siRNA-based gene silencing reveals specialized roles of IRS-1/Akt2 and IRS-2/Akt1 in glucose and lipid metabolism in human skeletal muscle. Cell Metabolism 4, 89-96Google Scholar
69Barthel, A. et al. (2001) Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. Biochemical and Biophysical Research Communications 285, 897-902CrossRefGoogle ScholarPubMed
70Liao, J. et al. (1998) Activation of protein kinase B/Akt is sufficient to repress the glucocorticoid and cAMP induction of phosphoenolpyruvate carboxykinase gene. The Journal of Biological Chemistry 273, 27320-27324CrossRefGoogle ScholarPubMed
71Bae, S.S. et al. (2003) Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. The Journal of Biological Chemistry 278, 49530-49536Google Scholar
72Jiang, Z.Y. et al. (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proceedings of the National Academy of Sciences of the United States of America 100, 7569-7574Google Scholar
73Larance, M. et al. (2005) Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. The Journal of Biological Chemistry 280, 37803-37813CrossRefGoogle ScholarPubMed
74Miinea, C.P. et al. (2005) AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. The Biochemical Journal 391, 87-93Google Scholar
75Ng, Y. et al. (2008) Rapid activation of Akt2 is sufficient to stimulate GLUT4 translocation in 3T3-L1 adipocytes. Cell Metabolism 7, 348-356Google Scholar
76Giorgino, F., Laviola, L. and Eriksson, J.W. (2005) Regional differences of insulin action in adipose tissue: insights from in vivo and in vitro studies. Acta Physiologica Scandinavica 183, 13-30CrossRefGoogle ScholarPubMed
77Gerin, I. et al. (2009) On the role of FOX transcription factors in adipocyte differentiation and insulin-stimulated glucose uptake. The Journal of Biological Chemistry 284, 10755-10763CrossRefGoogle ScholarPubMed
78Nakae, J. et al. (2003) The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Developmental Cell 4, 119-129CrossRefGoogle ScholarPubMed
79Wolfrum, C. et al. (2003) Role of Foxa-2 in adipocyte metabolism and differentiation. The Journal of Clinical Investigation 112, 345-356CrossRefGoogle ScholarPubMed
80Davis, K.E., Moldes, M. and Farmer, S.R. (2004) The forkhead transcription factor FoxC2 inhibits white adipocyte differentiation. The Journal of Biological Chemistry 279, 42453-42461CrossRefGoogle ScholarPubMed
81Krycer, J.R. et al. (2010) The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends in Endocrinology and Metabolism 21, 268-276Google Scholar
82Jiang, Z.Y. et al. (2005) Identification of WNK1 as a substrate of Akt/protein kinase B and a negative regulator of insulin-stimulated mitogenesis in 3T3-L1 cells. The Journal of Biological Chemistry 280, 21622-21628Google Scholar
83Levine, A.J. et al. (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes and Development 20, 267-275CrossRefGoogle ScholarPubMed
84Inohara, N. et al. (1998) CIDE, a novel family of cell death activators with homology to the 45 kDa subunit of the DNA fragmentation factor. The EMBO Journal 17, 2526-2533Google Scholar
85Li, J.Z. et al. (2007) Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation. Diabetes 56, 2523-2532Google Scholar
86Zhou, Z. et al. (2003) Cidea-deficient mice have lean phenotype and are resistant to obesity. Nature Genetics 35, 49-56Google Scholar
87Danesch, U., Hoeck, W. and Ringold, G.M. (1992) Cloning and transcriptional regulation of a novel adipocyte-specific gene, FSP27. CAAT-enhancer-binding protein (C/EBP) and C/EBP-like proteins interact with sequences required for differentiation-dependent expression. The Journal of Biological Chemistry 267, 7185-7193CrossRefGoogle Scholar
88Nishino, N. et al. (2008) FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. The Journal of Clinical Investigation 118, 2808-2821Google Scholar
89Toh, S.Y. et al. (2008) Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of fsp27 deficient mice. PLoS One 3, e2890Google Scholar
90Keller, P. et al. (2008) Fat-specific protein 27 regulates storage of triacylglycerol. The Journal of Biological Chemistry 283, 14355-14365Google Scholar
91Puri, V. et al. (2007) Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. The Journal of Biological Chemistry 282, 34213-34218Google Scholar
92Nian, Z. et al. (2010) Fat-specific protein 27 undergoes ubiquitin-dependent degradation regulated by triacylglycerol synthesis and lipid droplet formation. The Journal of Biological Chemistry 285, 9604-9615Google Scholar
93Magre, J. et al. (2001) Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nature Genetics 28, 365-370CrossRefGoogle ScholarPubMed
94Payne, V.A. et al. (2008) The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation. Diabetes 57, 2055-2060CrossRefGoogle ScholarPubMed
95Agarwal, A.K. and Garg, A. (2004) Seipin: a mysterious protein. Trends in Molecular Medicine 10, 440-444Google Scholar
96Ito, D. et al. (2008) Characterization of seipin/BSCL2, a protein associated with spastic paraplegia 17. Neurobiology of Disease 31, 266-277Google Scholar
97Lundin, C. et al. (2006) Membrane topology of the human seipin protein. FEBS Letters 580, 2281-2284Google Scholar
98Miranda, D.M. et al. (2009) Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome. Clinical Endocrinology 71, 512-517Google Scholar
99Van Maldergem, L. et al. (2002) Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. Journal of Medical Genetics 39, 722-733CrossRefGoogle ScholarPubMed
100Windpassinger, C. et al. (2004) Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nature Genetics 36, 271-276CrossRefGoogle ScholarPubMed
101Antuna-Puente, B. et al. (2010) Higher adiponectin levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3-phosphate-o-acyltransferase-2 deficiency. The Journal of Clinical Endocrinology and Metabolism 95, 1463-1468Google Scholar
102Szymanski, K.M. et al. (2007) The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proceedings of the National Academy of Sciences of the United States of America 104, 20890-20895Google Scholar
103Fei, W. et al. (2008) Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast. Journal of Cell Biology 180, 473-482Google Scholar
104Chen, W. et al. (2009) The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin plays a key role in adipocyte differentiation. Endocrinology 150, 4552-4561Google Scholar
105Boutet, E. et al. (2009) Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy. Biochimie 91, 796-803Google Scholar
106Paton, C.M. and Ntambi, J.M. (2009) Biochemical and physiological function of stearoyl-CoA desaturase. American Journal of Physiology. Endocrinology and Metabolism 297, E28-E37Google Scholar
107Agarwal, A.K. et al. (2002) AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nature Genetics 31, 21-23Google Scholar
108Shindou, H. and Shimizu, T. (2009) Acyl-CoA:lysophospholipid acyltransferases. The Journal of Biological Chemistry 284, 1-5Google Scholar
109Takeuchi, K. and Reue, K. (2009) Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. American Journal of Physiology. Endocrinology and Metabolism 296, E1195-E1209Google Scholar
110Gale, S.E. et al. (2006) A regulatory role for 1-acylglycerol-3-phosphate-O-acyltransferase 2 in adipocyte differentiation. The Journal of Biological Chemistry 281, 11082-11089CrossRefGoogle ScholarPubMed
111Hollenback, D. et al. (2006) Substrate specificity of lysophosphatidic acid acyltransferase beta – evidence from membrane and whole cell assays. Journal of Lipid Research 47, 593-604Google Scholar
112Coon, M. et al. (2003) Inhibition of lysophosphatidic acid acyltransferase beta disrupts proliferative and survival signals in normal cells and induces apoptosis of tumor cells. Molecular Cancer Therapeutics 2, 1067-1078Google Scholar
113La Rosee, P. et al. (2006) Antileukemic activity of lysophosphatidic acid acyltransferase-beta inhibitor CT32228 in chronic myelogenous leukemia sensitive and resistant to imatinib. Clinical Cancer Research 12, 6540-6546Google Scholar
114Carrasco, S. and Merida, I. (2007) Diacylglycerol, when simplicity becomes complex. Trends Biochem Sci 32, 27-36Google Scholar
115Guo, Y. et al. (2008) Functional genomic screen reveals genes involved in lipid-droplet formation and utilization. Nature 453, 657-661CrossRefGoogle ScholarPubMed
116Cortes, V.A. et al. (2009) Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metabolism 9, 165-176Google Scholar
117Cohen, A.W. et al. (2004) Role of caveolae and caveolins in health and disease. Physiological Reviews 84, 1341-1379Google Scholar
118Fan, J.Y. et al. (1983) Morphological changes of the 3T3-L1 fibroblast plasma membrane upon differentiation to the adipocyte form. Journal of Cell Science 61, 219-230CrossRefGoogle Scholar
119Le Lay, S. et al. (2009) Filling up adipocytes with lipids. Lessons from caveolin-1 deficiency. Biochimica et Biophysica Acta 1791, 514-518Google Scholar
120Razani, B. et al. (2002) Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. The Journal of Biological Chemistry 277, 8635-8647Google Scholar
121Drab, M. et al. (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293, 2449-2452CrossRefGoogle ScholarPubMed
122Ring, A. et al. (2006) Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. Biochimica et Biophysica Acta 1761, 416-423Google Scholar
123Le Lay, S. et al. (2006) Cholesterol-induced caveolin targeting to lipid droplets in adipocytes: a role for caveolar endocytosis. Traffic 7, 549-561Google Scholar
124Blouin, C.M. et al. (2008) Regulated association of caveolins to lipid droplets during differentiation of 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications 376, 331-335Google Scholar
125Blouin, C.M. et al. (2010) Lipid droplet analysis in caveolin-deficient adipocytes: alterations in surface phospholipid composition and maturation defects. Journal of Lipid Research 51, 945-956Google Scholar
126Brasaemle, D.L. et al. (2004) Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes. The Journal of Biological Chemistry 279, 46835-46842Google Scholar
127Cohen, A.W. et al. (2004) Role of caveolin-1 in the modulation of lipolysis and lipid droplet formation. Diabetes 53, 1261-1270Google Scholar
128Cohen, A.W. et al. (2003) Role of caveolin and caveolae in insulin signaling and diabetes. American Journal of Physiology. Endocrinology and Metabolism 285, E1151-E1160Google Scholar
129Fruhbeck, G., Lopez, M. and Dieguez, C. (2007) Role of caveolins in body weight and insulin resistance regulation. Trends in Endocrinology and Metabolism 18, 177-182Google Scholar
130Liu, L. et al. (2008) Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metabolism 8, 310-317Google Scholar
131Hill, M.M. et al. (2008) PTRF-Cavin, a conserved cytoplasmic protein required for caveola formation and function. Cell 132, 113-124Google Scholar
132Koh, Y.K. et al. (2008) Lipin1 is a key factor for the maturation and maintenance of adipocytes in the regulatory network with CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma 2. The Journal of Biological Chemistry 283, 34896-34906Google Scholar

Further reading

Garg, A. and Agarwal, A.K. (2009) Lipodystrophies: disorders of adipose tissue biology. Biochimica et Biophysica Acta 1791, 507-513Google Scholar
Hayashi, Y.K. et al. (2009) Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. The Journal of Clinical Investigation 119, 2623-2633Google Scholar
Rubio-Cabezas, O. et al. (2009) Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Molecular Medicine 1, 280-287Google Scholar
Unger, R.H. and Scherer, P.E. (2010) Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends in Endocrinology and Metabolism 21, 345-352Google Scholar
Lefterova, M.I. and Lazar, M.A. (2009) New developments in adipogenesis. Trends in Endocrinology and Metabolism, 20, 107-114Google Scholar
Tran, T.T. et al. (2008) Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metabolism 7, 410-420Google Scholar