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Tetsuya Kubota,
Naoto Kubota,
Hiroki Kumagai,
Shinichi Yamaguchi, Hideki Kozono,
Takehiro Takahashi,
Mariko Inoue,
Shinsuke Itoh,
Iseki Takamoto,
Takayoshi Sasako, [......],
Nobuyuki Yanagihara,
Masato Tsutsui,
Yasuo Terauchi,
Kazuyuki Tobe,
Ryozo Nagai,
Katsuo Kamata,
Kenji Inoue,
Tatsuhiko Kodama,
Kohjiro Ueki,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.
Cell metabolism 03/2011; 13(3):294-307. · 17.35 Impact Factor
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Aiko Nitta,
Hideaki Fujii,
Satoshi Sakami,
Yutaka Nishimura,
Tomofumi Ohyama,
Mikiya Satoh,
Junko Nakaki,
Shiho Satoh,
Chifumi Inada, Hideki Kozono,
Hiroki Kumagai,
Masahiro Shimamura,
Tominaga Fukazawa,
Hideki Kawai
[show abstract]
[hide abstract]
ABSTRACT: Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.
Bioorganic & medicinal chemistry letters 10/2008; 18(20):5435-8. · 2.65 Impact Factor
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Naoto Kubota,
Tetsuya Kubota,
Shinsuke Itoh,
Hiroki Kumagai, Hideki Kozono,
Iseki Takamoto,
Tomoka Mineyama,
Hitomi Ogata,
Kumpei Tokuyama,
Mitsuru Ohsugi, [......],
Kaoru Sugi,
Shigeru Kakuta,
Yoichiro Iwakura,
Tetsuo Noda,
Shin Ohnishi,
Ryozo Nagai,
Kazuyuki Tobe,
Yasuo Terauchi,
Kohjiro Ueki,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Insulin receptor substrate (Irs) mediates metabolic actions of insulin. Here, we show that hepatic Irs1 and Irs2 function in a distinct manner in the regulation of glucose homeostasis. The PI3K activity associated with Irs2 began to increase during fasting, reached its peak immediately after refeeding, and decreased rapidly thereafter. By contrast, the PI3K activity associated with Irs1 began to increase a few hours after refeeding and reached its peak thereafter. The data indicate that Irs2 mainly functions during fasting and immediately after refeeding, and Irs1 functions primarily after refeeding. In fact, liver-specific Irs1-knockout mice failed to exhibit insulin resistance during fasting, but showed insulin resistance after refeeding; conversely, liver-specific Irs2-knockout mice displayed insulin resistance during fasting but not after refeeding. We propose the concept of the existence of a dynamic relay between Irs1 and Irs2 in hepatic insulin signaling during fasting and feeding.
Cell metabolism 08/2008; 8(1):49-64. · 17.35 Impact Factor
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Naoto Kubota,
Wataru Yano,
Tetsuya Kubota,
Toshimasa Yamauchi,
Shinsuke Itoh,
Hiroki Kumagai, Hideki Kozono,
Iseki Takamoto,
Shiki Okamoto,
Tetsuya Shiuchi, [......],
Yoichi Ueta,
Tatsuya Kondo,
Eiichi Araki,
Osamu Ezaki,
Ryozo Nagai,
Kazuyuki Tobe,
Yasuo Terauchi,
Kohjiro Ueki,
Yasuhiko Minokoshi,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin has been shown to stimulate fatty acid oxidation and enhance insulin sensitivity through the activation of AMP-activated protein kinase (AMPK) in the peripheral tissues. The effects of adiponectin in the central nervous system, however, are still poorly understood. Here, we show that adiponectin enhances AMPK activity in the arcuate hypothalamus (ARH) via its receptor AdipoR1 to stimulate food intake; this stimulation of food intake by adiponectin was attenuated by dominant-negative AMPK expression in the ARH. Moreover, adiponectin also decreased energy expenditure. Adiponectin-deficient mice showed decreased AMPK phosphorylation in the ARH, decreased food intake, and increased energy expenditure, exhibiting resistance to high-fat-diet-induced obesity. Serum and cerebrospinal fluid levels of adiponectin and expression of AdipoR1 in the ARH were increased during fasting and decreased after refeeding. We conclude that adiponectin stimulates food intake and decreases energy expenditure during fasting through its effects in the central nervous system.
Cell Metabolism 08/2007; 6(1):55-68. · 13.67 Impact Factor
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Toshimasa Yamauchi,
Yasunori Nio,
Toshiyuki Maki,
Masaki Kobayashi,
Takeshi Takazawa,
Masato Iwabu,
Miki Okada-Iwabu,
Sachiko Kawamoto,
Naoto Kubota,
Tetsuya Kubota, [......],
Tomohiro Ide,
Kouji Murakami,
Motoharu Awazawa,
Iseki Takamoto,
Philippe Froguel,
Kazuo Hara,
Kazuyuki Tobe,
Ryozo Nagai,
Kohjiro Ueki,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.
Nature Medicine 04/2007; 13(3):332-9. · 22.46 Impact Factor
