References

vtio

Вестник трансплантологии и искусственных органов

Russian Journal of Transplantology and Artificial Organs

1995-1191

Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation

10.15825/1995-1191-2014-4-135-143

vtio-484

Research Article

ДИСКУССИИ

DISCUSSION

ТРАНСПЛАНТАЦИЯ ЖИРОВОЙ ТКАНИ С ЦЕЛЬЮ ЗАМЕСТИТЕЛЬНОЙ ТЕРАПИИ

TRANSPLANTATION OF ADIPOSE TISSUE AS A REPLACEMENT THERAPY

Абламуниц

В. Г.

Ablamunits

V. G.

194100, Санкт-Петербург, СПбГПМУ Минздрава России, Литовская ул., 2. Тел. +7 (921) 754-23-87

ablamuhin@gmail.com

Клебанов

С. Э.

Klebanov

S. E.

Кафедра микробиологии, вирусологии и иммунологии Санкт-Петербургского государственного педиатрического медицинского университета, Санкт Петербург, Российская ФедерацияРоссияDepartment of Microbiology, Virology and Immunology, Saint-Petersburg State Pediatric Medical University, St. Petersburg, Russian FederationRussian Federation

Госпиталь Св. Луки, Центр по изучению ожирения, Колумбийский университет, Нью-Йорк, СШАРоссияDepartment of Microbiology, Virology and Immunology, Saint-Petersburg State Pediatric Medical University, St. Petersburg, Russian Federation St. Luke’s Hospital, Obesity Research Center, Columbia University, New York, USARussian Federation

2014

15012015

164135143

2014

Абламуниц В.Г., Клебанов С.Э.

Ablamunits V.G., Klebanov S.E.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://journal.transpl.ru/vtio/article/view/484

Трансплантацию эндокринных органов и тканей часто рассматривают как альтернативу инъекционной заместительной терапии гормонами и другими недостающими факторами, имеющую целый ряд преимуществ. Накопившиеся в течение последних двух десятилетий сведения о жировой ткани как эндокринном органе, играющем важнейшую роль в ряде ключевых физиологических процессов, поднимают вопрос о целесообразности ее использования для трансплантаций с целью компенсации врожденных метаболических дефицитов. В данном обзоре приведены примеры факторов, секретируемых жировой тканью, недостаток которых может быть связан с теми или иными патологическими состояниями у человека. Рассмотрены практические аспекты трансплантаций жира, такие как доступность донорской ткани, ее чувствительность к отторжению, целесообразность иммуносупрессии и возможности создания немедикаментозной толерантности.

Transplantation of endocrine organs and tissues is often considered as an alternative therapy which has a number of advantages compared to regular injections for replacement of a missing hormone or another factor. During the last two decades, accumulating evidence demonstrates that adipose tissue is an endocrine organ that plays a pivotal role in the key physiological processes, and this raises a possibility of its potential use in transplantations aimed to correct inborn metabolic defi ciencies. In this review, we provide examples of the factors, secreted by adipose tissue, and which may be responsible for particular human pathologies when missing. We discuss practical aspects of fat transplantation, such as availability of donor tissue, its susceptibility to rejection, rationality of immune suppression, and possible ways to achieve medication-free tolerance.

трансплантацияжировая тканьадипокинытолерантность

transplantationadipose tissueadipokinestolerance

References1

Gold RH, Steinbach HL. Lipoatrophic diabetes mellitus (generalized lipodystrophy): roentgen fi ndings in two brothers with congenital disease. Am J Roentgenol Radium Ther Nucl Med. 1967 Dec; 101 (4): 884–896.

Seip M, Trygstad O. Generalized lipodystrophy, congenital and acquired (lipoatrophy). Acta Paediatr. 1996; Suppl 13: 2.

Pardini VC, Victoria IM, Rocha SM, Andrade DG, Rocha AM, Pieroni FB et al. Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J Clin Endocrinol Metab. 1998; 83: 503–508.

Moitra J, Mason M M, Olive M, Krylov D, Gavrilova O, Marcus-Samuels B et al. Life without white WAT: a transgenic mouse. Genes Dev. 1998, 12: 3168–3181.

Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000; 105: 271–278.

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372: 425–432.

Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature. 1999; 401: 73–76.

Colombo C, Cutson JJ, Yamauchi T, Vinson C, Kadowaki T, Gavrilova O et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes. 2002; 51: 2727–2733.

Chessler SD, Fujimoto WY, Shofer JB, Boyko EJ, Weigle DS. Increased plasma leptin levels are associated with fat accumulation in Japanese Americans. Diabetes. 1998; 47: 239–243.

Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998; 395: 763–770.

Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000; 62: 413–437.

Ingalis AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Hered. 1950; 41: 317.

Klebanov S, Astle CM, De Simon O, Ablamunits V, Harrison DE. Transplantation of normal adipose tissue to female ob/ob mice protects them from obesity, normalizes their insulin sensitivity and restores fertility. J Endocrinol. 2005; 186: 203–211.

Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obesity. 2002; 26: 1407–1433.

Proenca AR, Sertie RA, Oliveira AC, Campaaa AB, Caminhotto RO, Chimin P et al. New concepts in white adipose tissue physiology. Braz J Med Biol Res. 2014; 47: 192–205.

Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ et al. Congenital leptin defi ciency is associated with severe early-onset obesity in humans. Nature. 1997; 387: 903–908.

Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998; 3: 213–215.

Woods KA, Camacho-Hubner C, Clark AJL, Savage MO. Intrauterine growth retardation and postnatal growth failure associated with deletion of insulin-like growth factor I gene. New Engl J Med. 1996; 355: 1363–1367.

Bonapace G, Concolino D, Formicola S, Strisciuglio P. A novel mutation in a patient with insulin-like growth factor 1 (IGF1) defi ciency. J Med Genet. 2003; 40: 913– 917.

Ghiselli G, Schaefer EJ, Gascon P, Brewer HB, Jr. Type III hyperlipoproteinemia associated with apolipoprotein E defi ciency. Science. 1981; 214: 1239–1241.

Zannis VI, Breslow JL. Characterization of a unique human apolipoprotein E variant associated with type III hyperlipoproteinemia. J. Biol. Chem. 1980; 255: 1759– 1762.

Hayden MR, Ma Y. Molecular genetics of human lipoprotein lipase defi ciency. Mol Cell Biochem. 1992; 113: 171–176.

Dieval J, Nguyen G, Gross S, Delobel J, Kruithof EKO. A lifelong bleeding disorder associated with a defi ciency of plasminogen activator inhibitor type 1. Blood. 1991; 77: 528–532.

Billings E Jr, May JW Jr. Historical review and present status of free fat graft autotransplantation in plastic and reconstructive surgery. Plast Reconstr Surg. 1989; 83: 368–381.

Wyatt HR. The prevalence of obesity. Prim Care. 2003; 30: 267–279.

Fagan FD. Liposuction. An update on one of the most frequently performed and controversial surgeries. Can Oper Room Nurs J. 2001; 19: 22–24.

Billings E Jr, May JW Jr. Historical review and present status of free fat graft autotransplantation in plastic and reconstructive surgery. Plast Reconstr Surg. 1989; 83: 368–381.

Sommer B, Sattler G. Current concepts of fat graft survival: histology of aspirated adipose tissue and review of the literature. Dermatol Surg. 2000; 26: 1159–1166.

Hausberger FX. Behavior of transplanted adipose tissue of hereditary obese mice. Anat Rec. 1959; 135: 109–113.

Liebelt RA. Response of adipose tissue in experimental obesity as infl uenced by genetic, hormonal and neurogenic factors. Ann NY Acad Sci. 1963; 110: 723– 748.

Meade CJ, Ashwell M, Sowter C. Is genetically transmitted obesity due to an adipose tissue defect? Proc R Soc Lond B Biol Sci. 1979; 205: 395–410.

Ablamunits V, Goldstein AJ, Tovbina MH, Gaetz HP, Klebanov S. Acute rejection of white adipose tissue allograft. Cell Transplant. 2007; 16 (4): 375–390.

Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-defi cient mice have no mature B and T lymphocytes. Cell. 1992; 68: 869– 877.

Ablamunits V, Klebanov S, Giese SY, Herold KC. Functional human to mouse adipose tissue xenotransplantation. J Endocrinol. 2012 Jan; 212 (1): 41–47.

McDiarmid SV, Ettenger RB, Hawkins RA et al. The impairment of true glomerular fi ltration rate in longterm cyclosporine-treated pediatric allograft recipients. Transplantation. 1990; 49: 81–85.

Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal failure following liver transplantation: A retrospective analysis. Transplantation. 1998; 66: 59–66.

Stepkowski SM. Molecular targets for existing and novel immunosuppressive drugs. Expert Rev Mol Med. 2000, Jun 21: 1–23.

Min DI, Monaco AP. Complications associated with immunosuppressive therapy and their management. Pharmacotherapy. 1991; 11: 119S–125S.

Danesi R, Del Tacca M. Hematologic toxicity of immunosuppressive treatment. Transplant Proc. 2004; 36: 703–704.

Boitard C, Bach JF. Long term complications on conventional immunosuppressive treatment. Adv Nephrol. 1989; 18: 335–354.

Ferran C, Sheenan K, Dy M et al. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. Eur J Immunol. 1990; 20: 509–515.

Sgro C. Side effects of a monoclonal antibody, muromonab CD3/orthoclone OKT3: Bibliographic review. Toxicology. 1995; 105: 23–29.

Kupiec-Weglinski JW, Padberg W, Uhteg LC, Towpik E, Lord RH, Ma L et al. Anti-interleukin-2 receptor (IL- 2R) antibody against rejection of organ grafts. Transplant Proc. 1987; 19: 591–593.

Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature. 1996; 381: 434–437.

Qin S, Cobbold S, Benjamin R, Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989; 169: 779–794.

Newell KA, He G, Guo Z, Kim O, Szot GL, Rulifson I et al. Cutting edge: blockade of the CD28/B7 costimulatory pathway inhibits intestinal allograft rejection mediated by CD4+ but not CD8+ T cells. J Immunol. 1999; 163: 2358–2362.

Tinubu SA, Hakimi J, Kondas JA, Bailon P, Familletti PC, Spence C et al. Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival. J Immunol. 1994; 153: 4330–4338.

Thomas JM, Hubbard WJ, Sooudi SK, Thomas FT. STEALTH matters: a novel paradigm of durable primate allograft tolerance. Immunol Rev. 2001; 183: 223–233.

Laub R, Brecht R, Dorsch M, Valley U, Wenk K, Emmrich F. Anti-human CD4 induces peripheral tolerance in a human CD4+, murine CD4-, HLA-DR+ advanced transgenic mouse model. J Immunol. 2002; 169: 2947– 2955.

Kirk AD, Burkly LC, Batty DS, Baumgartner RE, Berring JD, Buchanan K et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med. 1999; 5: 686–690.

Gozzo JJ, Wood ML, Monaco AP. Use of allogenic, homozygous bone marrow cells for the induction of specifi c immunologic tolerance in mice treated with antilymphocyte serum. Surg Forum. 1970; 21: 281–284.

De Vries-van der Zwan A, Besseling AC, van Twuyver E, Boog CJP, de Waal LP. A substantial level of mixed chimerism is required for the induction of permanent transplantation tolerance. Transplant Immunol. 1996; 4: 232–240.

Wekerle T, Sykes M. Mixed chimerism and transplantation tolerance. Annu Rev Med. 2001; 52: 353–370.

Wekerle T, Blaha P, Koporc Z, Bigenzahn S, Pusch M, Muehlbacher F. Mechanisms of tolerance induction through the transplantation of donor hematopoietic stem cells: central versus peripheral tolerance. Transplantation. 2003; 75: 21S–25S.

Sharabi Y, Sachs DH. Mixed chimerism and permanent specifi c transplantation tolerance induced by a nonlethal preparative regimen. J Exp Med. 1989; 169: 493–502.

Down JD, Tarbell NJ, Thames HD, Mauch PM. Syngeneic and allogeneic bone marrow engraftment after total body irradiation: dependence on dose, dose rate, and fractionation. Blood. 1991; 77: 661–669.

Kripke ML. Antigenicity of murine skin tumors induced by ultraviolet light. J Natl Cancer Inst. 1974; 53: 1333–1336.

Aubin F, Mousson C. Ultraviolet light-induced regulatory (suppressor) T cells: an approach for promoting induction of operational allograft tolerance? Transplantation. 2004; 77 (1 Suppl): S29–31.

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299: 1057–1061.

Wang R, Wang-Zhu Y, Grey H. Interactions between double positive thymocytes and high affi nity ligands presented by cortical epithelial cells generate double negative thymocytes with T cell regulatory activity. Proc Natl Acad Sci U S A. 2002 Feb 19; 99 (4): 2181– 2186.

Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G. Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact- independent type 1-like regulatory T cells. J Exp Med. 2002; 196: 247–253.

Cosmi L, Liotta F, Lazzeri E, Francalanci M, Angeli R, Mazzinghi B et al. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood. 2003; 102: 4107–4114.

Liu J, Liu Z, Witkowski P, Vlad G, Manavalan JS, Scotto L et al. Rat CD8+ FOXP3+ T suppressor cells mediate tolerance to allogeneic heart transplants, inducing PIR-B in APC and rendering the graft invulnerable to rejection. Transpl Immunol. 2004; 13: 239–247.

Rivas JM, Ullrich SE. The role of IL-4, IL-10, and TNFalpha in the immune suppression induced by ultraviolet radiation. J Leukoc Biol. 1994; 56: 769–775.

Schwarz A, Beissert S, Grosse-Heitmeyer K, Gunzer M, Bluestone JA, Grabbe S et al. Evidence for functional relevance of CTLA-4 in ultraviolet-radiation-induced tolerance. J Immunol. 2000; 165: 1824–1831.

Tomimori Y, Ikawa Y, Oyaizu N. Ultraviolet-irradiated apoptotic lymphocytes produce interleukin-10 by themselves. Immunol Lett. 2000; 71: 49–54.

Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995; 270: 26746–26749.

Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med. 2002; 8: 731–737.

Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR et al. Adipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science. 1987; 237: 402–405.

White RT, Damm D, Hancock N, Rosen BS, Lowell BB, Usher P et al. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J Biol Chem. 1992; 267: 9210–9213.

Li Y, Totsune K, Takeda K, Furuyama K, Shibahara S, Takahashi K. Decreased expression of adrenomedullin during adipocyte-differentiation of 3T3-L1 cells. Hypertens Res. 2003; 26 Suppl: S41–44.

Shimosawa T, Ogihara T, Matsui H, Asano T, Ando K, Fujita T. Defi ciency of adrenomedullin induces insulin resistance by increasing oxidative stress. Hypertension. 2003; 41: 1080–1085.

Cassis LA, Saye J, Peach MJ. Location and regulation of rat angiotensinogen messenger RNA. Hypertension. 1988; 11 (6 Pt 2): 591–596.

Kim HS, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, Best CF et al. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci U S A. 1995; 92: 2735–2739.

Juge-Aubry CE, Somm E, Chicheportiche R, Burger D, Pernin A, Cuenod-Pittet B et al. Regulatory effects of interleukin (IL)-1, interferon-beta, and IL-4 on the production of IL-1 receptor antagonist by human adipose tissue. J Clin Endocrinol Metab. 2004; 89: 2652–2658.

Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A et al. Development of chronic infl ammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-defi cient mice. J Exp Med. 2000; 191: 313–320.

Chun HJ, Ali ZA, Kojima Y, Kundu RK, Sheikh AY, Agrawal R et al. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J Clin Invest. 2008; 118: 3343–3354.

Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, Verstuyft JG et al. Severe hypercholesterolemia and therosclerosis in apolipoprotein E-defi cient mice created by homologous recombination in ES cells. Cell. 1992; 71: 343–353.

Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992; 258: 468–471.

Kuipers F, Lin Y, Havinga R, Bloks V, Verkade HJ, Jong MC et al. Impaired production of very low ensity lipid proteins by apolipoprotein E-defi cient mouse hepatocytes in primary culture. J Clin Invest. 1997; 100: 2915–2922.

Murray I, Havel PJ, Sniderman AD, Cianfl one K. Reduced body weight, adipose tissue, and leptin levels despite increased energy intake in female mice lacking acylation-stimulating proten. Endocrinology. 2000; 141: 1041–1049.

Xia Z, Sniderman AD, Cianfl one K. Acylation-stimulating protein (ASP) defi ciency induces obesity resistance and increased energy expenditure in ob/ob mice. J Biol Chem. 2002; 277: 45874–45879.

Wada J. Vaspin: a novel serpin with insulin-sensitizing effects. Expert Opin Investig Drugs. 2008; 17: 327–333, doi: 10.1517/13543784.17.3.327.

Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K et al. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science. 2005; 307: 426–430.

Sawdey M, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specifi city and induction by lipopolysaccharide, tumor necrosis factor-α, and transforming growth factor-β. J Clin Invest. 1991; 88: 1346–1353.

Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J Clin Invest. 1996; 97: 37–46.

Carmeliet P, Stassen JM, Schoonjans L, Ream B, Van den Oord JJ, De Mol M et al. Plasminogen activator inhibitor- 1 gene-defi cient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest. 1993; 92: 2756–2760.

Doglio A, Dani C, Fredrikson G, Grimaldi P, Ailhaud G. Acute regulation of insulin-like growth factor-I gene expression by growth hormone during adipose cell differentiation. EMBO J. 1987; 6: 4011–4016.

Liu J-P, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF-I receptor (Igf1r). Cell. 1993; 75: 59–72.

Baker J, Hardy MP, Zhou J, Bondy C, Lupu F, Bellve AR et al. Effects of an IGF1 gene null mutation on mouse reproduction. Mol Endocrinol. 1996; 10: 903–918.

Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997; 82: 4196–4200.

Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T et al. Impaired immune and acute phase response in interleukin-6-defi cient mice. Nature. 1994; 368: 339–342.

Dalrymple SA, Slattery R, Aud DM, Krishna M, Lucian LA, and Murray R. Interleukin-6 is required for a protective immune response to systemic Escherichia coli infection. Infect. Immun. 1996; 64: 3231–3235.

Fried SK, DiGirolamo M. Lipoprotein lipase secretion from isolated rat fat cells of different size. Life Sci. 1986; 39: 2111–2119.

Coleman T, Seip RL, Gimble JM, Lee D, Maeda N, Semenkovich CF. COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity. J Biol Chem. 1995; 270: 12518–12525.

Weinstock PH, Bisgaier CL, Aalto-Setala K, Radner H, Ramakrishnan R, Levak-Frank S et al. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest. 1995; 96: 2555–2568.

McPherron AC, Lee SJ. Suppression of body fat accumulation in myostatin-defi cient mice. J Clin Invest. 2002; 109: 595–601.

Yang RZ, Lee MJ, Hu H, Pray J, Wu HB, Hansen BC et al. Identifi cation of omentin as a novel depot-specifi c adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab. 2006; 290: E1253–E1261.

Bradshaw AD, Graves DC, Motamed K, Sage EH. SPARC-null mice exhibit increased adiposity without signifi cant differences in overall body weight. Proc Natl Acad Sci U S A. 2003; 100: 6045–6050.

100

Smas CM, Sul HS. Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation. Cell. 1993; 73: 725–734.

101

Moon YS, Smas CM, Lee K, Villena JA, Kim KH, Yun EJ et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol Cell Biol. 2002; 22: 5585–5592.

102

Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY et al. The hormone resistin links obesity to diabetes. Nature. 2001; 409: 307–312.

103

Richardson RL, Campion DR, Hausman GJ, Wright JT. Transforming growth factor type beta (TGF-beta) and adipogenesis in pigs. J Anim Sci. 1989; 67: 2171– 2180.

104

Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC et al. Transforming growth factor beta 1 null mutation in mice causes excessive infl ammatory response and early death. Proc Natl Acad Sci U S A. 1993; 90: 770–774.

105

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science. 1993: 259: 87–91.

106

Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol. 2002; 168 (9): 4620–4627.

The authors declare that there are no conflicts of interest present.