2007 Annual Report 1a.Objectives (from AD-416) LAB: Obesity and Metabolism (2) To determine role and molecular mechanisms by which perilipin regulates fat cell lipolysis and fat storage in adipocytes. To determine the mechanism(s) by which the absence of perilipin expression in mouse adipocytes (perilipin null mice) results in resistance to diet and genetic-induced obesity. To define how age, sex, genetic background, and diet alters the susceptibility of perilipin null and wild type mice to the development of insulin resistance and diabetes. 1b.Approach (from AD-416) LAB: Obesity and Metabolism (2) Adipocytes are not only the major repository of body fat, they are also critical regulators of whole lipid body fatty acid flux. Insights into how adipocytes regulate fat metabolism will provide important & necessary info to prevent obesity and its complications. Perilpins(peri)are proteins that coat intracellular stores of fat in adipocytes. Peri act as gatekeepers to regulate fat storage and lipolysis at the lipid droplet surface. While certain details of peri are known, the molecular mechanisms that underlie how peri regulates fat metabolism and the consequences of peri ablation on systemic insulin and glucose homeostasis remain unclear. We will use peri null to delineate the role & molecular mechanisms of peri in regulating adipocyte lipolysis. Peri null mice are resistant to the development of diet-induced & genetic obesity. Investigate potential mechanisms that underlie how peri ablation protects against the development of obesity. Additionally, investigate how different genetic backgrounds, age, percent gender interact with peri ablation to alter susceptibility for the development of insulin resistance. 4.Accomplishments 1) Saturated Fatty Acids But Not Unsaturated Fatty Acids Block Insulin Action. Obese individuals are at increased risk of developing diabetes because they are resistant to the actions of the antidiabetic hormone insulin. To reduce an obese individual’s risk of becoming diabetic it is important to determine which nutrients make cells resistant to the actions of insulin (insulin resistance). We have found that saturated fatty acids, but not unsaturated fatty acids, block the actions of insulin in human muscle cells. Additionally, unsaturated fatty acids added in combination with saturated fatty acids were found to protect against the detrimental actions of saturated fatty acids to increase insulin resistance. These studies provide important data about how different fatty acids can affect the development of insulin resistance. Thus, these data will prove useful to national committees in making recommendations to reduce an individual’s risk of developing obesity-associated diabetes. This accomplishment aligns with National Program 107 Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle. 2)Hormones Reduce Fat Stores by Several Mechanisms. Both weight-loss diets and exercise increase blood levels of hormones that reduce fat mass in obese individuals but the mechanisms how these hormone actually promote weight loss are unclear. It is controversial whether hormone-mediated breakdown of fat in fat cells, also activates pathways that promote fat burning (oxidation) and inhibit fat synthesis. We have found that the breakdown of fat, in fat cells, activates pathways that promote fat burning and reduce fat synthesis. These data provide new insights into understanding how reduced intake of calories during dieting and also exercise, both of which increase circulating blood levels of hormones that increase fat breakdown, promote fat loss. These data will be useful for national committees in designing programs for preventing obesity and promoting weight loss. This accomplishment aligns with National Program 107 Component 6-Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle. 5.Significant Activities that Support Special Target Populations None. 6.Technology Transfer Number of non-peer reviewed presentations and proceedings 6 Number of newspaper articles and other presentations for non-science audiences 4