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Motoharu Awazawa,
Kohjiro Ueki,
Kazunori Inabe,
Toshimasa Yamauchi,
Naoto Kubota,
Kazuma Kaneko,
Masatoshi Kobayashi,
Aya Iwane,
Takayoshi Sasako,
Yukiko Okazaki,
Mitsuru Ohsugi,
Iseki Takamoto,
Satoshi Yamashita,
Hiroshi Asahara,
Shizuo Akira,
Masato Kasuga,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.
Cell metabolism 04/2011; 13(4):401-12. · 17.35 Impact Factor
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Naoki Kobayashi,
Kohjiro Ueki,
Yukiko Okazaki,
Aya Iwane,
Naoto Kubota,
Mitsuru Ohsugi, Motoharu Awazawa,
Masatoshi Kobayashi,
Takayoshi Sasako,
Kazuma Kaneko, [......],
Kazuo Hara,
Kotaro Yoshimura,
Isao Koshima,
Susumu Goyama,
Koji Murakami,
Junko Sasaki,
Ryozo Nagai,
Mineo Kurokawa,
Takehiko Sasaki,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.
Proceedings of the National Academy of Sciences 03/2011; 108(14):5753-8. · 9.68 Impact Factor
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Kazuma Kaneko,
Kohjiro Ueki,
Noriko Takahashi,
Shinji Hashimoto,
Masayuki Okamoto, Motoharu Awazawa,
Yukiko Okazaki,
Mitsuru Ohsugi,
Kazunori Inabe,
Toshihiro Umehara,
Masashi Yoshida,
Masafumi Kakei,
Tadahiro Kitamura,
Ji Luo,
Rohit N Kulkarni,
C Ronald Kahn,
Haruo Kasai,
Lewis C Cantley,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Type 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca(2+) influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.
Cell metabolism 12/2010; 12(6):619-32. · 17.35 Impact Factor
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[show abstract]
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ABSTRACT: Adiponectin, one of the insulin-sensitizing adipokines, has been shown to activate fatty acid oxidation in liver and skeletal muscle, thus maintaining insulin sensitivity. However, the precise roles of adiponectin in fatty acid synthesis are poorly understood. Here we show that adiponectin administration acutely suppresses expression of sterol regulatory element-binding protein (SREBP) 1c, the master regulator which controls and upregulates the enzymes involved in fatty acid synthesis, in the liver of +Lepr(db)/+Lepr(db) (db/db) mouse as well as in cultured hepatocytes. We also show that adiponectin suppresses SREBP1c by AdipoR1, one of the functional receptors for adiponetin, and furthermore that suppressing either AMP-activated protein kinase (AMPK) via its upstream kinase LKB1 deletion cancels the negative effect of adiponectin on SREBP1c expression. These data show that adiponectin suppresses SREBP1c through the AdipoR1/LKB1/AMPK pathway, and suggest a possible role for adiponectin in the regulation of hepatic fatty acid synthesis.
Biochemical and Biophysical Research Communications 05/2009; 382(1):51-6. · 2.48 Impact Factor
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Taku Watanabe,
Naoto Kubota,
Mitsuru Ohsugi,
Tetsuya Kubota,
Iseki Takamoto,
Masato Iwabu, Motoharu Awazawa,
Hisayuki Katsuyama,
Chiaki Hasegawa,
Kumpei Tokuyama,
Masao Moroi,
Kaoru Sugi,
Toshimasa Yamauchi,
Tetsuo Noda,
Ryozo Nagai,
Yasuo Terauchi,
Kazuyuki Tobe,
Kohjiro Ueki,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Rimonabant has been shown to not only decrease the food intake and body weight but also to increase serum adiponectin levels. This increase of the serum adiponectin levels has been hypothesized to be related to the rimonabant-induced amelioration of insulin resistance linked to obesity, although experimental evidence to support this hypothesis is lacking. To test this hypothesis experimentally, we generated adiponectin knock-out (adipo(-/-))ob/ob mice. After 21 days of 30 mg/kg rimonabant, the body weight and food intake decreased to similar degrees in the ob/ob and adipo(-/-)ob/ob mice. Significant improvement of insulin resistance was observed in the ob/ob mice following rimonabant treatment, associated with significant up-regulation of the plasma adiponectin levels, in particular, of high molecular weight adiponectin. Amelioration of insulin resistance in the ob/ob mice was attributed to the decrease of glucose production and activation of AMP-activated protein kinase (AMPK) in the liver induced by rimonabant but not to increased glucose uptake by the skeletal muscle. Interestingly, the rimonabant-treated adipo(-/-)ob/ob mice also exhibited significant amelioration of insulin resistance, although the degree of improvement was significantly lower as compared with that in the ob/ob mice. The effects of rimonabant on the liver metabolism, namely decrease of glucose production and activation of AMPK, were also less pronounced in the adipo(-/-)ob/ob mice. Thus, it was concluded that rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways.
Journal of Biological Chemistry 12/2008; 284(3):1803-12. · 4.77 Impact Factor
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Wataru Yano,
Naoto Kubota,
Shinsuke Itoh,
Tetsuya Kubota, Motoharu Awazawa,
Masao Moroi,
Kaoru Sugi,
Iseki Takamoto,
Hitomi Ogata,
Kumpei Tokuyama,
Tetsuo Noda,
Yasuo Terauchi,
Kohjiro Ueki,
Takashi Kadowaki
[show abstract]
[hide abstract]
ABSTRACT: Adiponectin has been proposed to act as an antidiabetic adipokine, suppressing gluconeogenesis and stimulating fatty acid oxidation in the liver and skeletal muscle. Although adiponectin-knockout (adipo(-/-)) mice are known to exhibit insulin resistance, the degrees of insulin resistance and glucose intolerance are unexpectedly only moderate. In this study, the adipo(-/-) mice showed hepatic, but not muscle, insulin resistance. insulin-stimulated phosphorylation of IRS-1 and IRS-2 was impaired, the IRS-2 protein level was decreased, and insulin-stimulated phosphorylation of Akt was decreased in the liver of the adipo(-/-) mice. However, the triglyceride content in the liver was not increased in these mice, despite the decrease in the PPARalpha expression involved in lipid combustion, since the expressions of lipogenic genes such as SREBP-1 and SCD-1 were decreased in association with the increased leptin sensitivity. Consistent with this, the down-regulation SREBP-1 and SCD-1 observed in the adipo(-/-) mice was no longer observed, and the hepatic triglyceride content was significantly increased in the adiponectin leptin double-knockout (adipo(-/-)ob/ob) mice. On the other hand, the triglyceride content in the skeletal muscle was significantly decreased in the adipo(-/-) mice, probably due to up-regulated AMPK activity associated with the increased leptin sensitivity. In fact, these phenotypes in the skeletal muscle of these mice were no longer observed in the adipo(-/-)ob/ob mice. In conclusion, adipo(-/-) mice showed impaired insulin signaling in the liver to cause hepatic insulin resistance, however, no increase in the triglyceride content was observed in either the liver or the skeletal muscle, presumably on account of the increased leptin sensitivity.
Endocrine Journal 08/2008; 55(3):515-22. · 2.03 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
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Clinical calcium 09/2003; 13(8):1077-82.
