PPAR-α agonism improves whole body and muscle mitochondrial fat oxidation, but does not alter intracellular fat concentrations in burn trauma children in a randomized controlled trial

Melanie G Cree,G Lynis Dohm,Dayoung Sun,Ronald P Mlcak,David N Herndon,Beatrice Morio,Ting Qian,Ricki Y Fram,Jennifer J Zwetsloot,Asle Aarsland,Bradley R Newcomer,Robert R Wolfe

doi:10.1186/1743-7075-4-9

Abstract

BackgroundInsulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat β-oxidation. It was unknown if this relationship was present in patients with acute insulin resistance induced by trauma.MethodsA double blind placebo controlled trial was conducted in 18 children with severe burn injury. Metabolic studies to assess whole body palmitate oxidation and insulin sensitivity, muscle biopsies for mitochondrial palmitate oxidation, diacylglycerol, fatty acyl Co-A and fatty acyl carnitine concentrations, and magnetic resonance spectroscopy for muscle and liver triglycerides were compared before and after two weeks of placebo or PPAR-α agonist treatment.ResultsInsulin sensitivity and basal whole body palmitate oxidation as measured with an isotope tracer increased significantly (P = 0.003 and P = 0.004, respectively) after PPAR-α agonist treatment compared to placebo. Mitochondrial palmitate oxidation rates in muscle samples increased significantly after PPAR-α treatment (P = 0.002). However, the concentrations of muscle triglyceride, diacylglycerol, fatty acyl CoA, fatty acyl carnitine, and liver triglycerides did not change with either treatment. PKC-θ activation during hyper-insulinemia decreased significantly following PPAR-α treatment.ConclusionPPAR-α agonist treatment increases palmitate oxidation and decreases PKC activity along with reduced insulin sensitivity in acute trauma, However, a direct link between these responses cannot be attributed to alterations in intracellular lipid concentrations.

Highlights

Insulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat β-oxidation
Both DAG and long chain fatty acyl CoA have been shown to disrupt the insulin signaling pathway at the level of the insulin receptor signalling-1 protein (IRS-1), preventing translocation of glucose transporter to the cell surface membrane, and insulin stimulated glucose uptake [6]. This response has been proposed to be mediated by activation of protein kinase C-θ (PKC-θ) and protein kinase C-β (PKC-β) [6]
We have recently demonstrated that Peroxisome proliferator activating receptors (PPAR)-α agonist treatment improves both peripheral and hepatic glucose sensitivity and improves the response of the insulin signaling cascade in muscle to insulin in burns [15] but, the effect of PPAR-α agonism on fat metabolism has not been examined

Summary

Introduction

Insulin resistance is often associated with increased levels of intracellular triglycerides, diacylglycerol and decreased fat β-oxidation It was unknown if this relationship was present in patients with acute insulin resistance induced by trauma. It is further proposed that intra-cellular TAG per se may not cause insulin resistance, but instead may be associated with increases in TAG metabolites such as diacylglycerol (DAG) and long chain fatty acyl CoA [6] Both DAG and long chain fatty acyl CoA have been shown to disrupt the insulin signaling pathway at the level of the insulin receptor signalling-1 protein (IRS-1), preventing translocation of glucose transporter to the cell surface membrane, and insulin stimulated glucose uptake [6]. This response has been proposed to be mediated by activation of protein kinase C-θ (PKC-θ) and protein kinase C-β (PKC-β) [6]

Results

Discussion

Conclusion