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

Results from differential change analyses. a) Venn diagram showing significant genes (<0.05 P value) with 1.5X differential fold change between different datasets. b) Venn diagram showing overlap of significant genes with more than 1.5X fold change difference in CL-316,243 treated (Treated) vs untreated MKR (MKR) fat and untreated MKR vs WT fat tissues datasets c) Ether lipid metabolism KEGG pathway – color scheme is corresponding to the color scheme in Venn diagram. Other colors correspond to genes found in mouse genome but not in either datasets.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Results from differential change analyses. a) Venn diagram showing significant genes (<0.05 P value) with 1.5X differential fold change between different datasets. b) Venn diagram showing overlap of significant genes with more than 1.5X fold change difference in CL-316,243 treated (Treated) vs untreated MKR (MKR) fat and untreated MKR vs WT fat tissues datasets c) Ether lipid metabolism KEGG pathway – color scheme is corresponding to the color scheme in Venn diagram. Other colors correspond to genes found in mouse genome but not in either datasets.

Mentions: The results of the microarray analysis are summarized in Venn diagrams shown in Figure 1a and 1b. KEGG pathways analysis was done to determine overrepresented pathways (containing high number of differentially expressed genes). The results of KEGG pathway analysis of lipid metabolism is shown in Table 1. The following pathways were found to be significantly overrepresented in fat tissues of MKR vs WT mice: fatty acid degradation, glycerolipid metabolism, and glycerophospholipid metabolism. When fat tissues of CL-316,243 treated MKR mice were compared with non-treated MKR mice, the glycerolipid metabolism, glycerophospholipid metabolism, fat digestion and absorption, and ether lipid metabolism were found to be significantly overrepresented. Circulating ether lipid levels have previously found to be significantly higher in obese and diabetic subjects [37]. As shown in Figure 1c when fat tissues of treated MKR were compared with non-treated MKR difference in dysregulation of ether lipid metabolism was observed. Most of the genes in fat tissues related to ether lipid metabolism were found to be down-regulated in MKR compared with WT mice. Following treatment this trend was reversed. A complete list of KEGG enrichment analysis results is provided in Additional file 1: Table S1. In addition, pathways related to carbohydrate metabolism such as TCA cycle, pentose phosphate pathway, fructose and mannose metabolism, pyruvate metabolism, and propanoate metabolism were found to be overrepresented only in fat tissues of MKR vs WT mice and not in the fat tissues of CL-316,243 treated MKR compared with non-treated MKR. Moreover, carbohydrate metabolism pathway amino sugar and nucleotide sugar metabolism was found to be overrepresented only after treatment with CL-316,243 in fat tissues of MKR mice.Figure 1


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)

Results from differential change analyses. a) Venn diagram showing significant genes (<0.05 P value) with 1.5X differential fold change between different datasets. b) Venn diagram showing overlap of significant genes with more than 1.5X fold change difference in CL-316,243 treated (Treated) vs untreated MKR (MKR) fat and untreated MKR vs WT fat tissues datasets c) Ether lipid metabolism KEGG pathway – color scheme is corresponding to the color scheme in Venn diagram. Other colors correspond to genes found in mouse genome but not in either datasets.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Results from differential change analyses. a) Venn diagram showing significant genes (<0.05 P value) with 1.5X differential fold change between different datasets. b) Venn diagram showing overlap of significant genes with more than 1.5X fold change difference in CL-316,243 treated (Treated) vs untreated MKR (MKR) fat and untreated MKR vs WT fat tissues datasets c) Ether lipid metabolism KEGG pathway – color scheme is corresponding to the color scheme in Venn diagram. Other colors correspond to genes found in mouse genome but not in either datasets.
Mentions: The results of the microarray analysis are summarized in Venn diagrams shown in Figure 1a and 1b. KEGG pathways analysis was done to determine overrepresented pathways (containing high number of differentially expressed genes). The results of KEGG pathway analysis of lipid metabolism is shown in Table 1. The following pathways were found to be significantly overrepresented in fat tissues of MKR vs WT mice: fatty acid degradation, glycerolipid metabolism, and glycerophospholipid metabolism. When fat tissues of CL-316,243 treated MKR mice were compared with non-treated MKR mice, the glycerolipid metabolism, glycerophospholipid metabolism, fat digestion and absorption, and ether lipid metabolism were found to be significantly overrepresented. Circulating ether lipid levels have previously found to be significantly higher in obese and diabetic subjects [37]. As shown in Figure 1c when fat tissues of treated MKR were compared with non-treated MKR difference in dysregulation of ether lipid metabolism was observed. Most of the genes in fat tissues related to ether lipid metabolism were found to be down-regulated in MKR compared with WT mice. Following treatment this trend was reversed. A complete list of KEGG enrichment analysis results is provided in Additional file 1: Table S1. In addition, pathways related to carbohydrate metabolism such as TCA cycle, pentose phosphate pathway, fructose and mannose metabolism, pyruvate metabolism, and propanoate metabolism were found to be overrepresented only in fat tissues of MKR vs WT mice and not in the fat tissues of CL-316,243 treated MKR compared with non-treated MKR. Moreover, carbohydrate metabolism pathway amino sugar and nucleotide sugar metabolism was found to be overrepresented only after treatment with CL-316,243 in fat tissues of MKR mice.Figure 1

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