Alterations in fatty acid metabolism in muscle, liver and heart of non-obese diabetic rats

Objectives The epidemic of obesity and type 2 diabetes mellitus (T2DM) is on the rise; however, it is often neglected that 20% of diabetic patients are non-obese. Since alterations in lipid metabolism have been implicated in the pathogenesis of T2DM and obesity, the objective of this was to characterize fatty acid (FA) metabolism in the heart, liver and muscle of non-obese diabetic rats.

Methods We used 24wk-old non-obese Goto-Kakizaki (GK) rats, which spontaneously develop T2DM. GK (N=9) and Wistar control rats (N=7) were subjected to a multi-tracer preclinical PET imaging protocol consisting of a 20-minute dynamic PET acquisition with [11C] Acetate (0.6-0.8mCi) to quantify myocardial blood flow (MBF) and 0.6-0.8mCi of [11C]Palmitate to quantify FA metabolism. After imaging, rats were sacrificed and tissues were flash frozen. The expression of 84 genes involved in FA metabolism was determined for a subset of 4 randomly selected rats per group. . PET images were quantified as previously described (Nemanich et al., 2013). For qPCR, genes were normalized to Ldha. Normalization and statistical analysis were conducted independently for each tissue. Results were subjected to student’s t-test and p<0.05 was considered significant.

Results Analyses of PET data indicates that GK rat hearts exhibit nearly a two-fold increased uptake and metabolism of FA whereas GK liver exhibit two-fold decrease. Muscle did not exhibit significant differences in uptake rate-constants. Supporting our PET results, gene expression analyses suggest that out of 84 genes analyzed for, majority of the significantly altered genes were up-regulated in the heart 2-12 fold and down regulated in the liver 2-4 fold, while muscle shows a mixed response.

Conclusions GK rats exhibit enhanced preference to FA metabolism independent of obesity, suggesting that GK rats can be employed to investigate the efficacy of therapies in multiple tissues independent of confounding factors associated with obesity.

Research Support This work was funded by NIH/NIDDK grant 5R01DK085298 and NIH/NHLBI grant R01EB012284.