SUBSTRATE REGULATION DURING ENERGY DEFICIT IN OBESITY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recent estimates indicate that nearly two-thirds of all adults in the United States are overweight or obese. Despite attempts by millions of people to lose weight the prevalence of obesity continues to increase at an alarming rate. Weight-loss requires that fewer calories be ingested than expended (i.e.; energy deficit), but the mechanisms that recognize and respond to energy deficit are poorly understood. The human body is very sensitive to a reduced availability of carbohydrate, and the major hormonal responses known to affect energy metabolism are primarily influenced by changes in carbohydrate availability rather than dietary fat. The mechanisms that "sense" a reduction in energy availability, without a change in carbohydrate availability are not well defined. Accordingly, identifying mechanisms by which the human body responds and adapts to energy deficit, per se, could lead to improved dietary and/or pharmacological treatments for obesity. Our first aim is to evaluate the involvement of the gastrointestinal tract on the regulation of lipid and protein metabolism when ingesting a low calorie-low fat diet. We will measure lipolysis, glucose uptake, protein degradation, and protein synthesis in abdominally obese men and women (Class I and II obesity) after a weight-maintenance diet and again after 2 days of a 40% energy deficit, induced by lowering fat intake to <5g/day. On a third visit, subjects will ingest the low-fat diet for 2 days but we will prevent an energy deficit by infusing lipids intravenously, by-passing the gastrointestinal tract. Our second aim is to identify novel peptides released from skeletal muscle and adipose tissue in response to a low calorie-low fat diet. Our overall hypothesis is that the energy deficit from a low-fat diet is primarily "sensed" in the gastrointestinal tract. This initiates a cascade of signals that stimulate metabolic processes such as lipolysis and proteolysis, while reducing protein synthesis. However, we also believe that novel peripheral factors are released from adipose tissue and skeletal muscle to augment the metabolic response to systemic energy availability. The findings from this study will identify mechanisms involved in sensing and responding to energy deficit, which is critical for the development of improved pharmacological and dietary treatments for weight-loss.