The role of LMNA in adipose: a novel mouse model of lipodystrophy based on the Dunnigan-type familial partial lipodystrophy mutation

We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance. We investigated the role of LMNA in adipose tissue by developing a novel mouse model of lipodystrophy. Transgenic mice were generated that express the LMNA mutation that causes familial partial lipodystrophy of the Dunnigan type (FPLD2). The phenotype observed in FPLD-transgenic mice resembles many of the features of human FPLD2, including lack of fat accumulation, insulin resistance, and enlarged, fatty liver. Similar to the human disease, FPLD-transgenic mice appear to develop normally, but after several weeks they are unable to accumulate fat to the same extent as their wild-type littermates. One poorly understood aspect of lipodystrophies is the mechanism of fat loss. To this end, we have examined the effects of the FPLD2 mutation on fat cell function. Contrary to the current literature, which suggests FPLD2 results in a loss of fat, we found that the key mechanism contributing to the lack of fat accumulation involves not a loss, but an apparent inability of the adipose tissue to renew itself. Specifically, preadipocytes are unable to differentiate into mature and fully functional adipocytes. These findings provide insights not only for the treatment of lipodystrophies, but also for the study of adipogenesis, obesity, and insulin resistance. Type 2 diabetes and insulin resistance are often associated with obesity. However, an extreme paucity of fat, as occurs in lipodystrophies, can also give rise to these syndromes (1Agarwal A.K. Garg A. Genetic basis of lipodystrophies and management of metabolic complications.Annu. Rev. Med. 2006; 57: 297-311Crossref PubMed Scopus (119) Google Scholar). Thus, it has become evident that adipose tissue mass plays a significant role in regulating whole body metabolism (2Rajala M.W. Scherer P.E. Minireview: The adipocyte–at the crossroads of energy homeostasis, inflammation, and atherosclerosis.Endocrinology. 2003; 144: 3765-3773Crossref PubMed Scopus (984) Google Scholar). Years of research have revealed many new genes and proteins that have been defined as having a key role in regulating adipose tissue metabolism. Despite these revelations, the function of many of these genes in adipose tissue is unclear. Mutations in the LMNA gene have been shown to cause Dunnigan-type familial partial lipodystrophy (FPLD2) (3Cao H. Hegele R.A. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy.Hum. Mol. Genet. 2000; 9: 109-112Crossref PubMed Scopus (577) Google Scholar). Approximately 90% of LMNA mutations that cause FPLD2 are localized to exon 8 and occur at amino acid 482 (4Jacob K.N. Garg A. Laminopathies: multisystem dystrophy syndromes.Mol. Genet. Metab. 2006; 87: 289-302Crossref PubMed Scopus (99) Google Scholar). FPLD2 patients present with a variety of clinical symptoms. The hallmark is a progressive loss of subcutaneous fat from the trunk and extremities, and accumulation of subcutaneous fat in the face and neck. The redistribution of adipose tissue is most apparent after puberty (5Garg A. Peshock R.M. Fleckenstein J.L. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety).J. Clin. Endocrinol. Metab. 1999; 84: 170-174PubMed Scopus (0) Google Scholar). The disease is also characterized by a host of metabolic complications, including insulin resistance, type 2 diabetes, dyslipidemia, and hepatic steatosis (6Hegele R.A. Cao H. Anderson C.M. Hramiak I.M. Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy.J. Clin. Endocrinol. Metab. 2000; 85: 3431-3435PubMed Google Scholar, 7Haque W.A. Vuitch F. Garg A. Post-mortem findings in familial partial lipodystrophy, Dunnigan variety.Diabet. Med. 2002; 19: 1022-1025Crossref PubMed Scopus (45) Google Scholar). LMNA (Lmna in mice) encodes for A-type lamins, including the major isoforms lamin A and C (8Lin F. Worman H.J. Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C.J. Biol. Chem. 1993; 268: 16321-16326Abstract Full Text PDF PubMed Google Scholar). They are produced via alternate splicing and share the first 566 amino acids. Mature lamin A is produced from the multi-step posttranslational processing of its precursor, prelamin A (9Corrigan D.P. Kuszczak D. Rusinol A.E. Thewke D.P. Hrycyna C.A. Michaelis S. Sinensky M.S. Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24.Biochem. J. 2005; 387: 129-138Crossref PubMed Scopus (145) Google Scholar, 10Sasseville A.M. Raymond Y. Lamin A precursor is localized to intranuclear foci.J. Cell Sci. 1995; 108: 273-285PubMed Google Scholar). Lamin A and C, along with other lamin proteins, are primarily localized underneath the inner nuclear membrane and help to form a meshwork called the nuclear lamina (11Aebi U. Cohn J. Buhle L. Gerace L. The nuclear lamina is a meshwork of intermediate-type filaments.Nature. 1986; 323: 560-564Crossref PubMed Scopus (685) Google Scholar). Like adipose tissue, the nuclear lamina was once thought to play a silent structural role but has since been demonstrated to have a more active role in regulating gene transcription and expression (12Hutchison C.J. Worman H.J. A-type lamins: guardians of the soma?.Nat. Cell Biol. 2004; 6: 1062-1067Crossref PubMed Scopus (175) Google Scholar, 13Moir R.D. Spann T.P. Goldman R.D. The dynamic properties and possible functions of nuclear lamins.Int. Rev. Cytol. 1995; 162B: 141-182PubMed Google Scholar). A-type lamins associate not only with the lamina, but are also distributed throughout the nuclear interior where they have been associated with a range of nuclear bodies, suggesting a role in transcription and RNA processing (14Hutchison C.J. Lamins: building blocks or regulators of gene expression?.Nat. Rev. Mol. Cell Biol. 2002; 3: 848-858Crossref PubMed Scopus (249) Google Scholar, 15Kennedy B.K. Barbie D.A. Classon M. Dyson N. Harlow E. Nuclear organization of DNA replication in primary mammalian cells.Genes Dev. 2000; 14: 2855-2868Crossref PubMed Scopus (249) Google Scholar). In addition, they have been reported to associate with a number of transcription factors, including retinoblastoma protein (16Ozaki T. Saijo M. Murakami K. Enomoto H. Taya Y. Sakiyama S. Complex formation between lamin A and the retinoblastoma gene product: identification of the domain on lamin A required for its interaction.Oncogene. 1994; 9: 2649-2653PubMed Google Scholar) and sterol response element binding protein 1 (SREBP1) (17Capanni C. Mattioli E. Columbaro M. Lucarelli E. Parnaik V.K. Novelli M. S. A processing is a mechanism to lipodystrophy.Hum. Mol. Genet. 2005; 14: PubMed Scopus Google Scholar, S. A novel between lamin A and for partial lipodystrophy and other Mol. Genet. 2002; PubMed Scopus Google Scholar). mutations in that cause FPLD2, are for at other to as They dystrophy and (4Jacob K.N. Garg A. Laminopathies: multisystem dystrophy syndromes.Mol. Genet. Metab. 2006; 87: 289-302Crossref PubMed Scopus (99) Google Scholar, J. Mutations in the LMNA gene encoding lamin 2000; PubMed Scopus Google Scholar, L. S. The nuclear Genet. Dev. 2003; PubMed Scopus Google Scholar). The of lamins in many cell and the of that from mutations in LMNA that lamin proteins have in (14Hutchison C.J. Lamins: building blocks or regulators of gene expression?.Nat. Rev. Mol. Cell Biol. 2002; 3: 848-858Crossref PubMed Scopus (249) Google Scholar, A. T. Goldman R.D. Y. Nuclear lamins, and Cell Biol. 2006; PubMed Scopus Google Scholar). can in a nuclear lamin protein in an adipose phenotype as The are unclear. In an to the role of LMNA in adipose tissue, we generated mice that in human lamin A or C the R482Q human In this we the phenotype of which a number of and clinical with the FPLD2 human Despite the of clinical for the human the mechanism of lipodystrophy and the role of LMNA in adipose and FPLD2 unclear. To this end, we have the effects of the FPLD2 mutation on fat cell function and found that appear to in are significant in of the of a FPLD2 and the role of LMNA in adipose provide insights not only into lipodystrophies, but also into the of adipose tissue and insulin resistance as it occurs in obesity. The fat expression of wild-type and lamin A or C were by the of as lamin was from Goldman in E. expression The lamin A/C was as a A was between the and and an was between the and to The lamin A was into a the and as J. M. D. L. E. T. M. a Dev. PubMed Scopus Google Scholar). The lamin A/C mutation was amino acid 482 from to an the wild-type or lamin A or C, and the and was of by and Transgenic mice were produced by into and by on DNA with and for the were the of or from a lamin were One lamin and a lamin C with the same R482Q FPLD2 is an and to only or mutations have been patients have been (3Cao H. Hegele R.A. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy.Hum. Mol. Genet. 2000; 9: 109-112Crossref PubMed Scopus (577) Google Scholar, R.A. Garg A. F. L. E. M. A.M. and of with familial partial lipodystrophy (Dunnigan mutations in the domain of lamin J. Genet. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). to the human disease as as for the study were for the at the were for were on a mice were a from fat from or a from fat as in were by the and was by cell protein was from of adipose tissue as was with in 1 of 1 and a A of was after The was at for in a The the and the was and the in and with a were at for and from were to membrane were in a of Lamin A and C proteins were with from was with mouse was and were by from human were a of and was as of was in and after The was for at and for in a at were with of to were by with were and at for was and the in were for at and cell were as in the body fat, and tissue were the for mice body was a at and to which mice were and were were by the of was from at the insulin was by and with a mice were body and was and at the after was with a were by the of as M. M. J. insulin in mice is associated with 2004; PubMed Scopus Google Scholar). were from fat by to the M. of fat of on metabolism and Biol. Chem. Full Text PDF PubMed Google Scholar) as by C. protein and in adipocytes. of with and Biol. Chem. Full Text PDF PubMed Google Scholar, C. protein and in adipocytes. Cell and in Biol. Chem. Full Text PDF PubMed Google Scholar) in the were for 1 at and a to The was for at to of from the and the was were in and of the were for at was and were in a were in for or for were for at was and for into the into the was by a for and PubMed Scopus Google Scholar) to C. 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L. K. of on and metabolism by Biol. 2005; PubMed Scopus Google Scholar, F. A. loss of adipose tissue to in the PubMed Scopus Google Scholar) and in with a of adipose precursor S. U. expression of and genes in human with insulin 2003; PubMed Scopus Google Scholar). the of fat including and fat were with mice fat in examined fat from mice from wild-type mice but not has been observed in human FPLD2 patients C.A. N. T. A. J.L. with familial partial lipodystrophy of the Dunnigan type to a LMNA mutation and Clin. Endocrinol. Metab. 2004; PubMed Scopus Google we mass in and wild-type mass was but in mice with wild-type the not as of body is not apparent is not as in the as it is in the human One is that expression of the FPLD2 as occurs in the the effects of the mutation in other as where it is not One was that expression of the of the was to cause the observed was on cell from Worman H.J. Nuclear lamin A for Dunnigan-type familial partial lipodystrophy.Hum. Mol. Genet. 2006; PubMed Scopus Google which that of wild-type lamin A to a FPLD2 To we generated a mouse in which expression of wild-type human lamin A. Thus, mice wild-type mouse and human lamin A. and that body of wild-type mice not from wild-type that expression of the lamin and not of wild-type lamin causes the In addition, we a of the from wild-type and found of steatosis not which is observed in with FPLD2 present with metabolic as insulin resistance, and fatty D. L. F. J. in with familial partial lipodystrophy (Dunnigan to a nuclear lamin A/C Metab. 2003; PubMed Scopus Google Scholar, W.A. K. A.M. A.K. Garg A. for diabetes in familial partial lipodystrophy, Dunnigan 2003; PubMed Scopus Google A. J. J. M. M. Worman H.J. steatosis in Dunnigan-type familial partial J. 2005; PubMed Scopus Google Scholar). 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These results that accumulation was in preadipocytes from They also that in in these To this we examined the expression of several of We found that expression of a fatty acid binding protein that is a of R.A. A. A is the primary of gene expression for in Sci. 87: PubMed Scopus Google from to in wild-type In expression of not in The between the were significant by of of and which is also to with of Rev. Cell Dev. Biol. 2000; PubMed Scopus Google of expression in with wild-type these appear not of the were to these results that preadipocytes from mice are unable to develop into mature and accumulate suggests that the major that mice unable to accumulate fat is an inability to a mature of adipocytes. One was that of expression in from in of expression of the LMNA the To this and that was in we expression of the human LMNA as as expression of mouse LMNA mouse LMNA was at with expression of human was expression of human LMNA in wild-type In mice expression of the human throughout The were from other at and These that expression of is to expression of the LMNA expression of of mouse LMNA with in from with a in wild-type and a in at of results are with in most fat LMNA expression with cell other fat an in LMNA expression by a at C.J. L. D. F. S. A. Lamin expression in human adipose in to and Clin. Endocrinol. Metab. 2002; 87: PubMed Scopus Google Scholar). the in expression of mouse LMNA are not between the the are The for these are not but mice to for the of LMNA by expression of wild-type mouse The results reported as the basis for lipodystrophy in is in to the current that suggests adipose tissue is the of the We have a mouse that an adipose form of lamin which causes FPLD2 in The observed in the mouse resembles many of the features of human lack of fat accumulation, insulin resistance, and an enlarged, fatty liver. The redistribution of fat in mice not appear to as defined as in FPLD2 patients fat primarily from the trunk and extremities, mice appear to have in fat is to in fat distribution in many have fat in expression M. L. V.K. of have effects on human Clin. PubMed Scopus Google Scholar, T. T. K. S. S. H. expression of and isoforms in human adipose PubMed Scopus Google Scholar). the fat redistribution that occurs in with human FPLD2, expression in their fat In addition, as gene expression fat T. N. T. Y. R.A. M. M. J. in primary and human J. 2002; PubMed Scopus Google Scholar). the that are most to in the gene and the most by the LMNA and these in mice Adipose tissue in FPLD2 patients The lipodystrophy at the of puberty with a loss of adipose tissue (5Garg A. Peshock R.M. Fleckenstein J.L. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety).J. Clin. Endocrinol. Metab. 1999; 84: 170-174PubMed Scopus (0) Google Scholar). mice appear to develop in the same the phenotype not at but at a suggests that puberty not for the phenotype to develop in The in phenotype also to the expression of the The most between with FPLD2 and mice to as diabetes, and disease occur more often in in D. L. F. J. in with familial partial lipodystrophy (Dunnigan to a nuclear lamin A/C Metab. 2003; PubMed Scopus Google Scholar, A. in the of metabolic in familial partial lipodystrophy (Dunnigan variety).J. Clin. Endocrinol. Metab. 2000; 85: PubMed Scopus (145) Google Scholar). We found the FPLD2 phenotype to more in mice in One that mice are more to mice M. C. S. N. M. D. Genetic the of diabetes and insulin resistance in 2004; PubMed Scopus Google Scholar, M. E. J. and E. is by of fat and in Scholar) and more to fat was the at which the phenotype on the with the with to body and insulin suggests that the FPLD2 phenotype the energy in or the energy with These or in fat distribution or the of the One key in human FPLD2 is the in fat distribution the metabolic or of fat is to other metabolic by the LMNA mouse model that to adipose tissue or by in metabolic current the of fat the metabolic mass in mice to from wild-type weeks of The metabolic appear after this at weeks of and not appear significant after weeks of also that in other mouse of lipodystrophy, as the and mouse J. M. D. L. E. T. M. a Dev. PubMed Scopus Google Scholar, S. K. J. J. S. R.A. is of adipose Clin. PubMed Scopus Google Scholar, S. M.S. 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L. Scherer P.E. of a new mouse model of and Med. 2005; PubMed Scopus Google Scholar). These that functional after of treatment that causes their However, has shown that treatment more the effects were not fully suggesting can is that we not factors, other which the FPLD2 is in and the LMNA is by an it was not that it was in adipose tissue and was is to the that express of with M.S. The fatty protein is required in Clin. 2006; PubMed Scopus Google Scholar). One is that and adipose cell to the lack of fat this mechanism not a major to the phenotype it help to the phenotype where D. M. M. is associated with accumulation in adipose Clin. 2003; PubMed Scopus Google Scholar, H. D. C.J. J. A. in fat plays a role in the of insulin Clin. 2003; PubMed Scopus Google Scholar). mutations in lamin A to One from by (17Capanni C. Mattioli E. Columbaro M. Lucarelli E. Parnaik V.K. Novelli M. S. A processing is a mechanism to lipodystrophy.Hum. Mol. Genet. 2005; 14: PubMed Scopus Google Scholar). They have shown that prelamin the form of lamin is at a and in FPLD2 In addition, they that a transcription that with prelamin A. of prelamin A at the nuclear its to the nuclear These were with mice have accumulation of prelamin which and it from the of other transcription that as and accumulation of prelamin A was observed in are to this is a mechanism in The to for with and and for the and for human for for with mouse and for in the wild-type

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