Adipose Tissue Hypoxia in Obesity and Its Impact on Adipocytokine Dysregulation

Diabetes - Tập 56 Số 4 - Trang 901-911 - 2007
Naomi Hosogai1, Atsunori Fukuhara1, Kazuya Oshima1, Yugo Miyata1, Sachiyo Tanaka1, Kouji Segawa1, Shigetada Furukawa1, Yoshihiro Tochino1, Ryutaro Komuro1, Morihiro Matsuda1, Iichiro Shimomura1
1From the Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

Tóm tắt

Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress–mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.

Từ khóa


Tài liệu tham khảo

Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K, Tokunaga K, Matsuzawa Y: Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 2: 800–803,1996

Matsuzawa Y, Funahashi T, Nakamura T: Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substances. Ann N Y Acad Sci 892: 146–154,1999

Hotamisligil GS, Spiegelman BM: TNF-α: a key component of the obesity-diabetes link. Diabetes 43: 1271–1278,1994

Berg AH, Combs TP, Scherer PE: ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13: 84–89,2002

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

Kahn BB, Flier JS: Obesity and insulin resistance. J Clin Invest 106: 473–481,2000

Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7: 941–946,2001

Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y: Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 8: 731–737,2002

Trayhurn P: Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand 184: 285–293,2005

Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K: cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 221: 286–289,1996

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 257: 79–83,1999

Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y: Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20: 1595–1599,2000

Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y: Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96: 1723–1732,2000

Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N, Nagasawa A, Funahashi T, Matsuzawa Y: Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 109: 2046–2049,2004

Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y: Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106: 2767–2770,2002

Brook CG, Lloyd JK, Wolf OH: Relation between age of onset of obesity and size and number of adipose cells. Br Med J 2: 25–27,1972

Helmlinger G, Yuan F, Dellian M, Jain RK: Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3: 177–182,1997

Semenza GL: HIF-1 and human disease: one highly involved factor. Genes Dev 14: 1983–1991,2000

Semenza GL: Surviving ischemia: adaptive responses mediated by hypoxia-inducible factor 1. J Clin Invest 106: 809–812,2000

Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, Harding H, Novoa I, Varia M, Raleigh J, Scheuner D, Kaufman RJ, Bell J, Ron D, Wouters BG, Koumenis C: ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. Embo J 24: 3470–3481,2005

Kaufman RJ: Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 13: 1211–1233,1999

Mori K: Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101: 451–454,2000

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306: 457–461,2004

Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka TA, Ozawa K, Ogawa S, Hori M, Yamasaki Y, Matsuhisa M: Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem 280: 847–851,2005

Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I: Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52: 1655–1663,2003

Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415: 92–96,2002

Gitlin L, Karelsky S, Andino R: Short interfering RNA confers intracellular antiviral immunity in human cells. Nature 418: 430–434,2002

Varia MA, Calkins-Adams DP, Rinker LH, Kennedy AS, Novotny DB, Fowler WC Jr, Raleigh JA: Pimonidazole: a novel hypoxia marker for complementary study of tumor hypoxia and cell proliferation in cervical carcinoma. Gynecol Oncol 71: 270–277,1998

Arteel GE, Thurman RG, Yates JM, Raleigh JA: Evidence that hypoxia markers detect oxygen gradients in liver: pimonidazole and retrograde perfusion of rat liver. Br J Cancer 72: 889–895,1995

Ron D, Habener JF: CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev 6: 439–453,1992

Park SK, Oh SY, Lee MY, Yoon S, Kim KS, Kim JW: CCAAT/enhancer binding protein and nuclear factor-Y regulate adiponectin gene expression in adipose tissue. Diabetes 53: 2757–2766,2004

Semenza GL: Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8: 588–594,1998

Wellen KE, Hotamisligil GS: Inflammation, stress, and diabetes. J Clin Invest 115: 1111–1119,2005

Di Girolamo M, Skinner NS, Jr, Hanley HG, Sachs RG: Relationship of adipose tissue blood flow to fat cell size and number. Am J Physiol 220: 932–937,1971

Digirolamo M, Esposito J: Adipose tissue blood flow and cellularity in the growing rabbit. Am J Physiol 229: 107–112,1975

West DB, Prinz WA, Francendese AA, Greenwood MR: Adipocyte blood flow is decreased in obese Zucker rats. Am J Physiol 253: R228–R233,1987

Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ: Adipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci U S A 99: 10730–10735,2002

Brakenhielm E, Cao R, Gao B, Angelin B, Cannon B, Parini P, Cao Y: Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice. Circ Res 94: 1579–1588,2004

Franko AJ, Chapman JD: Binding of 14C-misonidazole to hypoxic cells in V79 spheroids. Br J Cancer 45: 694–699,1982

Maxwell AP, MacManus MP, Gardiner TA: Misonidazole binding in murine liver tissue: a marker for cellular hypoxia in vivo. Gastroenterology 97: 1300–1303,1989

Gross MW, Karbach U, Groebe K, Franko AJ, Mueller-Klieser W: Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids. Int J Cancer 61: 567–573,1995

Mizock BA, Falk JL: Lactic acidosis in critical illness. Crit Care Med 20: 80–93,1992

Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ: Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3′ enhancer. Proc Natl Acad Sci U S A 91: 6496–6500,1994

Virtanen KA, Lonnroth P, Parkkola R, Peltoniemi P, Asola M, Viljanen T, Tolvanen T, Knuuti J, Ronnemaa T, Huupponen R, Nuutila P: Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J Clin Endocrinol Metab 87: 3902–3910,2002

Jansson PA, Larsson A, Smith U, Lonnroth P: Glycerol production in subcutaneous adipose tissue in lean and obese humans. J Clin Invest 89: 1610–1617,1992

Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, Koromilas A, Wouters BG: Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2alpha. Mol Cell Biol 22: 7405–7416,2002

Carriere A, Carmona MC, Fernandez Y, Rigoulet M, Wenger RH, Penicaud L, Casteilla L: Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation: a mechanism for hypoxia-dependent effect. J Biol Chem 279: 40462–40469,2004

Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL: Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood 103: 1876–1882,2004

Feldman DE, Chauhan V, Koong AC: The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res 3: 597–605,2005

McGary EC, Rondon IJ, Beckman BS: Post-transcriptional regulation of erythropoietin mRNA stability by erythropoietin mRNA-binding protein. J Biol Chem 272: 8628–8634,1997

McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S: Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 267: H1921–H1927,1994

Sachs AB: Messenger RNA degradation in eukaryotes. Cell 74: 413–421,1993