This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Worldwide, there is truly an epidemic of obesity and 'type 2 diabetes' (distinguished from 'type 1 diabetes' which usually develops before adulthood and has a different cause). Although there are many complications of obesity, type 2 diabetes is an important one and does not develop in all obese people but does develop in some people who are not obese. It is thus important to understand whether diet may promote the development of type 2 diabetes. Type 2 diabetes is thought to develop, in part, because the hormone, insulin, does not function adequately in allowing blood sugar (glucose) to enter the muscle cells. Defective activity of insulin is in turn thought to develop because fat is not optimally burned in the muscle cell leading to the accumulation of 'toxic fats' in the muscle cell which prevent insulin from signaling the muscle cell to allow more glucose to enter it. Some examples of 'toxic fats' are 'DAG, ceramide, -hydroxybutyrate, and acyl-carnitines'. Our preliminary data in young, non-obese, human subjects suggest that increasing dietary saturated fat (palmitic acid, PA) lowers the rate of fat burning, especially in females and also lowers the daily energy cost for maintaining body weight by lowering the energy cost of performing exercise (especially in males). We also have preliminary data from our co-investigator at Duke University, Deborah Muoio, who studies isolated muscle cells from rodents and humans. She has shown that monounsaturated fat (oleic acid, OA) causes increased activity of genes which govern fat oxidation in the cell ('PPAR genes'). She also has shown that saturated fat causes less production ('transcription) of the gene, PGC-1, which activates other genes that stimulate both fat and energy burning. These genes also inhibit the activity of an enzyme which manufactures monounsaturated fat from saturated fat in the cell (called SCD1), within certain compartments of the cell which may be distinct from the compartments where dietary fat is stored. Animals which have lower activity of SCD1 are protected from obesity and are able to burn fat and energy at an increased rate. Dr Muoio's preliminary data show that OA caused less activity of SCD1. We will conduct a feeding trial in 28 healthy, non-obese, adults, 18-40 yr of age, who will be fed experimental diets (moderately high in fat), in random order: both a high OA/low PA diet called HI OA and a high PA diet, called HI PA (each for 3 wk). The subjects and the investigators will be masked to the identity of the order of the diets until the data are judged to be complete and adequate. Each subject will be screened to determine eligibility: healthy and not on medication (including birth control pills); non-obese; sedentary and not exceptionally physically fit; normal serum glucose and lipids in blood. Then, each subject will be fed a low-fat, control diet for one week after which blood will be drawn and muscle tissue will be obtained by needle biopsy of the thigh in the pre-breakfast and post-breakfast state. Then the subject will be fed one of the two experimental diets for three weeks. The blood and muscle tests will be repeated and then the subject will be fed the low-fat diet for one week followed by the second experimental diet for three weeks. The final (third) series of blood and muscle tests will be repeated. In addition, at the end of each of the experimental diets, the subjects will undergo measurements of fat and calorie burning (overnight) and a test of insulin action and secretion (intravenous glucose tolerance test). The following Aims will be assessed: 1. To investigate how PPAR and PGC genes are regulated in muscle in response to the experimental diets in comparison to the control, low fat, diet. 2. To correlate changes in whole-body fat burning and gene activity with levels of various toxic lipids in muscle.3. To assess whether increasing the intake of OA lowers the activity of SCD1.4. To evaluate the role of gender in affecting responses to PA and OA. This project will provide important new information regarding how diet fat alters the functions of muscle and whether it plays a central role in the development of obesity, type 2 diabetes, and both inherited and age-related metabolic diseases.
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