Limits...
The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice.

Kumar A, Shiloach J, Betenbaugh MJ, Gallagher EJ - Nutr Metab (Lond) (2015)

Bottom Line: To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary.These genes were not previously known to be regulated by CL-316,243 treatment.This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 14A, Bethesda, MD 20892 USA ; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218-2686 USA.

ABSTRACT

Background: The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype.

Methods: Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis.

Results: Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment.

Conclusions: This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study.

No MeSH data available.


Related in: MedlinePlus

Gene network analysis of the fatty acid oxidation pathway in skeletal muscle from MKR vs WT mice. Green represents down-regulation, red represents up-regulation, white symbols denote neighboring genes. The intensity of color represents the average of fold changes in the tissue from the MKR mice vs WT mice. The numbers below the symbols denote the fold change in gene expression of MKR vs WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4362840&req=5

Fig3: Gene network analysis of the fatty acid oxidation pathway in skeletal muscle from MKR vs WT mice. Green represents down-regulation, red represents up-regulation, white symbols denote neighboring genes. The intensity of color represents the average of fold changes in the tissue from the MKR mice vs WT mice. The numbers below the symbols denote the fold change in gene expression of MKR vs WT mice.

Mentions: We next examined the expression of fatty acid oxidation genes in the skeletal muscle of the MKR and WT mice by microarray analysis. Significant differences were found in the fatty acid oxidation pathway between MKR and WT mice. The MKR mice had a significant downregulation of many of the genes involved in fatty acid beta-oxidation (Figure 3, Table 3). Notable exceptions to the general downregulation of fatty acid oxidation genes in the skeletal muscle of the MKR mice include carnitine palmitoyl transferase 1a (CPT1A), the peroxisomal acyl CoA oxidase ACOX3, the alcohol dehydrogenase ADH6A, dicarbonyl/L-xylulose reductase DCXR, and the aldehyde/retinaldehyde dehydrogenase ALDH1A2, which were upregulated approximately 2 fold (Table 3). ACOX3 was upregulated in both the adipose tissue and the skeletal muscle of the MKR mice. It is one of the three acyl CoA oxidases that perform the first step of fatty acid oxidation in mouse peroxisomes, specifically the oxidation of branched-chain fatty acids [38-45]. ACOX1, which was downregulated in the skeletal muscle and adipose tissue of MKR mice, metabolizes very long-chain fatty acids and long-chain dicarboxylic acids (DCAs). The primary genetic defect in the MKR mice is in the skeletal muscle, and the muscle of the MKR mice have been previously shown to have greater accumulation of fatty acid intermediates compared to WT mice. Therefore, the results of our microarray analysis on the skeletal muscle were consistent with our previously published data showing a decrease in fatty acid oxidation; although the microarray data demonstrated previously unidentified novel changes in gene expression in this pathway in the skeletal muscle of the MKR mice.Figure 3


The beta-3 adrenergic agonist (CL-316,243) restores the expression of down-regulated fatty acid oxidation genes in type 2 diabetic mice.

Kumar A, Shiloach J, Betenbaugh MJ, Gallagher EJ - Nutr Metab (Lond) (2015)

Gene network analysis of the fatty acid oxidation pathway in skeletal muscle from MKR vs WT mice. Green represents down-regulation, red represents up-regulation, white symbols denote neighboring genes. The intensity of color represents the average of fold changes in the tissue from the MKR mice vs WT mice. The numbers below the symbols denote the fold change in gene expression of MKR vs WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362840&req=5

Fig3: Gene network analysis of the fatty acid oxidation pathway in skeletal muscle from MKR vs WT mice. Green represents down-regulation, red represents up-regulation, white symbols denote neighboring genes. The intensity of color represents the average of fold changes in the tissue from the MKR mice vs WT mice. The numbers below the symbols denote the fold change in gene expression of MKR vs WT mice.
Mentions: We next examined the expression of fatty acid oxidation genes in the skeletal muscle of the MKR and WT mice by microarray analysis. Significant differences were found in the fatty acid oxidation pathway between MKR and WT mice. The MKR mice had a significant downregulation of many of the genes involved in fatty acid beta-oxidation (Figure 3, Table 3). Notable exceptions to the general downregulation of fatty acid oxidation genes in the skeletal muscle of the MKR mice include carnitine palmitoyl transferase 1a (CPT1A), the peroxisomal acyl CoA oxidase ACOX3, the alcohol dehydrogenase ADH6A, dicarbonyl/L-xylulose reductase DCXR, and the aldehyde/retinaldehyde dehydrogenase ALDH1A2, which were upregulated approximately 2 fold (Table 3). ACOX3 was upregulated in both the adipose tissue and the skeletal muscle of the MKR mice. It is one of the three acyl CoA oxidases that perform the first step of fatty acid oxidation in mouse peroxisomes, specifically the oxidation of branched-chain fatty acids [38-45]. ACOX1, which was downregulated in the skeletal muscle and adipose tissue of MKR mice, metabolizes very long-chain fatty acids and long-chain dicarboxylic acids (DCAs). The primary genetic defect in the MKR mice is in the skeletal muscle, and the muscle of the MKR mice have been previously shown to have greater accumulation of fatty acid intermediates compared to WT mice. Therefore, the results of our microarray analysis on the skeletal muscle were consistent with our previously published data showing a decrease in fatty acid oxidation; although the microarray data demonstrated previously unidentified novel changes in gene expression in this pathway in the skeletal muscle of the MKR mice.Figure 3

Bottom Line: To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary.These genes were not previously known to be regulated by CL-316,243 treatment.This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 14A, Bethesda, MD 20892 USA ; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218-2686 USA.

ABSTRACT

Background: The hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype.

Methods: Male MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis.

Results: Significant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment.

Conclusions: This study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study.

No MeSH data available.


Related in: MedlinePlus