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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 adipose tissue from CL-316,243 MKR vs vehicle-treated MKR 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 CL-316,243 treated MKR mice vs vehicle treated MKR mice. The numbers below the symbols denote the fold change in gene expression of MKR CL-316,243 treated vs vehicle treated mice.
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Fig5: Gene network analysis of the fatty acid oxidation pathway in adipose tissue from CL-316,243 MKR vs vehicle-treated MKR 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 CL-316,243 treated MKR mice vs vehicle treated MKR mice. The numbers below the symbols denote the fold change in gene expression of MKR CL-316,243 treated vs vehicle treated mice.

Mentions: WT and MKR mice were treated for two weeks with CL-316,243. Consistent with our previous studies, a decrease in random fed blood glucose, fed plasma insulin, serum triglyceride concentration and body fat was observed in the MKR mice after two weeks of treatment (Table 6). Microarray analysis of adipose tissue from MKR mice treated with CL-316,243 revealed a significant change in the expression of a number of the genes in the FA oxidation pathway that were differentially regulated in the MKR compared to WT mice (Figure 5, Table 7). Genes that were downregulated in the MKR adipose tissue, but then were upregulated after CL-316,243 treatment included acyl CoA acyltransferase (ACAA1), the acyl CoA synthetase ACSL6, the alcohol dehydrogenase ADHFE1, and the hydroxysteroid dehydrogenase HSD17B4. Genes that were upregulated in the adipose tissue of MKR mice compared to WT mice and were downregulated after CL-316,343 treatment included the peroxisomal fatty acid oxidation enzyme ACOX3, and the aldehyde dehydrogenases ALDH3A2, ALDH7A1. Chronic CL-316,243 treatment led to a significant downregulation of retinaldehyde dehydrogenases, including ALDH1A1 in the adipose tissue of MKR mice, the deficiency of which has previously been associated with browning of adipose tissue, a phenomenon observed with CL-316,243 treatment [46]. As shown in Table 7, a number of genes in the FA oxidation pathway were altered by CL-316,243 treatment but were not differentially regulated between the WT and MKR mice, and many genes were further downregulated by CL-316,243 treatment. These genes may be downregulated after chronic administration of CL-316,243, but may be increased in the acute setting, or their altered expression may be related to the browning of white adipose tissue observed after CL-316,243 treatment.Table 6


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 adipose tissue from CL-316,243 MKR vs vehicle-treated MKR 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 CL-316,243 treated MKR mice vs vehicle treated MKR mice. The numbers below the symbols denote the fold change in gene expression of MKR CL-316,243 treated vs vehicle treated mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig5: Gene network analysis of the fatty acid oxidation pathway in adipose tissue from CL-316,243 MKR vs vehicle-treated MKR 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 CL-316,243 treated MKR mice vs vehicle treated MKR mice. The numbers below the symbols denote the fold change in gene expression of MKR CL-316,243 treated vs vehicle treated mice.
Mentions: WT and MKR mice were treated for two weeks with CL-316,243. Consistent with our previous studies, a decrease in random fed blood glucose, fed plasma insulin, serum triglyceride concentration and body fat was observed in the MKR mice after two weeks of treatment (Table 6). Microarray analysis of adipose tissue from MKR mice treated with CL-316,243 revealed a significant change in the expression of a number of the genes in the FA oxidation pathway that were differentially regulated in the MKR compared to WT mice (Figure 5, Table 7). Genes that were downregulated in the MKR adipose tissue, but then were upregulated after CL-316,243 treatment included acyl CoA acyltransferase (ACAA1), the acyl CoA synthetase ACSL6, the alcohol dehydrogenase ADHFE1, and the hydroxysteroid dehydrogenase HSD17B4. Genes that were upregulated in the adipose tissue of MKR mice compared to WT mice and were downregulated after CL-316,343 treatment included the peroxisomal fatty acid oxidation enzyme ACOX3, and the aldehyde dehydrogenases ALDH3A2, ALDH7A1. Chronic CL-316,243 treatment led to a significant downregulation of retinaldehyde dehydrogenases, including ALDH1A1 in the adipose tissue of MKR mice, the deficiency of which has previously been associated with browning of adipose tissue, a phenomenon observed with CL-316,243 treatment [46]. As shown in Table 7, a number of genes in the FA oxidation pathway were altered by CL-316,243 treatment but were not differentially regulated between the WT and MKR mice, and many genes were further downregulated by CL-316,243 treatment. These genes may be downregulated after chronic administration of CL-316,243, but may be increased in the acute setting, or their altered expression may be related to the browning of white adipose tissue observed after CL-316,243 treatment.Table 6

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