| MPA6 | |
| Project ID |  MPA6 [Protein] |
| Project Theme | Structure-based functional analyses and development of drug intervention in metabolic syndrome and diabetes- AdipoR/AMPK/ACC as key targets |
| Project Theme (short) | Metabolic disease: adiponectin pathway |
| Principal Investigator | Takashi Kadowaki |
| Affiliation | Graduate School of Medical Science, The University of Tokyo |
| Backgrounds | - Obesity increases the likelihood of various diseases, particularly metabolic syndrome (MS), type 2 diabetes and heart disease - We have discovered that the deficiency or downregulation of adiponectin is partly responsible for MS and type 2 diabetes - Detailed understanding of the signaling mechanism mediated by adiponectin/adiponectin receptors (AdipoR) could lead to therapeutics developments for MS and type 2 diabetes |
| Highlights | - Analyses of AdipoR1 actions in muscle cells revealed that the activation of AdipoR1 induces effects in a similar fashion to exercise - Among the enzymes in the adiponectin signaling pathway, the structures of CaMKK2 and AMPKα2 in complex with each inhibitor have been determined. Compounds screening is in progress based on the structural information - We have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway independently of the known receptors |
| Outline | We have discovered that the deficiency or downregulation of adiponectin is partly responsible for type 2 diabetes and metabolic syndrome (MS). Adiponectin is a protein hormone secreted from adipose tissue into the bloodstream and modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism. The binding of adiponectin with adiponectin receptors (AdipoR) on the membrane surface of liver and skeletal muscle cells mediates the increase in the downstream target AMP kinase (AMPK), resulting in fatty acids degradation. In this project, we select, in addition to AdipoR, enzymes AMPK and ACC (acetyl-Coenzyme A carboxylase) among the enzymes in the adiponectin signaling pathway as our primary target proteins. ACC is involved in the biosynthesis of fatty acids and its activity is inhibited by AMPK. We will determine the structures of these target proteins and find compounds that regulate the proteins to build the molecular basis in drug developments for MS and diabetes. |
| Review | Nutrition Cell Metab. |
| CSML File | MPA6.csml |