title: A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity.
abstract: 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.
authors.affiliation: 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [3] Department of Molecular Medicinal Sciences on Metabolic Regulation, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo 113-0033, Japan [4].
authors.forename: Miki
authors.initials: M
authors.lastname: Okada-Iwabu
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Masato
authors.initials: M
authors.lastname: Iwabu
authors.forename: Teruki
authors.initials: T
authors.lastname: Honma
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Hamagami
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Mamiko
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanabe
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kimura-Someya
authors.forename: Mikako
authors.initials: M
authors.lastname: Shirouzu
authors.forename: Hitomi
authors.initials: H
authors.lastname: Ogata
authors.forename: Kumpei
authors.initials: K
authors.lastname: Tokuyama
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nagano
authors.forename: Akiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism / Q000494:pharmacology; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D059305:Diet, High-Fat; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000188:drug therapy; D004789:Enzyme Activation / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008136:Longevity / Q000187:drug effects*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects; D009132:Muscles / Q000166:cytology; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D054419:Receptors, Adiponectin / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry; D014157:Transcription Factors / Q000096:biosynthesis; D014280:Triglycerides / Q000378:metabolism
chemical_list: C585113:AdipoRon; D052242:Adiponectin; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010880:Piperidines; C485290:Ppargc1a protein, mouse; D054419:Receptors, Adiponectin; D054852:Small Molecule Libraries; D014157:Transcription Factors; D014280:Triglycerides; C475419:adiponectin receptor 1, mouse; C475421:adiponectin receptor 2, mouse; D000263:Adenylate Kinase