Pref-1 and ADSF/Resistin: Two Secreted Factors Inhibiting Adipose Tissue Development

Abstract

Adipose tissue is the source of a wide array of factors of great biological significance that are involved in many aspects of organism physiology, including appetite control and peripheral metabolism. Here, we describe two secreted factors from adipose tissue that inhibit adipogenesis. Pref-1 is a preadipocyte secreted factor synthesized as a transmembrane protein that undergoes proteolitic cleavage to generate two distinct soluble forms. In vitro assays have demonstrated that only the large soluble form of Pref-1 is biologically active and inhibits adipocyte differentiation. In vivo, mice lacking Pref-1 expression show accelerated fat deposition, perinatal mortality and growth retardation as well as distinct skeletal malformations, highlighting the importance of Pref-1 during mouse development in addition to its role in adipose tissue development. ADSF/resistin is secreted by adipocytes and inhibits adipose cells differentiation in vitro. Its function is still unclear, but its expression and high circulating levels have been associated with an impairment of insulin action. The findings show that Pref-1 and possibly ADSF/resistin secretion control fat cell differentiation and adipose tissue development.

Dlk1 - Preadipocyte - Adipocyte Differentiation - Obesity - Uniparental Disomy - Insulin Resistance

References

• 1 Ahima R S, Flier J S. Leptin.  Annu Rev Physiol. 2000;  62 413-437
• 2 Hotamisligil G S, Shargill N S, Spiegelman B M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
• 3 Mohamed-Ali V, Goodrick S, Rawesh A, Katz D R, Miles J M, Yudkin J S, Klein S, Coppack S W. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.  J Clin Endocrinol Metab. 1997;  82 4196-4200
• 4 Gerhardt C C, Romero I A, Cancello R, Camoin L, Strosberg A D. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes.  Mol Cell Endocrinol. 2001;  175 81-92
• 5 White R T, Damm D, Hancock N, Rosen B S, Lowell B B, Usher P, Flier J S, Spiegelman B M. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue.  J Biol Chem. 1992;  267 9210-9213
• 6 Choy L N, Rosen B S, Spiegelman B M. Adipsin and an endogenous pathway of complement from adipose cells.  J Biol Chem. 1992;  267 12 736-12 741
• 7 Cianflone K, Maslowska M. Differentiation-induced production of ASP in human adipocytes.  Eur J Clin Invest. 1995;  25 817-825
• 8 Scherer P E, Williams S, Fogliano M, Baldini G, Lodish H F. A novel serum protein similar to C1q, produced exclusively in adipocytes.  J Biol Chem. 1995;  270 26 746-26 749
• 9 Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity.  Biochem Biophys Res Commun. 1999;  257 79-83
• 10 Stephens J M, Pekala P H. Transcriptional repression of the C/EBP-alpha and GLUT4 genes in 3T3-L1 adipocytes by tumor necrosis factor-alpha. Regulations is coordinate and independent of protein synthesis.  J Biol Chem. 1992;  267 13 580-13 584
• 11 Hube F, Hauner H. The role of TNF-alpha in human adipose tissue: prevention of weight gain at the expense of insulin resistance?.  Horm Metab Res. 1999;  31 626-631
• 12 Fruebis J, Tsao T S, Javorschi S, Ebbets-Reed D, Erickson M R, Yen F T, Bihain B E, Lodish H F. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.  Proc Natl Acad Sci USA. 2001;  98 2005-2010
• 13 Stefan N, Stumvoll M. Adiponectin - its role in metabolism and beyond.  Horm Metab Res. 2002;  34 469-474
• 14 Hill J O, Peters J C. Environmental contributions to the obesity epidemic.  Science. 1998;  280 1371-1374
• 15 Comuzzie A G, Allison D B. The search for human obesity genes.  Science. 1998;  280 1374-1377
• 16 Rangwala S M, Lazar M A. Transcriptional control of adipogenesis.  Annu Rev Nutr. 2000;  20 535-559
• 17 Rosen E D, Spiegelman B M. Molecular regulation of adipogenesis.  Annu Rev Cell Dev Biol. 2000;  16 145-171
• 18 Gregoire F M, Smas C M, Sul H S. Understanding adipocyte differentiation.  Physiol Rev. 1998;  78 783-809
• 19 Zhao L, Gregoire F, Sook S ul. Transient induction of ENC-1, a Kelch-related actin-binding protein, is required for adipocyte differentiation.  J Biol Chem. 2000;  275 16 845-16 850
• 20 Smas C M, Sul H S. Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation.  Cell. 1993;  73 725-734
• 21 Tax F E, Yeargers J J, Thomas J H. Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with delta and serrate of Drosophila. .  Nature. 1994;  368 150-154
• 22 Smas C M, Chen L, Sul H S. Cleavage of membrane-associated pref-1 generates a soluble inhibitor of adipocyte differentiation.  Mol Cell Biol. 1997;  17 977-988
• 23 Mei B, Zhao L, Chen L, Sul H S. Only the large soluble form of preadipocyte factor-1 (Pref-1), but not the small soluble and membrane forms, inhibits adipocyte differentiation: role of alternative splicing.  Biochem J. 2002;  364 137-144
• 24 Smas C M, Kachinskas D, Liu C M, Xie X, Dircks L K, Sul H S. Transcriptional control of the pref-1 gene in 3T3-L1 adipocyte differentiation. Sequence requirement for differentiation-dependent suppression.  J Biol Chem. 1998;  273 31 751-31 758
• 25 Smas C M, Chen L, Zhao L, Latasa M J, Sul H S. Transcriptional repression of pref-1 by glucocorticoids promotes 3T3-L1 adipocyte differentiation.  J Biol Chem. 1999;  274 12 632-12 641
• 26 Garces C, Ruiz-Hidalgo M J, Bonvini E, Goldstein J, Laborda J. Adipocyte differentiation is modulated by secreted delta-like (dlk) variants and requires the expression of membrane-associated dlk.  Differentiation. 1999;  64 103-114
• 27 Jensen C H, Krogh T N, Hojrup P, Clausen P P, Skjodt K, Larsson L I, Enghild J J, Teisner B. Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growth-factor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2.  Eur J Biochem. 1994;  225 83-92
• 28 Floridon C, Jensen C H, Thorsen P, Nielsen O, Sunde L, Westergaard J G, Thomsen S G, Teisner B. Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation.  Differentiation. 2000;  66 49-59
• 29 Bachmann E, Krogh T N, Hojrup P, Skjodt K, Teisner B. Mouse fetal antigen 1 (mFA1), the circulating gene product of mdlk, pref-1 and SCP-1: isolation, characterization and biology.  J Reprod Fertil. 1996;  107 279-285
• 30 Carlsson C, Tornehave D, Lindberg K, Galante P, Billestrup N, Michelsen B, Larsson L I, Nielsen J H. Growth hormone and prolactin stimulate the expression of rat preadipocyte factor-1/delta-like protein in pancreatic islets: molecular cloning and expression pattern during development and growth of the endocrine pancreas.  Endocrinology. 1997;  138 3940-3948
• 31 Kaneta M, Osawa M, Sudo K, Nakauchi H, Farr A G, Takahama Y. A role for pref-1 and HES-1 in thymocyte development.  J Immunol. 2000;  164 256-264
• 32 Halder S K, Takemori H, Hatano O, Nonaka Y, Wada A, Okamoto M. Cloning of a membrane-spanning protein with epidermal growth factor-like repeat motifs from adrenal glomerulosa cells.  Endocrinology. 1998;  139 3316-3328
• 33 Moon Y S, Smas C M, Lee K, Villena J A, Kim K H, Yun E J, Sul H S. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity.  Mol Cell Biol. 2002;  22 5585-5592
• 34 Schmidt J V, Matteson P G, Jones B K, Guan X J, Tilghman S M. The Dlk1 and Gtl2 genes are linked and reciprocally imprinted.  Genes Dev. 2000;  14 1997-2002
• 35 Takada S, Tevendale M, Baker J, Georgiades P, Campbell E, Freeman T, Johnson M H, Paulsen M, Ferguson-Smith A C. Delta-like and gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12.  Curr Biol. 2000;  10 1135-1138
• 36 Wylie A A, Murphy S K, Orton T C, Jirtle R L. Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/ H19 regulation.  Genome Res. 2000;  10 1711-1718
• 37 Charlier C, Segers K, Wagenaar D, Karim L, Berghmans S, Jaillon O, Shay T, Weissenbach J, Cockett N, Gyapay G, Georges M. Human-ovine comparative sequencing of a 250-kb imprinted domain encompassing the callipyge (clpg) locus and identification of six imprinted transcripts: DLK1, DAT, GTL2, PEG11, antiPEG11, and MEG8.  Genome Res. 2001;  11 850-862
• 38 Georgiades P, Watkins M, Surani M A, Ferguson-Smith A C. Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12.  Development. 2000;  127 4719-4728
• 39 Berends M J, Hordijk R, Scheffer H, Oosterwijk J C, Halley D J, Sorgedrager N. Two cases of maternal uniparental disomy 14 with a phenotype overlapping with the Prader-Willi phenotype.  Am J Med Genet. 1999;  84 76-79
• 40 Fokstuen S, Ginsburg C, Zachmann M, Schinzel A. Maternal uniparental disomy 14 as a cause of intrauterine growth retardation and early onset of puberty.  J Pediatr. 1999;  134 689-695
• 41 Hordijk R, Wierenga H, Scheffer H, Leegte B, Hofstra R M, Stolte-Dijkstra I. Maternal uniparental disomy for chromosome 14 in a boy with a normal karyotype.  J Med Genet. 1999;  36 782-785
• 42 Manzoni M F, Pramparo T, Stroppolo A, Chiaino F, Bosi E, Zuffardi O, Carrozzo R. A patient with maternal chromosome 14 UPD presenting with a mild phenotype and MODY.  Clin Genet. 2000;  57 406-408
• 43 Kim K H, Lee K, Moon Y S, Sul H S. A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation.  J Biol Chem. 2001;  276 11 252-11 256
• 44 Steppan C M, Bailey S T, Bhat S, Brown E J, Banerjee R R, Wright C M, Patel H R, Ahima R S, Lazar M A. The hormone resistin links obesity to diabetes.  Nature. 2001;  409 307-312
• 45 Holcomb I N, Kabakoff R C, Chan B, Baker T W, Gurney A, Henzel W, Nelson C, Lowman H B, Wright B D, Skelton N J, Frantz G D, Tumas D B, Peale F V, Shelton D L, Hebert C C. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family.  EMBO J. 2000;  19 4046-4055
• 46 Steppan C M, Brown E J, Wright C M, Bhat S, Banerjee R R, Dai C Y, Enders G H, Silberg D G, Wen X, Wu G D, Lazar M A. A family of tissue-specific resistin-like molecules.  Proc Natl Acad Sci U S A. 2001;  98 502-506
• 47 Bing C, Gomez-Ambrosi J, Zabalegui N, Williams G, Trayhurn P. Resistin and RELM-alpha gene expression in white adipose tissue of lactating mice.  Biochem Biophys Res Commun. 2002;  296 458
• 48 Rajala M W, Lin Y, Ranalletta M, Yang X M, Qian H, Gingerich R, Barzilai N, Scherer P E. Cell type-specific expression and coregulation of murine resistin and resistin-Like molecule-alpha in adipose tissue.  Mol Endocrinol. 2002;  16 1920-1930
• 49 Blagoev B, Kratchmarova I, Nielsen M M, Fernandez M M, Voldby J, Andersen J S, Kristiansen K, Pandey A, Mann M. Inhibition of adipocyte differentiation by Resistin like molecule alpha (RELM alpha): Biochemical characterization of its oligomeric nature.  J Biol Chem. 2002;  19 19
• 50 Banerjee R R, Lazar M A. Dimerization of resistin and resistin-like molecules is determined by a single cysteine.  J Biol Chem. 2001;  276 25 970-25 973
• 51 Way J M, Gorgun C Z, Tong Q, Uysal K T, Brown K K, Harrington W W, Oliver W R, Willson T M, Kliewer S A, Hotamisligil G S. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists.  J Biol Chem. 2001;  276 25 651-25 653
• 52 Fukui Y, Motojima K. Expression of resistin in the adipose tissue is modulated by various factors including peroxisome proliferator-activated receptor alpha.  Diabetes Obes Metab. 2002;  4 342-345
• 53 McTernan C L, McTernan P G, Harte A L, Levick P L, Barnett A H, Kumar S. Resistin, central obesity, and type 2 diabetes.  Lancet. 2002;  359 46-47
• 54 McTernan P G, McTernan C L, Chetty R, Jenner K, Fisher F M, Lauer M N, Crocker J, Barnett A H, Kumar S. Increased resistin gene and protein expression in human abdominal adipose tissue.  J Clin Endocrinol Metab. 2002;  87 2407
• 55 Janke J, Engeli S, Gorzelniak K, Luft F C, Sharma A M. Resistin gene expression in human adipocytes is not related to insulin resistance.  Obes Res. 2002;  10 1-5
• 56 Savage D B, Sewter C P, Klenk E S, Segal D G, Vidal-Puig A, Considine R V, O'Rahilly S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans.  Diabetes. 2001;  50 2199-2202
• 57 Juan C C, Au L C, Fang V S, Kang S F, Ko Y H, Kuo S F, Hsu Y P, Kwok C F, Ho L T. Suppressed gene expression of adipocyte resistin in an insulin-resistant rat model probably by elevated free fatty acids.  Biochem Biophys Res Commun. 2001;  289 1328-1333
• 58 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Tumor necrosis factor alpha is a negative regulator of resistin gene expression and secretion in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2001;  288 1027-1031
• 59 Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Isoproterenol inhibits resistin gene expression through a G(S)-protein-coupled pathway in 3T3-L1 adipocytes.  FEBS Lett. 2001;  500 60-63
• 60 Delhanty P J, Mesotten D, McDougall F, Baxter R C. Growth hormone rapidly induces resistin gene expression in white adipose tissue of spontaneous dwarf (SDR) rats.  Endocrinology. 2002;  143 2445-2448
• 61 Zhong Q, Lin C, Clarke K, Kemppainen R, Schwartz D, Judd R. Endothelin-1 inhibits resistin secretion in 3T3-L1 adipocytes.  Biochem Biophys Res Commun. 2002;  296 383