Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes
Toshimasa Yamauchi,Hironori Waki,Junji Kamon,Koji Murakami,Kiyoto Motojima,Kajuro Komeda,Hiroshi Miki,Naoto Kubota,Yasuo Terauchi,Atsuko Tsuchida,Nobuyo Tsuboyama-Kasaoka,Naoko Yamauchi,Tomohiro Ide,Wataru Hori,Shigeaki Kato,Masashi Fukayama,Yasuo Akanuma,Osamu Ezaki,Akiko Itai,Ryozo Nagai,Satoshi Kimura,Kazuyuki Tobe,Hiroyuki Kagechika,Koichi Shudo,Takashi Kadowaki +24 more
TLDR
It is shown that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver, thereby ameliorating HF diet-induced obesity and insulin resistance.Abstract:
PPARγ is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARγ by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARγ activity observed in heterozygous PPARγ-deficient mice or the Pro12Ala polymorphism in human PPARγ, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARγ/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARγ antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin’s effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARγ-deficient mice with an RXR antagonist or a PPARγ antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARγ/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.read more
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Adiponectin and Adiponectin Receptors
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Short-Chain Fatty Acids protect against High-Fat Diet-Induced Obesity via a PPARγ-dependent switch from lipogenesis to fat oxidation
Gijs den Besten,Aycha Bleeker,Albert Gerding,Karen van Eunen,Rick Havinga,Theo H. van Dijk,Maaike H. Oosterveer,Johan W. Jonker,Albert K. Groen,Dirk-Jan Reijngoud,Barbara M. Bakker +10 more
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Nuclear receptors and the control of metabolism.
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Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity
Atsushi Tsuchida,Toshimasa Yamauchi,Yusuke Ito,Yusuke Hada,Toshiyuki Maki,Sato Takekawa,Junji Kamon,Masaki Kobayashi,Ryo Suzuki,Kazuo Hara,Naoto Kubota,Yasuo Terauchi,Philippe Froguel,Jun Nakae,Masato Kasuga,Domenico Accili,Kazuyuki Tobe,Kohjiro Ueki,Ryozo Nagai,Takashi Kadowaki +19 more
TL;DR: The expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyper-insulinemia models via the insulin/phosphoinositide 3-kinase/Foxo1 pathway and is correlated with adiponectin sensitivity.
References
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The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity
Toshimasa Yamauchi,Junji Kamon,Hironori Waki,Yasuo Terauchi,Naoto Kubota,Kazuo Hara,Y. Mori,Tomohiro Ide,Kouji Murakami,Nobuyo Tsuboyama-Kasaoka,Osamu Ezaki,Y. Akanuma,Oksana Gavrilova,Charles Vinson,Marc L. Reitman,Hiroyuki Kagechika,Koichi Shudo,Madoka Yoda,Yasuko Nakano,Kazuyuki Tobe,R. Nagai,Shigeko Kimura,Motowo Tomita,Philippe Froguel,Takashi Kadowaki +24 more
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UK Prospective Diabetes,Rury R. Holman,Susan E. Manley,R C Turner,Carole A. Cull,Irene M Stratton,Matthews,Michael Gnant +7 more
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An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ)
Jürgen M. Lehmann,Linda B. Moore,Tracey Smith-Oliver,William O. Wilkison,Timothy M. Willson,Steven A. Kliewer +5 more
TL;DR: It is reported that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis, and raised the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compounds.
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