Roy O. Greep Award for Outstanding Research
Takashi Kadowaki, MD, PhD
Adiponectin is an adipocyte hormone that is most abundantly expressed in white adipose tissue. Dr. Kadowaki discovered that adiponectin enhances insulin sensitivity and possesses anti-diabetic actions. He identified and cloned the receptors of adiponectin (AdipoR1 and AdipoR2), both of which are seven-transmembrane receptors. Remarkably, they were found to represent a new family of receptors with their N-terminals inside, and their C-terminals outside of the cells, with the reverse topology of G-protein-coupled receptors (GPCR).
Dr. Kadowaki showed that AdipoR1 activates the AMP kinase pathway and AdipoR2 activates the PPAR pathway, both of which regulate oxidation of glucose and fatty acids and enhance insulin sensitivity. In obese subjects, both adiponectin and AdipoR1/R2 levels are reduced, substantially contributing to the pathophysiology of type 2 diabetes, metabolic syndrome, cardiovascular disease, and reduced longevity.
“Endocrine research is quite rewarding since it will reveal truth and secrets of health and disease after a certain amount of hard work, which you will enjoy with a sense of accomplishment.”
He was the first to succeed in developing a small-molecule adiponectin receptor agonist (AdipoR Agonist: AdipoRon). Orally administered AdipoRon activates the same signaling pathway as caloric restriction and physical exercise, thereby improving obesity-related diseases as a whole, including type 2 diabetes. This proof of concept for an oral Adiponectin drug has fostered tremendous interest in adiponectin therapeutics, facilitated by his recent elucidation of the three-dimensional structure of adiponectin receptors.
Dr. Kadowaki has also led important genetic and clinical studies that have important impact for understanding, diagnosis and treatment of metabolic disorders. His recent genetics have confirmed the importance of identifying genetic variation and diabetes susceptibility in Asian populations. Dr. Kadowaki’s accomplishments have not only enabled essential understanding of the molecular mechanisms of adiponectin action but have re-invigorated adiponectin-based drug development programs for type 2 diabetes. Collectively, his body of work, broadly focused on insulin action in health and disease, exhibits both a high degree of novelty and immediate translational relevance.
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