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The metabolic syndrome is a constellation of abdominal obesity, insulin resistance, hyperlipidemia, and hypertension, all of which increase independently a risk of atherosclerotic diseases. It is a multi-factorial pathologic condition that arises from complex interactions between genetic and environmental factors. However, the molecular basis for the clustering of such independent risks for atherosclerosis has not been fully elucidated, with visceral fat obesity considered most important.
　　The adipose tissue is not merely an energy storage organ but an important endocrine organ that secretes many biologically active substances such as leptin, free fatty acids (FFAs), tumor necrosis factor-α (TNF-α), and adiponectin, which are collectively termed adipocytokines. Dysregulation of pro- and anti-inflammatory adipocytokine function and production seen in visceral fat obesity is associated with the metabolic syndrome, suggesting that inflammation may critically contribute to the development of the metabolic syndrome and results in atherosclerosis. However, the molecular mechanism underlying inflammatory changes in the metabolic syndrome is largely unknown.
　　In April 2003, we opened a new laboratory at Department of Molecular Medicine and Metabolism in Medical Research Institute, Tokyo Medical and Dental University, with a mission to elucidate the molecular basis of the metabolic syndrome and to identify therapeutic targets that may reduce the metabolic syndrome associated with excess adiposity. Our studies have been focused on the pathophysiologic and therapeutic implications of adipocytokines, nuclear hormone receptors, and transcriptional co-activators/co-repressors in the metabolic syndrome toward the better understanding of the molecular mechanism of the metabolic syndrome and its related diseases, and to help establish novel therapeutic strategies.

Obese adipose tissue is characterized by adipocyte hypertrophy, followed by increases in angiogenesis, macrophage infiltration, and pro-inflammatory adipocytokine production, suggesting the previously unrecognized dynamic changes, which may be referred to as “adipose tissue remodeling”. Using an in vitro co-culture system composed of 3T3-L1 adipocytes and RAW264 macrophages, we have provided evidence that a paracrine loop involving saturated fatty acids and TNFα derived from adipocytes and macrophages, respectively, establishes a vicious cycle that aggravates inflammatory changes in obese adipose tissue (Arterioscler. Thromb. Vasc. Biol. 25: 2062-2068, 2005). Interestingly, saturated fatty acids, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in obese adipose tissue (Arterioscler. Thromb. Vasc. Biol. 27: 84-91, 2007; Biochem. Biophys. Res. Commun. 354: 45-49, 2007). Recently, we have demonstrated the anti-inflammatory effect of PPARα ligands in the interaction between adipocytes and macrophages in obese adipose tissue (Obesity 16: 1199-1207, 2008), suggesting the potential of adipose tissue remodeling as therapeutic target for the metabolic syndrome.

Recently, we have found that highly purified eicosapentaenoic acid (EPA), the only class of n-3 polyunsaturated fatty acids that has been used clinically to treat hyperlipidemia, is capable of antagonizing the saturated fatty acid-induced inflammatory changes in macrophages (Arterioscler. Thromb. Vasc. Biol. 27: 1918-1925, 2007). Furthermore, we also showed that highly purified EPA reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in patients with the metabolic syndrome, thus highlighting the anti-inflammatory effect of n-3 polyunsaturated fatty acids (Diabetes Care 30: 144-146, 2007).

MCP-1, an important chemokine whose expression is increased during the course of obesity, may play a role in macrophage infiltration into obese adipose tissue via its cognate receptor CCR2. We have found that MCP-1 production is induced, which is followed by ERK activation and MAPK phosphatase-1 (MKP-1) down-regulation in obese adipose tissue prior to macrophage infiltration. In vitro studies with 3T3-L1 adipocytes revealed that ERK activation through MKP-1 down-regulation is involved in increased production of MCP-1 during the course of adipocyte hypertrophy, suggesting that MKP-1 down-regulation is critical for the inflammatory changes in hypertrophied adipocytes at the early stage of obesity. This study suggest that MKP-1 activation may offer a novel therapeutic strategy to reduce the otherwise increased production of MCP-1 at the early stage of obesity and thus macrophage infiltration at the late stage of obesity (J. Biol. Chem. 282: 25445-25452, 2007).

Our data help elucidate the molecular mechanism underlying “adipose tissue remodeling” and identify a novel therapeutic target that may reduce obesity-induced adipose tissue inflammation and obesity-related metabolic sequelae.

The skeletal muscle as a target organ of the metabolic syndrome
A well-balanced body energy budget controlled by limitation of calorie uptake and/or increment of energy expenditure that is typically achieved by proper physical exercise is effective against obesity and diabetes. The skeletal muscle is the largest organ and plays important roles in exercise, energy expenditure, and glucose metabolism. The mass and composition of the skeletal muscle are critical for its function, and is regulated in response to changes in physical activity, environment or pathologic conditions. We have found that FOXO1, a member of the FOXO forkhead-type transcription factors and also a transcriptional co-activator/co-repressor of nuclear hormone receptors, is markedly up-regulated in the skeletal muscle during muscle atrophy. Using transgenic mice overexpressing FOXO1 in the skeletal muscle (FOXO1 transgenic mice), we previously demonstrated that FOXO1 plays a role in the regulation of the skeletal muscle mass and function (J. Biol. Chem. 279: 41114-41123, 2004).

SREBP1c is a master regulator of lipogenic gene expression in the liver and adipose tissue, where its expression is regulated by a heterodimer of nuclear receptor-type transcription factors, RXRα and LXRα. Recently, we found that RXRγ mRNA expression is markedly decreased by fasting and is restored by refeeding in the mouse skeletal muscle, in parallel with changes in SREBP1c mRNA expression. Transgenic mice overexpressing RXRγ specifically in the skeletal muscle show increased SREBP1c mRNA expression with increased triglyceride content in the skeletal muscle. In contrast, transgenic mice overexpressing dominant negative form of RXRγ show decreased SREBP1c mRNA expression. Expression of mRNA for FOXO1, which can suppress the function of multiple nuclear receptors, is negatively correlated to that of SREBP1c in the skeletal muscle during nutritional change. Moreover, FOXO1 transgenic mice exhibit decreased both RXRγ and SREBP1c mRNA expression. In addition, FOXO1 suppresses RXRα/LXRα-mediated SREBP1c promoter activity in vitro. Our data provide evidence that RXR/LXR up-regulates SREBP1c gene expression, and that FOXO1 antagonizes the effect in the skeletal muscle (Endocrinology 149: 2293-2305, 2008)

Homozygous mutations in human NPR-B in acromesomelic dysplasia, type Maroteaux

Natriuretic peptide receptor-B (NPR-B; gene name NPR2) is a guanylyl cyclase-coupled receptor that mediates the effect of C-type natriuretic peptide (CNP). Homozygous mutations in human NPR-B cause acromesomelic dysplasia, type Maroteaux (AMDM; OMIM 602875), an autosomal recessive skeletal dysplasia. NPR-B has an intracellular kinase homology domain (KHD), which has no kinase activity and its functional significance in vivo is currently unknown. We have identified a novel missense mutation L658F in KHD of NPR-B in homozygous and heterozygous states in a 28-year-old Japanese male patient and his parents, respectively. The mutation conferred normal binding affinity for CNP but no discernable ligand-induced cGMP production. Furthermore, L658F mutant impaired wildtype NPR-B-mediated cGMP production in a dose-dependent manner, suggesting that short stature found in L658F heterozygote can be caused by its dominant negative effect. This study provides the first evidence that intact KHD of NPR-B is essential for skeletal development (J. Clin. Endocrinol. Metab. 92: 4009-4014, 2007).

Nobutaka Nakagawa

Erina Shibagaki

Natsumi Sorimachi

1. Y. Kamei, S. Miura, T. Suganami, F. Akaike, S. Kanai, S. Sugita, A. Katsumata, H. Aburatani, T. G. Unterman, O. Ezaki, and Y. Ogawa. Regulation of SREBP1c gene expression in skeletal muscle: role of retinoid X receptor/liver X receptor and forkhead-O1 transcription factor. Endocrinology 149: 2293-2305, 2008.

2. R. Hachiya, Y. Ohashi, Y. Kamei, T. Suganami, H. Mochizuki, N. Mitsui, M. Saitoh, M. Sakuragi, G. Nishimura, H. Ohashi, T. Hasegawa, and Y. Ogawa. Intact kinase homology domain of natriuretic peptide receptor-B is essential for skeletal development. J. Clin. Endocrinol. Metab. 92: 4009-4014, 2007.

3. M. Itoh, T. Suganami, N. Satoh, K. Tanimoto-Koyama, X. Yuan, M. Tanaka, H. Kawano, T. Yano, S. Aoe, M. Takeya, A. Shimatsu, H. Kuzuya, Y. Kamei, and Y. Ogawa. Increased adiponectin secretion by highly purified eicosapentaenoic acid in rodent models of obesity and human obese subjects. Arterioscler. Thromb. Vasc. Biol. 27: 1918-1925, 2007.

4. A. Ito, T. Suganami, Y. Miyamoto, Y. Yoshimasa, M. Takeya, Y. Kamei, and Y. Ogawa. Role of mitogen-activated protein kinase phosphatase-1 in the induction of monocyte chemoattractant protein-1 during the course of adipocyte hypertrophy. J. Biol. Chem. 282: 25445-25452, 2007.

5. K. Ebihara, T. Kusakabe, M. Hirata, H. Masuzaki, F. Miyanaga, N. Kobayashi, T. Tanaka, H. Chusho, T. Miyazawa, T. Hayashi, K. Hosoda, Y. Ogawa, A.M. Depaoli, M. Fukushima, and K. Nakao. Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J. Clin. Endocrinol. Metab. 92: 532-541, 2007.

6. N. Satoh, A. Shimatsu, K. Kotani, N. Sakane, K. Yamada, T. Suganami, H. Kuzuya, and Y. Ogawa. Purified eicosapentaenoic acid reduces small dense LDL, remnant lipoprotein particles, and C-reactive protein in metabolic syndrome. Diabetes Care 30: 144-146, 2007.

7. T. Suganami, K. Tanimoto-Koyama, J. Nishida, M. Itoh, X. Yuan, S. Mizuarai, H. Kotani, S. Yamaoka, K. Miyake, S. Aoe, Y. Kamei, and Y. Ogawa. Role of the Toll-like receptor 4/NF-?B pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler. Thromb. Vasc. Biol. 27: 84-91, 2007.

8. H. Makino, M. Mukoyama, K. Mori, T. Suganami, M. Kasahara, K. Yahata, T. Nagae, H. Yokoi, K. Sawai, Y. Ogawa, S. Suga, Y. Yoshimasa, A. Sugawara, I. Tanaka, and K. Nakao. Transgenic overexpression of brain natriuretic peptide prevents the progression of diabetic nephropathy in mice. Diabetologia 49: 2514-2524, 2006.

9. J. Park, S. S. Choe, A. H. Choi, K. H. Kim, M. J. Yoon, N. Houstis, E. D. Rogen, T. Suganami, Y. Ogawa, and J. B. Kim. Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signal. Diabetes 55: 2939-2949, 2006.

10. T. Suganami, J. Nishida, and Y. Ogawa. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor α. Arterioscler. Thromb. Vasc. Biol. 25:2062-2068, 2005.

11. R. Kouyama*, T. Suganami*, J. Nishida, M. Tanaka, T. Toyoda, M. Kiso, T. Chiwata, Y. Miyamoto, Y. Yoshimasa, A. Fukamizu, M. Horiuchi, Y. Hirata, and Y. Ogawa (*These authors contributed equally to this work). Attenuation of diet-induced weight gain and adiposity through increased energy expenditure in mice lacking angiotensin II type 1a receptor. Endocrinology 146:3481-3489, 2005.

12. T. Tanaka*, S. Hidaka*, H. Masuzaki, S. Yasue, Y. Minokoshi, K. Ebihara, H. Chusho, Y. Ogawa, T. Toyoda, K. Sato, F. Miyanaga, M. Fujimoto, T. Tomita, T. Kusakabe, N. Kobayashi, H. Tanioka, T. Hayashi, K. Hosoda, H. Yoshimatsu, T. Sakata, and K. Nakao (*These authors contributed equally to this work). Skeletal muscle AMPK phosphorylation parallels metabolic phenotypes in leptin transgenic mice under dietary modification. Diabetes 54: 2365-2374, 2005.

13. S. Yura*, H. Itoh*, N. Sagawa, H. Yamamoto, H. Masuzaki, K. Nakao, M. Kawamura, M. Takemura, K. Kakui, Y. Ogawa, and S. Fujii (*These authors contributed equally to this work). Role of premature leptin surge in obesity resulting from intrauterine undernutrition. Cell Metab. 1: 371-378, 2005.

14. Y. Oike, M. Akao, K. Yasunaga, T. Yamauchi, T. Morisada, Y. Ito, T. Urano, Y. Kimura, Y. Kubota, H. Maekawa, T. Miyamoto, K. Miyata, S. Matsumoto, J. Sakai, N. Nakagata, M. Takeya, H. Koseki, Y. Ogawa, T. Kadowaki, and T. Suda. Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat. Med. 11: 400-408, 2005.

15. H. Iwakura, K. Hosoda, C. Son, J. Fujikura, T. Tomita, M. Noguchi, H. Ariyasu, K. Takaya, H. Masuzaki, Y. Ogawa, T. Hayashi, G. Inoue, T. Akamizu, H. Hosoda, M. Kojima, H. Itoh, S. Toyokuni, K. Kangawa, and K. Nakao. Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice. J. Biol. Chem. 280: 15247-15256, 2005.

16. T. Suganami, M. Mukoyama, K. Mori, H. Yokoi, M. Koshikawa, K. Sawai, S. Hidaka, K. Ebihara, T. Tanaka, A. Sugawara, H. Kawachi, C. Vinson, Y. Ogawa, and K. Nakao. Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy. FASEB J. 19: 127-129, 2005.

17. R. Kawakami, Y. Saito, I. Kishimoto, M. Harada, K. Kuwahara, N. Takahashi, Y. Nakagawa, M. Nakanishi, K. Tanimoto, S. Usami, S. Yasuno, H. Kinoshita, H. Chusho, N. Tamura, Y. Ogawa, and K. Nakao. Overexpression of brain natriuretic peptide facilitates neutrophil infiltration and cardiac matrix metalloproteinase-9 expression after acute myocardial infarction. Circulation 110: 3306-3312, 2004.

18. N. Satoh, M. Naruse, T. Usui, T. Tagami, T. Suganami, K. Yamada, H. Kuzuya, A. Shimatsu, and Y. Ogawa. Leptin-to-adiponectin ratio as a potential atherogenic index in obese type 2 diabetic patients. Diabetes Care 27: 2488-2490, 2004.

19. E. Suganami, H. Takagi, H. Ohashi, K. Suzuma, I. Suzuma, H. Oh, D. Watanabe, T. Ojima, T. Suganami, Y. Fujio, K. Nakao, Y. Ogawa, and N. Yoshimura. Leptin stimulates ischemia-induced retinal neovascularization: possible role of vascular endothelial growth factor expressed in retinal endothelial cells. Diabetes 53: 2443-2448, 2004.

20. K. Ebihara*, T. Kusakabe*, H. Masuzaki, N. Kobayashi, T. Tanaka, H. Chusho, F. Miyanaga, T. Miyazawa, T. Hayashi, K. Hosoda, Y. Ogawa, and K. Nakao (*These authors contributed equally to this work). Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene. J. Clin. Endocrinol. Metab. 89: 2360-2364, 2004.

21. F. Elefteriou*, S. Takeda*, K. Ebihara, J. Magre, N. Patano, C. Ae Kim, Y. Ogawa, X. Liu, S. M. Ware, W. J. Craigen, J. J. Robert, C. Vinson, K. Nakao, J. Capeau, and G. Karsenty (*These authors contributed equally to this work). Serum leptin level is a regulator of bone mass. Proc. Natl. Acad. Sci. USA 101: 3258-3263, 2004.

22. A. Yasoda, Y. Komatsu, H. Chusho, T. Miyazawa, A. Ozasa, M. Miura, T. Kurihara, T. Rogi, S. Tanaka, M. Suda, N. Tamura, Y. Ogawa, and K. Nakao. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat. Med. 10: 80-86, 2004.

23. F. Miyanaga, Y. Ogawa, K. Ebihara, S. Hidaka, T. Tanaka, S. Hayashi, H. Masuzaki, and K. Nakao. Leptin as an adjunct of insulin therapy in insulin-dependent diabetes. Diabetologia 46: 1329-1337, 2003.

24. N. Satoh, Y. Ogawa, T. Usui, T. Tagami, S. Kohno, H. Uesugi, H. Sugiyama, A. Sugawara, K. Yamada, A. Shimatsu, H. Kuzuya, and K. Nakao. Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 26: 2493-2499, 2003.

25. K. Yamahara, H. Itoh, T.-H. Chun, Y. Ogawa, J. Yamashita, N. Sawada, Y. Fukunaga, M. Sone, T. Yurugi-Kobayashi, K. Miyashita, H. Tsujimoto, H. Kook, R. Feil, D. L. Garbers, F. Hofmann, and K. Nakao. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc. Natl. Acad. Sci. USA 100: 3404-3409, 2003.

26. H. Kobayashi, Y. Ogawa, M. Shintani, K. Ebihara, M. Shimodahira, T. Iwakura, M. Hino, T. Ishihara, K. Ikekubo, H. Kurahachi, and K. Nakao. A novel homozygous missense mutation of melanocortin-4 receptor (MC4R) in a Japanese woman with severe obesity. Diabetes 51: 243-246, 2002.

27. M. Shintani, H. Nishimura, S. Yonemitsu, Y. Ogawa, T. Hayashi, K. Hosoda, G. Inoue, and K. Nakao. Troglitazone not only increases GLUT4 but also induces its translocation in rat adipocytes. Diabetes 50: 2296-2300, 2001.

28. K. Ebihara, Y. Ogawa, H. Masuzaki, M. Shintani, F. Miyanaga, M. Aizawa-Abe, T. Hayashi, K. Hosoda, G. Inoue, Y. Yoshimasa, O. Gavrilova, M. L. Reitman, and K. Nakao. Transgenic overexpression of leptin rescues insulin resistance and diabetes in a mouse model of lipoatrophic diabetes. Diabetes 50: 1440-1448, 2001.

29. S. Yonemitsu, H. Nishimura, M. Shintani, R. Inoue, Y. Yamamoto, H. Masuzaki, Y. Ogawa, T. Hayashi, K. Hosoda, G. Inoue, and K. Nakao. Troglitazone induces GLUT4 translocation in L6 myotubes. Diabetes 50: 1093-1101, 2001.

30. H. Chusho*, N. Tamura*, Y. Ogawa, A. Yasoda, M. Suda, T. Miyazawa, K. Nakamura, K. Nakao, T. Kurihara, Y. Komatsu, H. Itoh, K. Tanaka, Y. Saito, M. Katsuki, and K. Nakao (*These authors contributed equally to this work). Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc. Natl. Acad. Sci. USA 98: 4016-4021, 2001.

31. M. Shintani, Y. Ogawa, K. Ebihara, M. Aizawa-Abe, F. Miyanaga, K. Takaya, T. Hayashi, G. Inoue, K. Hosoda, M. Kojima, K. Kangawa, and K. Nakao. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50: 227-232, 2001.

32. T. Kuramoto, K. Kitada, T. Inui, Y. Sasaki, K. Ito, T. Hase, S. Kawaguchi, Y. Ogawa, K. Nakao, G. S. Barsh, M. Nagao, T. Ushijima, and T. Serikawa. Attractin/mahogany/zitter plays a critical role in myelination of the central nervous system. Proc. Natl. Acad. Sci. USA 98: 559-564, 2001.

33. M. Aizawa-Abe, Y. Ogawa, H. Masuzaki, K. Ebihara, N. Satoh, H. Iwai, N. Matsuoka, T. Hayashi, K. Hosoda, G. Inoue, Y. Yoshimasa, and K. Nakao. Pathophysiological role of leptin in obesity-related hypertension. J. Clin. Invest. 105: 1243-1252, 2000.

34. N. Tamura, Y. Ogawa, H. Chusho, K. Nakamura, K. Nakao, M. Suda, M. Kasahara, R. Hashimoto, G. Katsuura, M. Mukoyama, H. Itoh, Y. Saito, I. Tanaka, H. Otani, M. Katsuki, and K. Nakao. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc. Natl. Acad. Sci. USA 97: 4239-4244, 2000.

35. S. Yura*, Y. Ogawa*, N. Sagawa, H. Masuzaki, H. Itoh, K. Ebihara, M. Aizawa-Abe, S. Fujii, and K. Nakao (*These authors contributed equally to this work). Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin. J. Clin. Invest. 105: 749-755, 2000.

36. Y. Yamamoto, Y. Yoshimasa, M. Koh, J. Suga, H. Masuzaki, Y. Ogawa, K. Hosoda, H. Nishimura, Y. Watanabe, G. Inoue, and K. Nakao. Constitutively active mitogen-activated protein kinase kinase increases GLUT1 expression and recruits both GLUT1 and GLUT4 at the cell surface in 3T3-L1 adipocytes. Diabetes 49: 332-339, 2000.

37. K. Ebihara, Y. Ogawa, G. Katsuura, Y. Numata, H. Masuzaki, N. Satoh, M. Tamaki, T. Yoshioka, M. Hayase, N. Matsuoka, M. Aizawa-Abe, Y. Yoshimasa, and K. Nakao. Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action. Diabetes 48: 2028-2033, 1999.

38. Y. Ogawa*, H. Masuzaki*, K. Hosoda, M. Aizawa-Abe, J. Suga, M. Suda, K. Ebihara, H. Iwai, N. Matsuoka, N. Satoh, H. Odaka, H. Kasuga, Y. Fujisawa, G. Inoue, H. Nishimura, Y. Yoshimasa, and K. Nakao (*These authors contributed equally to this work). Increased glucose metabolism and insulin sensitivity in transgenic skinny mice overexpressing leptin. Diabetes 48: 1822-1829, 1999.

39. N. Satoh, Y. Ogawa, G. Katsuura, Y. Numata, T. Tsuji, M. Hayase, K. Ebihara, H. Masuzaki, K. Hosoda, Y. Yoshimasa, and K. Nakao. Sympathetic activation of leptin via the ventromedial hypothalamus: leptin-induced increase in catecholamine secretion. Diabetes 48: 1787-1793, 1999.

40. H. Masuzaki, Y. Ogawa, M. Aizawa-Abe, K. Hosoda, J. Suga, K. Ebihara, N. Satoh, H. Iwai, G. Inoue, H. Nishimura, Y. Yoshimasa, and K. Nakao. Glucose metabolism and insulin sensitivity in transgenic mice overexpressing leptin with lethal yellow agouti mutation: usefulness of leptin for the treatment of obesity-associated diabetes. Diabetes 48: 1615-1622, 1999

41. K. Mori, Y. Ogawa, K. Ebihara, N. Tamura, K. Tashiro, T. Kuwahara, M. Mukoyama, A. Sugawara, S. Ozaki, I. Tanaka, and K. Nakao. Isolation and characterization of CA XIV, a novel membrane-bound carbonic anhydrase from mouse kidney. J. Biol. Chem. 274: 15701-15705, 1999.

42. K. Imagawa, Y. Numata, G. Katsuura, I. Sakaguchi, A. Morita, S. Kikuoka, Y. Matsumoto, T. Tsuji, M. Tamaki, K. Sasakura, H. Teraoka, K. Hosoda, Y. Ogawa, and K. Nakao. Structure-function studies of human leptin. J. Biol. Chem. 273: 35245-35249, 1998.

43. J. Yamashita, T. Yoshimasa, H. Arai, J. Hiraoka, K. Takaya, Y. Miyamoto, Y. Ogawa, H. Itoh, and K. Nakao. Identification of cis-elements of the human endothelin-A receptor gene and inhibition of the gene expression by the decoy strategy. J. Biol. Chem. 273: 15993-15999, 1998.

44. A. Yasoda, Y. Ogawa, M. Suda, N. Tamura, K. Mori, Y. Sakuma, H. Chusho, K. Shiota, K. Tanaka, and K. Nakao. Natriuretic peptide regulation of endochondral ossification: evidence for possible roles of C-type natriuretic peptide/guanylyl cyclase-B pathway. J. Biol. Chem. 273: 11695-11700, 1998.

45. M. Suda, Y. Ogawa, K. Tanaka, N. Tamura, A. Yasoda, T. Takigawa, M. Uehira, H. Nishimoto, H. Itoh, Y. Saito, K. Shiota, and K. Nakao. Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide. Proc. Natl. Acad. Sci. USA 95: 2337-2342, 1998.

46. N. Sagawa, T. Mori, H. Masuzaki, Y. Ogawa, and K. Nakao. Leptin production by hydatidiform mole. Lancet 350: 1518-1519, 1997.

47. H. Masuzaki, Y. Ogawa, N. Sagawa, K. Hosoda, T. Matsumoto, H. Mise, H. Nishimura, Y. Yoshimasa, I. Tanaka, T. Mori, and K. Nakao. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat. Med. 3: 1029-1033, 1997.

48. K. Takaya, Y. Ogawa, J. Hiraoka, K. Hosoda, R. J. Koletsky, Y. Yamori, and K. Nakao. Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat. Nat. Genet. 14: 130-131, 1996.

49. N. Isse, Y. Ogawa, N. Tamura, H. Masuzaki, K. Mori, T. Okazaki, N. Satoh, M. Shigemoto, Y. Yoshimasa, S. Nishi, K. Hosoda, J. Inazawa, and K. Nakao. Structural organization and chromosomal assignment of the human obese gene. J. Biol. Chem. 270: 27728-27733, 1995.

50. Y. Ogawa, H. Masuzaki, N. Isse, T. Okazaki, K. Mori, M. Shigemoto, N. Satoh, N. Tamura, K. Hosoda, Y. Yoshimasa, H. Jingami, T. Kawada, and K. Nakao. Molecular cloning of rat obese cDNA and augmented gene expression in genetically obese Zucker fatty (fa/fa) rats. J. Clin. Invest. 96: 1647-1652, 1995.

51. Nakagawa, Y. Ogawa, H. Itoh, S. Suga, Y. Komatsu, I. Kishimoto, K. Nishino, T. Yoshimasa, and K. Nakao. Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy: evidence for brain natriuretic peptide as an "emergency" cardiac hormone against ventricular overload. J. Clin. Invest. 96: 1280-1287, 1995.

52. H. Masuzaki, Y. Ogawa, N. Isse, N. Satoh, T. Okazaki, M. Shigemoto, K. Mori, N. Tamura, K. Hosoda, Y. Yoshimasa, H. Jingami, T. Kawada, and K. Nakao. Human obese gene expression: adipocyte-specific expression and regional differences in the adipose tissue. Diabetes 44: 855-858, 1995.

53. I. Kishimoto, T. Yoshimasa, S. Suga, Y. Ogawa, Y. Komatsu, O. Nakagawa, H. Itoh, and K. Nakao. Natriuretic peptide clearance receptor is transcriptionally down-regulated by β2-adrenergic stimulation in vascular smooth muscle cells. J. Biol. Chem. 269: 28300-28308, 1994.

54. N. Tamura, Y. Ogawa, H. Itoh, H. Arai, S. Suga, O. Nakagawa, Y. Komatsu, I. Kishimoto, K. Takaya, T. Yoshimasa, S. Shiono, and K. Nakao. Molecular cloning of hamster brain and atrial natriuretic peptide cDNAs: cardiomyopathic hamsters are useful models for brain and atrial natriuretic peptides. J. Clin. Invest. 94: 1059-1068, 1994.

55. Y. Ogawa, H. Itoh, N. Tamura, S. Suga, T. Yoshimasa, M. Uehira, S. Matsuda, S. Shiono, H. Nishimoto, and K. Nakao. Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J. Clin. Invest. 93: 1911-1921, 1994.

56. H. Imura, K. Nakao, A. Shimatsu, Y. Ogawa, T. Sando, I. Fujisawa, and H. Yamabe. Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N. Engl. J. Med. 329: 683-689, 1993.

57. H. Arai, K. Nakao, K. Takaya, K. Hosoda, Y. Ogawa, S. Nakanishi, and H. Imura. The human endothelin-B receptor gene: structural organization and chromosomal assignment. J. Biol. Chem. 268: 3463-3470, 1993.

58. Y. Komatsu, K. Nakao, H. Itoh, S. Suga, Y. Ogawa, and H. Imura. Vascular natriuretic peptide. Lancet 340: 622, 1992.

59. K. Hosoda, K. Nakao, N. Tamura, H. Arai, Y. Ogawa, S. Suga, S. Nakanishi, and H. Imura. Organization, structure, chromosomal assignment and expression of the gene encoding the human endothelin-A receptor. J. Biol. Chem. 267: 18797-18804, 1992.

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