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Mol Med. 1999 June; 5(6): 361–371.
PMCID: PMC2230432

Regulation of macrophage migration inhibitory factor (MIF) expression by glucose and insulin in adipocytes in vitro.

Abstract

BACKGROUND: It has been reported that macrophage migration inhibitory factor (MIF) stimulated insulin secretion from pancreatic islet beta-cells in an autocrine manner, which suggests its pivotal role in the glucose metabolism. According to this finding, we evaluated MIF expression in cultured adipocytes and epididymal fat pads of obese and diabetic rats to investigate its role in adipose tissue. MATERIALS AND METHODS: The murine adipocyte cell line 3T3-L1 was used to examine MIF mRNA expression and production of MIF protein in response to various concentrations of glucose and insulin. Epididymal fat pads of Otsuka Long-Evans Tokushima fatty (OLETF) and Wistar fatty rats, animal models of obesity and diabetes, were subjected to Northern blot analysis to determine MIF mRNA levels. RESULTS: MIF mRNA of 3T3-L1 adipocytes was up-regulated by costimulation with glucose and insulin. Intracellular MIF content was significantly increased by stimulation, whereas its content in the culture medium was decreased. When the cells were treated with cytochalasin B, MIF secretion in the medium was increased. Pioglitazone significantly increased MIF content in the culture medium of 3T3-L1 cells. However, MIF mRNA expression of both epididymal fat pads of OLETF and Wistar fatty rats was down-regulated despite a high plasma glucose level. The plasma MIF level of Wistar fatty rats was significantly increased by treatment with pioglitazone. CONCLUSION: We show here that the intracellular glucose level is critical to determining the MIF mRNA level as well as its protein content in adipose tissue. MIF is known to play an important role in glucose metabolism as a positive regulator of insulin secretion. In this context, it is conceivable that MIF may affect the pathophysiology of obesity and diabetes.

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  • Bloom BR, Bennett B. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science. 1966 Jul 1;153(3731):80–82. [PubMed]
  • David JR. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A. 1966 Jul;56(1):72–77. [PubMed]
  • Bernhagen J, Calandra T, Mitchell RA, Martin SB, Tracey KJ, Voelter W, Manogue KR, Cerami A, Bucala R. MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia. Nature. 1993 Oct 21;365(6448):756–759. [PubMed]
  • Calandra T, Bernhagen J, Mitchell RA, Bucala R. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med. 1994 Jun 1;179(6):1895–1902. [PMC free article] [PubMed]
  • Bacher M, Metz CN, Calandra T, Mayer K, Chesney J, Lohoff M, Gemsa D, Donnelly T, Bucala R. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7849–7854. [PubMed]
  • Bernhagen J, Bacher M, Calandra T, Metz CN, Doty SB, Donnelly T, Bucala R. An essential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction. J Exp Med. 1996 Jan 1;183(1):277–282. [PMC free article] [PubMed]
  • Calandra T, Bernhagen J, Metz CN, Spiegel LA, Bacher M, Donnelly T, Cerami A, Bucala R. MIF as a glucocorticoid-induced modulator of cytokine production. Nature. 1995 Sep 7;377(6544):68–71. [PubMed]
  • Bacher M, Meinhardt A, Lan HY, Mu W, Metz CN, Chesney JA, Calandra T, Gemsa D, Donnelly T, Atkins RC, et al. Migration inhibitory factor expression in experimentally induced endotoxemia. Am J Pathol. 1997 Jan;150(1):235–246. [PubMed]
  • Waeber G, Calandra T, Roduit R, Haefliger JA, Bonny C, Thompson N, Thorens B, Temler E, Meinhardt A, Bacher M, et al. Insulin secretion is regulated by the glucose-dependent production of islet beta cell macrophage migration inhibitory factor. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4782–4787. [PubMed]
  • Hirokawa J, Sakaue S, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J. Identification of macrophage migration inhibitory factor in adipose tissue and its induction by tumor necrosis factor-alpha. Biochem Biophys Res Commun. 1997 Jun 9;235(1):94–98. [PubMed]
  • 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 Dec 1;372(6505):425–432. [PubMed]
  • 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 Jan 1;97(1):37–46. [PMC free article] [PubMed]
  • Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993 Jan 1;259(5091):87–91. [PubMed]
  • Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996 Feb 2;271(5249):665–668. [PubMed]
  • Hotamisligil GS, Budavari A, Murray D, Spiegelman BM. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. J Clin Invest. 1994 Oct;94(4):1543–1549. [PMC free article] [PubMed]
  • Sakai M, Nishihira J, Hibiya Y, Koyama Y, Nishi S. Glutathione binding rat liver 13k protein is the homologue of the macrophage migration inhibitory factor. Biochem Mol Biol Int. 1994 Jun;33(3):439–446. [PubMed]
  • Nishihira J, Kuriyama T, Sakai M, Nishi S, Ohki S, Hikichi K. The structure and physicochemical properties of rat liver macrophage migration inhibitory factor. Biochim Biophys Acta. 1995 Feb 22;1247(1):159–162. [PubMed]
  • Sugimoto H, Suzuki M, Nakagawa A, Tanaka I, Fujinaga M, Nishihira J. Crystallization of rat liver macrophage migration inhibitory factor for MAD analysis. J Struct Biol. 1995 Nov-Dec;115(3):331–334. [PubMed]
  • Hirokawa J, Sakaue S, Furuya Y, Ishii J, Hasegawa A, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J. Tumor necrosis factor-alpha regulates the gene expression of macrophage migration inhibitory factor through tyrosine kinase-dependent pathway in 3T3-L1 adipocytes. J Biochem. 1998 Apr;123(4):733–739. [PubMed]
  • Suzuki H, Kanagawa H, Nishihira J. Evidence for the presence of macrophage migration inhibitory factor in murine reproductive organs and early embryos. Immunol Lett. 1996 Jul;51(3):141–147. [PubMed]
  • Makita H, Nishimura M, Miyamoto K, Nakano T, Tanino Y, Hirokawa J, Nishihira J, Kawakami Y. Effect of anti-macrophage migration inhibitory factor antibody on lipopolysaccharide-induced pulmonary neutrophil accumulation. Am J Respir Crit Care Med. 1998 Aug;158(2):573–579. [PubMed]
  • RODBELL M. METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. J Biol Chem. 1964 Feb;239:375–380. [PubMed]
  • Chen L, Alam T, Johnson JH, Hughes S, Newgard CB, Unger RH. Regulation of beta-cell glucose transporter gene expression. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4088–4092. [PubMed]
  • Suzuki K, Kono T. Evidence that insulin causes translocation of glucose transport activity to the plasma membrane from an intracellular storage site. Proc Natl Acad Sci U S A. 1980 May;77(5):2542–2545. [PubMed]
  • Ikeda H, Shino A, Matsuo T, Iwatsuka H, Suzuoki Z. A new genetically obese-hyperglycemic rat (Wistar fatty). Diabetes. 1981 Dec;30(12):1045–1050. [PubMed]
  • Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992 Nov;41(11):1422–1428. [PubMed]
  • Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995 May;95(5):2409–2415. [PMC free article] [PubMed]
  • Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4854–4858. [PubMed]
  • Ishida K, Mizuno A, Murakami T, Shima K. Obesity is necessary but not sufficient for the development of diabetes mellitus. Metabolism. 1996 Oct;45(10):1288–1295. [PubMed]
  • Murase K, Odaka H, Suzuki M, Tayuki N, Ikeda H. Pioglitazone time-dependently reduces tumour necrosis factor-alpha level in muscle and improves metabolic abnormalities in Wistar fatty rats. Diabetologia. 1998 Mar;41(3):257–264. [PubMed]
  • Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953–12956. [PubMed]
  • Hallakou S, Doaré L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, Dugail I, Morin J, Auwerx J, Ferré P. Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes. 1997 Sep;46(9):1393–1399. [PubMed]
  • Sugiyama Y, Shimura Y, Ikeda H. Effects of pioglitazone on hepatic and peripheral insulin resistance in Wistar fatty rats. Arzneimittelforschung. 1990 Apr;40(4):436–440. [PubMed]
  • Szalkowski D, White-Carrington S, Berger J, Zhang B. Antidiabetic thiazolidinediones block the inhibitory effect of tumor necrosis factor-alpha on differentiation, insulin-stimulated glucose uptake, and gene expression in 3T3-L1 cells. Endocrinology. 1995 Apr;136(4):1474–1481. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ