A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity
| Autor: | Miki Okada-Iwabu, Mamiko Yamaguchi, Masato Iwabu, Tomomi Kimura-Someya, Akiko Tanaka, Toshimasa Yamauchi, Takashi Kadowaki, Teruki Honma, Tetsuo Nagano, Koichi Matsuda, Kumpei Tokuyama, Mikako Shirouzu, Hiroaki Tanabe, Ken-ichi Hamagami, Shigeyuki Yokoyama, Hitomi Ogata, Kohjiro Ueki |
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| Rok vydání: | 2012 |
| Předmět: |
Agonist
medicine.medical_specialty medicine.drug_class Adipose Tissue White Longevity Muscle Fibers Skeletal Drug Evaluation Preclinical Administration Oral Type 2 diabetes Diet High-Fat Small Molecule Libraries chemistry.chemical_compound Mice Insulin resistance Piperidines Internal medicine Diabetes mellitus Glucose Intolerance medicine Animals PPAR alpha Obesity Triglycerides Dyslipidemias Adiponectin receptor 1 Inflammation Multidisciplinary Adiponectin business.industry Muscles Adenylate Kinase AMPK medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha AdipoRon Mitochondria Enzyme Activation Oxidative Stress Endocrinology chemistry Diabetes Mellitus Type 2 Liver Insulin Resistance Receptors Adiponectin business Signal Transduction Transcription Factors |
| Zdroj: | Nature. 503(7477) |
| ISSN: | 1476-4687 |
| Popis: | Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes. |
| Databáze: | OpenAIRE |
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