Abstract
BackgroundDefects in skeletal muscle fatty acid oxidation have been implicated in the etiology of insulin resistance. Malonyl-CoA decarboxylase (MCD) has been a target of investigation because it reduces the concentration of malonyl-CoA, a metabolite that inhibits fatty acid oxidation. The in vivo role of muscle MCD expression in the development of insulin resistance remains unclear.ResultsTo determine the role of MCD in skeletal muscle of diet induced obese and insulin resistant mouse models we generated mice expressing a muscle specific transgene for MCD (Tg-fMCDSkel) stabilized posttranslationally by the small molecule, Shield-1. Tg-fMCDSkel and control mice were placed on either a high fat or low fat diet for 3.5 months. Obese and glucose intolerant as well as lean control Tg-fMCDSkel and nontransgenic control mice were treated with Shield-1 and changes in their body weight and insulin sensitivity were determined upon induction of MCD. Inducing MCD activity >5-fold in skeletal muscle over two weeks did not alter body weight or glucose intolerance of obese mice. MCD induction further potentiated the defects in insulin signaling of obese mice. In addition, key enzymes in fatty acid oxidation were suppressed following MCD induction.ConclusionAcute induction of MCD in the skeletal muscle of obese and glucose intolerant mice did not improve body weight and decreased insulin sensitivity compared to obese nontransgenic controls. Induction of MCD in skeletal muscle resulted in a suppression of mitochondrial oxidative genes suggesting a redundant and metabolite driven regulation of gene expression.
Highlights
Defects in skeletal muscle fatty acid oxidation have been implicated in the etiology of insulin resistance
Given the importance of Malonyl-CoA decarboxylase (MCD) in regulating skeletal muscle fatty acid oxidation, we generated transgenic mice where MCD (Tg-fMCD) can be regulated in a cell and chemical specific manner in order to determine the effect of acutely altering fatty acid metabolism in insulin resistance [40]
The destabilization domain was derivatized from FKBP12 (FK506 binding protein 12) enabling reversible and dose dependent protein stabilization with its synthetic ligand, Shield-1 [41]
Summary
Defects in skeletal muscle fatty acid oxidation have been implicated in the etiology of insulin resistance. Skeletal muscle has been demonstrated to be a primary tissue driving insulin resistance and is the target for several anti-diabetic drugs [1,2,3]. Excess lipid accumulation outside of adipose tissue is thought to contribute to diabetes by engaging pathways that inhibit insulin signaling. Skeletal muscle with its high capacity for fatty acid oxidation has been a target for genetic and pharmacological studies intended to restore lipid balance by promoting lipid oxidative pathways. From these studies, multiple mechanisms have been proposed to connect lipid metabolism and defects in insulin sensitivity. Methods that increase fatty acid oxidation, akin to exercise, in the muscle to relieve the toxicity caused by these lipid intermediates have been sought to improve insulin resistance
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