This proposal details a 3-year training program to develop the skills necessary for candidate Eric Goetzman to become an independent research scientist. In July 2006 Dr. Goetzman assumed an assistant professor position at the University of Pittsburgh with 90% protected time for developing his research career. His scientific background is in the study of the acyl-CoA dehydrogenases (ACADs), a key family of mitochondrial fatty acid oxidation enzymes. Dr. Goetzman now wishes to transfer his knowledge of fatty acid oxidation into the study of obesity and adipose tissue biology. Dr. Jerry Vockley, a biochemical geneticist and expert on inborn errors of fatty acid oxidation, will mentor Dr. Goetzman's career training. Dr. Robert O'Doherty will act as co-sponsor. Dr. O'Doherty is an obesity/diabetes researcher and an expert in insulin and leptin signaling. His mentorship will provide the applicant with training in new methodologies and guidance in navigating the field of obesity research using animal models. Dr. Goetzman presents three key pieces of preliminary data: 1) knockout mice with reduced fatty acid oxidation have dysregulated fatty acid release from adipose tissue;2) the insulin sensitizing drug rosiglitazone increases the expression and activity of fatty acid oxidation enzymes specifically in adipose tissue;and 3) fatty acid oxidation enzymes are subject to reversible acetylation which may regulate activity in adipose tissue.
Three specific aims are proposed to investigate questions raised by the preliminary data.
Aim 1 will use knockout mice and in vitro techniques to establish the importance of fatty acid oxidation as an energy source in adipose tissue.
Aim 2 will test the hypothesis that rosiglitazone activates a signaling cascade resulting in the phosphorylation-induced activation of the transcription factor PPARalpha, which in turn increases the expression of fatty acid oxidation enzymes.
Aim 3 will study the effect of enzyme acetylation on the rate of mitochondrial fatty acid oxidation in adipose tissue. Further, pure recombinant enzyme will be used to study the mechanism by which acetylation regulates activity. Understanding the regulation of fatty acid oxidation enzymes in adipose tissues is important for developing new anti-obesity therapies that shift adipocytes away from fat storage toward a more catabolic phenotype. The University of Pittsburgh is an ideal setting due to the strong research environment and the availability of outstanding mentors and consultants. This combination will maximize the potential for the principal investigator to realize his goal of becoming a successful research scientist. Relevance: For the first time in human history there are more overfed than underfed people on the planet. The applicant's research goal is to understand the metabolism of fat tissue in order find a way to convert fat-storing cells into fat-burning cells.
| Hirschey, Matthew D; Shimazu, Tadahiro; Jing, Enxuan et al. (2011) SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 44:177-90 |
| Skilling, Helen; Coen, Paul M; Fairfull, Liane et al. (2010) Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice. Biochem Biophys Res Commun 400:318-22 |
| Hirschey, Matthew D; Shimazu, Tadahiro; Goetzman, Eric et al. (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464:121-5 |
| Wang, Yudong; Mohsen, Al-Walid; Mihalik, Stephanie J et al. (2010) Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J Biol Chem 285:29834-41 |
