Obesity, a major dsk factor for type II diabetes and heart disease, has reached epidemic proportions in the U.S. Obesity results from an imbalance between energy input and output, where excess calories are stored as triglycerides. Mice lacking DGAT1, an enzyme involved in triacylglycerol synthesis, have increased energy expenditure and are therefore obesity resistant. The increased energy expenditure can be attributed to increased thermogenesis and physical activity. The objectives of this study are to investigate the mechanisms by which DGAT1 deficiency alters fatty acid metabolism. I hypothesize that DGAT1 deficiency decreases fatty acid synthesis and increases fatty acid oxidation.
My specific aims are:
Specific Aim 1 : To determine if fatty acid synthesis is decreased in Dgatl 4- mice.
Aim 1. 1: Determine if in vivofatty acid synthesis is decreased in livers of Dgatl 4- mice fed a high-fat diet by measuring the incorporation of tritiated water into fatty acids.
Aim 1. 2: Determine whether decreased activation of LXR-alpha, possibly due to increased levels of unsaturated fatty acids, is responsible for the decreased expression of fatty acid synthesis genes.
Aim 1. 3: Determine the contribution of decreased expression of SREBP-lc to the obesity-resistance phenotype by treating Dgatl -/- mice with an LXR-alpha agonist.
Specific Aim 2 : Determine if fatty acid oxidation is increased in Dgatl _- mice.
Aim 2. 1: Determine if there is increased fatty acid oxidation by measuring the formation of [1-14C] CO2 from [1-1""""""""C] palmitate and measuring the serum levels of ketone bodies.
Aim 2. 2: Determine if there is increased expression of genes implicated in fatty acid oxidation.
Aim 2. 3: Determine if PPAR_, a master transcriptional regulator of fatty acid oxidation, is required for the obesity resistance phenotype of Dgat1-/-mice.
| Villanueva, Claudio J; Monetti, Mara; Shih, Michelle et al. (2009) Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids. Hepatology 50:434-42 |
