Effects of metformin on skeletal muscle peroxisomal and mitochondrial handling of fatty acids in the obese (FA/FA) Zucker rat / by Jesse W. Price III.
| Author/creator | Price, Jesse W. author. |
| Other author | Cortright, Ronald N., degree supervisor. |
| Other author | East Carolina University. Department of Biology. |
| Format | Theses and dissertations |
| Production | 2008. |
| Description | 70 leaves : illustrations ; 29 cm |
| Supplemental Content | Access via ScholarShip |
| Subjects |
| Subject | Obesity is epidemic in Western Society and can be directly associated with a number of pathologies that significantly increase morbidity and mortality including type 2 diabetes. Metformin is a widely prescribed biguanide used for the treatment of type II diabetes. Although it serves to lower fasting blood glucose levels by 25-30%, its exact mechanism of action is currently unclear. Studies have shown that Metformin reduces triglyceride levels as well as alters the overall lipid profile in skeletal muscle (SKM). This is of potential therapeutic consequence as researchers have provided evidence suggesting that bioactive lipid accumulation often seen in the SKM of the obese is related to insulin resistance. However, peroxisomal oxidation yields metabolites that are more efficiently utilized by mitochondria. Research from our lab has shown that unlike SKM from lean subjects, the presence of peroxisomal activity has been detected in the obese. Since the peroxisome is capable of partial fatty acid oxidation and increasing mitochondrial oxidative efficiency, it has been hypothesized that the up-regulation of this organelle may be a compensatory mechanism to combat the buildup of bioactive lipids. Because Metformin's insulin sensitizing effects are associated with enhanced SKM mitochondrial oxidation of fatty acids, we hypothesized that chronic metformin treatment would improve mitochondrial function by increasing peroxisomal activity. Alternatively, metformin may act solely at the level of the mitochondria thereby reducing the compensatory need for peroxisomal activity in the presence of enhanced mitochondrial oxidative capacity. Hypotheses were tested in lean and obese-insulin resistant Zucker rats (fa/fa) by measuring rates of radiolabeled long-chain (l-¹⁴C palmitate) and very-long chain lignoceric acid) fatty acid oxidation for mitochondrial and peroxisomal oxidation respectively. Subjects were divided into four groups (n=8 per group) consisting of untreated and treated (daily dose of 320 mg/kg body weight/per day for 30 days) lean and obese animals. Oral glucose tolerance tests (OGTT) were also performed to ensure a drug effect. OGTT results indicated Metformin successfully increased (P[less-than]0.05) insulin sensitivity in the treated animals. The obese animals showed an increase in peroxisomal activity when compared to their lean counterparts. However, Metformin failed to alter peroxisomal activity in either the lean or obese treated animals. There was also no significant difference observed in palmitate oxidation rates between the treated and untreated animals in either of the obese or lean groups. Results recapitulated data from previous experiments demonstrating increased peroxisomal activity in the obese vs. lean rat SKM. However, data did not support Metformin's insulin sensitizing effects were acting through alterations in either SKM mitochondrial or peroxisomal fatty acid oxidation. Alternative mechanisms to explain the results are discussed. |
| General note | Presented to the faculty of the Department of Biology. |
| General note | Advisor: Ronald N. Cortright |
| Dissertation note | M.S. East Carolina University 2008 |
| Bibliography note | Includes bibliographical references (leaves 55-64). |
| Genre/form | dissertations. |
| Genre/form | Academic theses. |
| Genre/form | Academic theses. |
| Genre/form | Thèses et écrits académiques. |