Lipoprotein Lipase (LPL) is a hydrolytic enzyme which catalyses the rate limiting step in the delivery of lipoprotein triglyceride fatty acids to tissues. The purpose of the studies outlined in this proposal is to understand how the tissue-dependent relation of LPL by macronutrients relates to body weight maintenance. Prior research indicates that LPL activity responds in a tissue-specific manner to changes in nutritional state. However, because of variations in the time of examination, types and duration of diets fed, and the tissues examined, studies in this area remain incomplete. In addition, the role of changes in LPL gene activity in causing these events has not been systematically studied. Adipose tissue LPL (ATLPL) and to some extent muscle LPL activity is also altered in states of abnormal bodyweight regulation. In the obese or reduced-obese state, ATLPL activity is increased. In the cachexia of malignancy it is decreased; here tumor necrosis factor may play an important role. It is postulated that the tissue-specific activity of this enzyme is regulated in such a way that lipoprotein triglycerides are either delivered primarily to adipose tissue for energy storage or away from adipose tissue, e.g. to muscle for the provision of energy, depending on whether the organism is in positive or negative energy balance. In obesity, we believe the regulation of this enzyme is altered favoring storage of lipid in adipose tissue. LPL activity has also ben found in the central nervous system, where it responds to changes in nutrition. We believe that its function here may be to provide substrate to neurons at a rate dependent on the nutritional state of the animal, just as it does in other tissues. The delivery of lipoprotein triglyceride fatty acids could result in the transduction of metabolic information about total body energy stores and post-prandial lipid fluxes into neurochemical or electrical information about total body energy stores and post-prandial lipid fluxes into neurochemical or electrical information which could then modify eating behavior and central thermogenic mechanisms. The proposed experiments will systematically examine the impact of macronutrient composition, i.e. diets of normal composition (higher in carbohydrate) vs. diets high in fat, on tissue- specific LPL mRNA levels and LPL enzyme activities in lean and obese rats. LPL synthesis in the brain will be localized by in-situ hybridization, and the final location of the enzyme will be determined by immunohistochemistry. Genetic and nutritionally acquired models of obesity will be studied in both the obese and reduced-obese states, and tumor necrosis factor will be given a lean and obese rates to see if reduction in food intake and body weight are associated with concominant decreases in brain and adipose tissue LPL. These studies should provide exciting new insights into the role of LPL in the regulation of body weight.
