HARVARD COLLEGE, PRESIDENT & FELLOWS OF
Obesity, insulin resistance, fatty liver disease, and type 2 diabetes frequently cluster together and are among the most common chronic metabolic diseases threatening human welfare in the US and around the world. Our work in the past has demonstrated that these metabolic diseases have a strong inflammatory underpinning and that the pathways coordinately regulating immune and metabolic responses are central to the etiology of chronic metabolic diseases. In search for the role of lipids in coordinating inflammation and metabolism, we have discovered a critical role for fatty acid binding proteins, aP2 and mal1, acting in adipocytes and macrophages. Suppression or deletion of FABPs in mice results in marked protection against insulin resistance, fatty liver disease, type 2 diabetes, and atherosclerosis. These FABPs regulate the inflammatory function of macrophages particularly the responses elicited by saturated lipids or modified lipoproteins. They also regulate the endocrine signals emerging from adipose tissue to alter liver and muscle metabolism. Recently, we have made a surprising observation that aP2, which has long been considered an intracellular protein, is secreted from adipocytes through the non-classical pathway. More importantly, the secreted aP2 has strong biological activity and regulates glucose metabolism and potentially inflammatory responses, particularly in the liver. Our parent proposal was built on examining biological functions of secreted FABPs and developed methods to administer and neutralize this protein in live animals. During the course of this work, we realized that aP2 secretion is nutritionally regulated and one of the major targets of its action is hepatic gluconeogenesis. To explore the regulation of hepatic glucose production by aP2, we would like to expand our current proposal and set up a live animal monitoring system, where we can examine the impact of aP2 and possibly other adipocyte products regulated by aP2, on hepatic glucose production. Since the experimentation would require manipulation of the nutritional status and possible combination of hormones such as glucagons, it is very difficult to explore this action of aP2 and link it to molecular mechanisms at the target tissue without a live animal monitoring system. Similarly, we would also incorporate live animal reporter systems for inflammatory responses, again to monitor the impact of aP2 on these responses during nutritional fluctuations.