Diabetes/insulin resistance and obesity are major health issues that cost the United States nearly $100 billion per year. Recent molecular, cellular and physiological studies have begun to identify several potential targets that can be used to develop novel therapeutics. There are three general classes of functional therapeutics that can be developed. The first are insulin sensitizers similar to the recently identified PPAR agonist thiazolidinedione family that reduce fatty acid levels through increase adipocyte function. The second target area to develop are agents that modify energy balance by modifying hypothalamic function. It has been shown that the MC4 receptor is a central mediator of satiety allowing for the development of both specific agonists and antagonists. Lastly, adipocytes have recently been shown to act as an endocrine organ by secreting various factors in response to the amount of energy stored in this tissue. These hormones enter the circulation and act on various tissues including the hypothalamus (leptin), and muscle tissue (resistin and Acrp30) to affect energy uptake, insulin resistance and increased oxidation and fatty acid metabolism.
A project team of the Institute headed by Dr. Pessin will develop Acrp30 agonists that will increase fatty acid metabolism in muscle and thereby increase insulin sensitivity. In parallel, this project team will establish a chemical biology approach (Dr. Raleigh, Dr. Tonge, Dr. Kisker, Dr. Simmerling) to identify lead agents that enhance adipocyte differentiation. These lead agents should function similar to thiazolidinediones by increasing fatty acid uptake and storage in adipocytes. Based on these drug leads, potential therapeutic drugs for treatment of diabetes and obesity will be developed through SAR study (Dr. Ojima, Dr. F. Johnson, Dr. Dueckhammer).