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J. Biol. Chem., Vol. 277, Issue 29, 25863-25866, July 19, 2002

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ACCELERATED PUBLICATION
Disruption of Adiponectin Causes Insulin Resistance and Neointimal Formation^*

Naoto Kubota^§¶, Yasuo Terauchi^§, Toshimasa Yamauchi^§, Tetsuya Kubota, Masao Moroi, Junji Matsui, Kazuhiro Eto^§, Tokuyuki Yamashita, Junji Kamon, Hidemi Satoh, Wataru Yano, Philippe Froguel^¶¶, Ryozo Nagai^**, Satoshi Kimura, Takashi Kadowaki^§, and Tetsuo Noda^¶§§

From the  Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, ^§ Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation, Saitama 332-0012,  Third Department of Internal Medicine, Toho University School of Medicine, Ohashi Hospital, Tokyo 153-0044, ^¶¶ Lille Institute of Biology-CNRS 8090 and Lille Pasteur Institute, 59000 Lille, France, ^** Department of Cardiovascular Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, ^¶ Department of Cell Biology, Japanese Foundation for Cancer Research-Cancer Institute, Tokyo 170-8455, and ^§§ Department of Molecular Genetics, Tohoku University School of Medicine, Sendai 980-8575, Japan

Received for publication, April 24, 2002, and in revised form, May 16, 2002

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The adipocyte-derived hormone adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity, and it has been reported to exhibit putative antiatherogenic properties in vitro. In this study we generated adiponectin-deficient mice to directly investigate whether adiponectin has a physiological protective role against diabetes and atherosclerosis in vivo. Heterozygous adiponectin-deficient (adipo^+/) mice showed mild insulin resistance, while homozygous adiponectin-deficient (adipo^/) mice showed moderate insulin resistance with glucose intolerance despite body weight gain similar to that of wild-type mice. Moreover, adipo^/ mice showed 2-fold more neointimal formation in response to external vascular cuff injury than wild-type mice (p = 0.01). This study provides the first direct evidence that adiponectin plays a protective role against insulin resistance and atherosclerosis in vivo.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Obesity, defined as increased adipose tissue mass, is a major risk factor for metabolic disorders such as diabetes, hypertension, and atherogenic diseases (1, 2). However, the molecular basis for the associations has remained to be elucidated.

The adipocyte-derived hormone adiponectin (3-6) has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity. Injection of adiponectin decreases plasma glucose levels by suppressing glucose production in the liver (7, 8), and injection of the globular domain of adiponectin decreases elevated fatty acid levels by oxidizing fatty acids in muscle (9). We have previously shown that administration of globular adiponectin increases fatty acid combustion in muscle, thereby ameliorating insulin resistance in obese mice (10). We have also shown that insulin resistance in lipoatrophic mice is completely reversed by a combination of physiological doses of adiponectin and leptin but only partially by either adiponectin or leptin alone (10). These observations suggested that adiponectin may be a major insulin-sensitizing hormone secreted by adipose tissue; however, the physiological role of adiponectin in vivo is not yet clear because the conclusions have been primarily based upon gain of function experiments. Dr. Matsuzawa's group (11, 12) has reported that adiponectin may have putative antiatherogenic properties, albeit in vitro, and adiponectin inhibits monocyte adhesion to endothelial cells and lipid accumulation in human monocyte-derived macrophages in vitro (11, 12). Thus, whether adiponectin has antiatherogenic properties in vivo is an important question that needs to be addressed.

We generated adiponectin-deficient mice as a means of directly investigating whether adiponectin has a physiological protective role against diabetes and atherosclerosis in vivo. Heterozygous adiponectin-deficient (adipo^+/) mice showed mild insulin resistance, while homozygous adiponectin-deficient (adipo^/) mice showed moderate insulin resistance and glucose intolerance despite a body weight gain similar to that of wild-type mice. Moreover, adipo^/ mice showed 2-fold more neointimal formation in response to external vascular cuff injury (13) than wild-type mice (p = 0.01). These results indicate that adiponectin plays a protective role against insulin resistance and neointimal formation in vivo.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Generation of Mutant Mice-- To construct the targeting vector for disruption of the adiponectin gene, a neomycin resistance gene (neoR) was substituted for exon2 and exon3, the coding region of the adiponectin gene (Fig. 1A). The strategy for culturing, electroporation of J1 embryonic stem (ES)¹ cells (129/Sv), and screening for homologous recombinant clones was as described previously (14) with slight modifications. Male chimeric mice were mated with C57Bl/6 female mice to generate heterozygous offspring, and F1 progeny from two independently generated male chimeric mice were crossed to obtain F2 mice. Although the knockout animals have a C57Bl/6 × 129/sv genetic background, all experiments in this study were performed using littermate mice.

RNA Preparation, Northern Blot Analysis, and RNase Protection Assay-- Total RNA was prepared from adipose tissue with ISOGEN Reagent Total RNA isolation reagent (Nippon Gene, Tokyo, Japan) according to the manufacturer's instructions. Northern blot analysis was performed with 10 µg of total RNA according to the standard protocol as described previously (15). The RNase protection assay to measure TNF mRNA was performed with RPA III^TM (Ambion) and TNF cRNA as described previously (15).

High Fat Diet Study-- The standard diet was purchased from Nippon CLEA Co. Ltd. (Shizuoka, Japan). The high fat diet containing 32% safflower oil, 33.1% casein, 17.6% sucrose, and 5.6% cellulose was prepared as described previously (15).

Blood Sample Assay and in Vivo Glucose Homeostasis-- The glucose tolerance test and insulin tolerance test were carried out according to previously described methods (16). Serum free fatty acid, triglyceride, total cholesterol, leptin, and adiponectin levels were determined by a NEFA C-test, TG L-type, Tchol E-type (Wako Pure Chemical Industries, Ltd., Osaka, Japan), Quintikine M kit (R&D System Inc.), and mouse adiponectin radioimmunoassay (RIA) kit (LINCO Research Inc.), respectively.

Cuff Injury Model-- The cuff injury model was used as described previously (13). The left femoral artery was isolated from surrounding tissues, and after loosely sheathing it with a 2.0-mm polyethylene cuff made of PE-50 tubing (inner diameter, 0.56 mm; outer diameter, 0.965 mm), the cuff was tied in place with an 8-0 suture. The cuffs were larger than the vessels and did not obstruct blood flow. The right femoral artery was dissected from surrounding tissues but not cuffed (sham-operated). 2 weeks after cuff placement, vessels were fixed with 10% formalin and embedded in paraffin. Continuous cross-sections (5 µm) were cut from one end of the cuffed portion to the other end and were stained for elastic fibers and with hematoxylin and eosin. Ten cross-sections each from the cuffed left and control right femoral artery of each animal were digitized with a Polaroid digital microscope camera (Olympus, Tokyo, Japan), and the thickness of the intima and media was measured in each arterial section. Area/volume calculations were based on four measurements made with an image analysis computer program (Scion Image, Frederick, MD): luminal circumference, luminal area, area inside the inner elastic lamina, and area inside the outer elastic lamina.

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Disruption of the Adiponectin Gene in Mice-- Two distinct adiponectin mutant mice were generated from distinct ES cell clones in which the adiponectin gene was disrupted by homologous recombination (Fig. 1, A and B). Both mice lines showed identical phenotypes in all the experiments carried out in this study. We confirmed homologous recombination by Southern blot analysis (Fig. 1C), and Northern blot analysis revealed an ~60% reduction of adiponectin mRNA expression in adipose tissue from adipo^+/ mice and the abrogation of adiponectin mRNA expression in adipose tissue from adipo^/ mice (Fig. 1D). The serum adiponectin levels were ~60% reduced in adipo^+/ mice, and they were undetectable in adipo^/ mice (Fig. 1E). The serum leptin levels of the adipo^+/, adipo^/, and wild-type mice were not significantly different (Fig. 1F). The TNF mRNA levels of the three mouse genotypes were indistinguishable (Fig. 1G).

View larger version (43K): [in this window] [in a new window]   Fig. 1.   Targeted disruption of the adiponectin gene. A, schematic representation of the gene targeting strategy. Top, partial restriction map of the adiponectin locus. Middle, adiponectin gene targeting vector. Bottom, the expected mutant locus. The DNA fragment used as a probe for Southern blotting is also shown under the top diagram. B and C, SpeI- and EcoRV-digested ES cells (B) and mice (C) genomic DNA hybridized with the probe. D, Northern blot analysis of total RNA from the adipose tissue of each genotype. Expression of the adiponectin gene was examined by using a cDNA probe for adiponectin. Mouse -actin was used as the loading control. E and F, serum adiponectin (E) and leptin levels (F) of each genotype. Values are means ± S.E. of the data obtained by analysis of wild-type (closed bars, n = 12), adipo+/ (open bars, n = 10), and adipo/ mice (hatched bars, n = 8). **, p < 0.01. G, RNase protection analysis to measure TNF mRNA levels in the adipose tissue of each genotype. Data are normalized to 36B4 and calculated as -fold intensity.

Adiponectin-deficient Mice Showed Insulin Resistance-- At 6 weeks the adipo^+/ mice and adipo^/ mice exhibited a body weight gain similar to that of the wild-type mice (Fig. 2A). Investigation of the insulin sensitivity of the adipo^+/ and wild-type littermate mice at 6 weeks by the insulin tolerance test (Fig. 2B) revealed that the glucose-lowering effect of insulin was slightly but significantly impaired in adipo^+/ mice compared with wild-type mice, suggesting that adipo^+/ mice exhibited mild insulin resistance. Next adipo^+/ and wild-type mice were subjected to an oral glucose tolerance test (OGTT) at 6 weeks (Fig. 2, C and D), and the results showed no significant differences between the adipo^+/ and wild-type mice in blood glucose (Fig. 2C) and plasma insulin (Fig. 2D) levels before and after the glucose load. After 10 weeks on a high fat diet, the adipo^+/ mice again exhibited a body weight gain similar to that of the wild-type mice (Fig. 2E), and food intake by the adipo^+/ and wild-type mice was not significantly different (2.6 ± 0.1 versus 2.7 ± 0.2 g/day). The blood glucose levels (Fig. 2F) before and after the glucose load of the OGTT, however, were significantly higher in the adipo^+/ mice than in the wild-type mice. The plasma insulin levels (Fig. 2G) before and after the glucose load were not significantly different between the adipo^+/ and wild-type mice. We investigated the insulin sensitivity of adipo^/ and wild-type littermates at 6 weeks by means of the insulin tolerance test (Fig. 2H). The results showed that the glucose-lowering effect of insulin was significantly impaired in the adipo^/ mice compared with the wild-type mice and adipo^+/ mice (p = 0.03, Fig. 2B), suggesting that the adipo^/ mice were more insulin-resistant than the adipo^+/ mice. When the OGTT was performed on adipo^/ and wild-type littermate mice at 6 weeks (Fig. 2, I and J), the blood glucose levels after the glucose load were also found to be significantly higher in the adipo^/ mice than in the wild-type mice (Fig. 2I). These data revealed moderate insulin resistance and glucose intolerance in the adipo^/ mice. There were no differences between the adipo^/ and wild-type mice in plasma insulin levels (Fig. 2J) before and 30 min after the glucose load, but the plasma insulin levels 15 min after the glucose load tended to be lower in the adipo^/ mice than in the wild-type mice.

View larger version (33K): [in this window] [in a new window]   Fig. 2.   Adiponectin-deficient mice showed insulin resistance and glucose intolerance. A, body weight of each genotype at 6 weeks. Values are means ± S.E. of the data obtained from the analysis of wild-type (open bars, n = 12), adipo+/ (closed bars, n = 10), and adipo/ mice (hatched bars, n = 8). B, insulin tolerance test of wild-type and adipo+/ mice at 6 weeks. Values are means ± S.E. of the data obtained from the analysis of wild-type (closed circles, n = 22) and adipo+/ mice (open circles, n = 17). *, p < 0.05. C and D, oral glucose tolerance test of wild-type and adipo+/ mice at 6 weeks. Values are means ± S.E. of the data obtained from the analysis of wild-type (closed circles, n = 28) and adipo+/ mice (open circles, n = 20). Blood glucose (C) and plasma insulin levels (D) were measured at the times indicated. E, body weight gain of wild-type and adipo+/ mice after 10 weeks on a high fat diet. Values are means ± S.E. of the data obtained from the analysis of wild-type (closed circles, n = 18) and adipo+/ mice (open circles, n = 12). F and G, oral glucose tolerance test of wild-type and adipo+/ mice after 10 weeks on a high fat diet. Values are means ± S.E. of the data obtained from the analysis of wild-type (closed circles, n = 10) and adipo+/ mice (open circles, n = 5). Blood glucose (F) and plasma insulin levels (G) were measured at the times indicated. H, insulin tolerance test of wild-type and adipo/ mice at 6 weeks. Values are means ± S.E. of the data obtained from the analysis of wild-type (open circles, n = 7) and adipo/ mice (closed circles, n = 8). *, p < 0.05. **, p < 0.01. I and J, oral glucose tolerance test of wild-type and adipo/ mice at 6 weeks. Values are means ± S.E. of the data obtained from the analysis of wild-type (open circles, n = 7) and adipo/ mice (closed circles, n = 8). Blood glucose (I) and plasma insulin levels (J) were measured at the times indicated.

Serum Lipid Levels in Adiponectin-deficient Mice-- At 6 weeks, the serum free fatty acid (FFA), triglyceride (TG), and total cholesterol (TC) levels did not differ significantly between the adipo^+/ mice and wild-type mice (Table I). The serum TG levels were slightly but significantly higher in adipo^/ mice than in wild-type mice, but the serum FFA and TC levels did not differ between the adipo^/ mice and wild-type mice (Table I).

Increased Neointimal Formation Is Induced by Cuff Injury in Adiponectin-deficient Mice-- We placed a cuff around the femoral artery to induce inflammation of the adventitia and subsequent neointimal formation 2 weeks after cuff placement. Luminal diameters did not differ between the adipo^/ and wild-type mice (Fig. 3, A and E), but intimal thickness was significantly greater (2-fold) in the adipo^/ mice than in the wild-type mice (Fig. 3, B and E). There were no significant differences in medial thickness between the two mouse groups (Fig. 3, C and E). The intimal (I)/medial (M) volume ratio was significantly higher (2-fold) in the adipo^/ than in the wild-type mice (Fig. 3, D and E).

View larger version (49K): [in this window] [in a new window]   Fig. 3.   Adiponectin-deficient mice showed increased neointimal formation. A-E, analysis of the femoral arteries of wild-type and adipo/ mice at 10 weeks, i.e. at 2 weeks after cuff placement. Values are means ± S.E. of the data obtained from the analysis of wild-type (closed bar, n = 5) and adipo/ mice (open bar, n = 4). A, luminal diameter. B, intimal thickness. *, p < 0.05. C, medial thickness. D, intima to media volume ratio (I/M). **, p = 0.01. E, histological analysis of femoral arteries of wild-type and adipo/mice.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Adiponectin has been shown to be decreased in insulin-resistant states such as obesity and type 2 diabetes (5). We have reported that administration of adiponectin ameliorates insulin resistance in lipoatrophic mice and type 2 diabetic mice (10). Others have also reported that administration of adiponectin decreases the plasma glucose levels of normal mice (7-9). These findings suggest that adiponectin is an insulin-sensitizing hormone; however, they were primarily based on gain of function experiments, and loss of function experiments were required to directly determine the physiological role of adiponectin in the regulation of insulin sensitivity. Accordingly in the present study we generated adiponectin-deficient mice. The results provide the first direct evidence that adiponectin is indeed required for normal regulation of insulin sensitivity and glucose homeostasis in vivo. Moreover, adipo^+/ mice with a 60% reduction of adiponectin levels were significantly more insulin-resistant than wild-type mice, suggesting that 40-70% reductions in plasma adiponectin levels due to genetic factors, such as single nucleotide polymorphisms of the adiponectin gene (17), or environmental factors, such as a high fat diet (10), may have been causally associated with the insulin resistance.

Leptin and adiponectin are two major adipocyte-derived insulin-sensitizing hormones (10, 18). The heterozygous leptin-deficient (ob/+) mice did not display a distinct phenotype, but homozygous leptin-deficient (ob/ob) mice exhibited severe obesity and associated insulin resistance and diabetes (19). Since adipo^+/ mice showed mild but significant insulin resistance, unlike ob/+ mice, adiponectin appears to play a greater regulatory role in the determination of insulin sensitivity under physiological and pathophysiological states as stated above. However, in contrast to ob/ob mice, adipo^/ mice showed normal body weight gain, although they showed insulin resistance and glucose intolerance. Although the role of adiponectin in this process has been a matter of controversy (9, 10), leptin clearly plays a much greater role in the regulation of appetite and energy expenditure than adiponectin. These findings indicate that adiponectin and leptin have distinct yet overlapping roles in the regulation of insulin sensitivity and energy homeostasis in vivo.

Dr. Matsuzawa's group (11, 12) has reported that adiponectin may have putative antiatherogenic properties, albeit in vitro, and adiponectin has been shown to inhibit monocyte adhesion to endothelial cells and lipid accumulation in human monocyte-derived macrophages in vitro (11, 12). In this study, we showed that adipo^/ mice formed 2-fold more neointima (I/M ratio, p = 0.01) in response to external vascular cuff injury than wild-type mice (Fig. 3, D and E), thereby providing the first direct evidence that adiponectin plays a protective role in neointimal formation in vivo. Although adipo^/ mice showed glucose intolerance and hypertriglyceridemia compared with wild-type mice, these metabolic abnormalities alone are unlikely to account for the increased neointimal formation since homozygous insulin receptor substrate-1 (IRS-1)-deficient (IRS-1^/) mice, which exhibit greater metabolic abnormalities than adipo^/ mice, failed to show any increase in neointimal formation when the same system was used.² These findings strongly suggest that the protective effect of adiponectin may be a direct consequence of adiponectin action on the vascular wall and/or macrophages rather than an indirect consequence of alteration of conventional atherosclerotic risk factors in vivo. The cuff injury model mimics features of human atherosclerosis with quantitative and reproducible endpoints (13). For example, neointima mainly was formed by cells that originate from bone marrow and medial smooth cells that migrate to subendothelial space and proliferate there.

In conclusion, this study provides the first direct evidence that adiponectin plays a protective role against insulin resistance and neointimal formation in vivo. The results of this study also suggest that administration of adiponectin may provide a novel treatment modality for both type 2 diabetes and atherosclerosis.

	ACKNOWLEDGEMENTS

We thank Yoshinobu Sugitani, Katsuko Takasawa, Eri Yoshida-Nagata, Ayumi Nagano, Hitomi Yamanaka, Ryuichi Taki, Miharu Nakashima, and Hiroshi Chiyonobu for excellent technical assistance and mouse care.

	FOOTNOTES

^* This work was supported by a grant from the Human Science Foundation, a grant-in-aid for the development of innovative technology from the Ministry of Education, Culture, Sports, Science and Technology, Grant-in-Aid for Creative Scientific Research 10NP0201 from the Japan Society for the Promotion of Science, and health science research grants (research on human genome and gene therapy) from the Ministry of Health and Welfare (all to T. Kadowaki).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel.: 81-3-5800-8818; Fax: 81-3-5689-7209; E-mail: kadowaki-3im@h.u-tokyo.ac.jp.

Published, JBC Papers in Press, May 24, 2002, DOI 10.1074/jbc.C200251200

² T. Kubota, N. Kubota, M. Moroi, and T. Kadowaki, manuscript in preparation.

	ABBREVIATIONS

The abbreviations used are: ES, embryonic stem; TNF, tumor necrosis factor; FFA, free fatty acid; TG, triglyceride; TC, total cholesterol; OGTT, oral glucose tolerance test; I, intimal; M, medial; IRS-1, insulin receptor substrate-1.

	REFERENCES

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