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Adipose tissue deficiency and chronic inflammation in diabetic Goto-Kakizaki rats.

Xue B, Sukumaran S, Nie J, Jusko WJ, Dubois DC, Almon RR - PLoS ONE (2011)

Bottom Line: Systemic inflammation was reflected by chronically elevated white blood cell counts.Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes.This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America.

ABSTRACT
Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.

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Examples of genes related to immune function.Expression of probe sets related to immune function/inflammation in adipose tissue as a function of age in GK and WKY rats. A Interferon-induced protein with tetra-tricopepetide repeats (Ifit 1: 1369836_at); B Interferon-inducible GTPase (Iigp 1: 1377950_at); C Phospholipade A2 activating protein (Plaa: 1396714_at); D Chemokine C-X-C motif ligand 14 (Cxcl14: 1388485_at); E Sialic acid binding Ig-like lectin 5 (Siglec5: 1385465_at); F Secretory phospholipase A group IIA (sPla2: 168128_at). The Y-axis represents raw, non-normalized probe set intensities, and the x-axis animal age. Data represent means and error bars 1 SD of the mean. Closed circles = GK; open circles = WKY). * = P<0.05; ** = P<0.001.
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pone-0017386-g007: Examples of genes related to immune function.Expression of probe sets related to immune function/inflammation in adipose tissue as a function of age in GK and WKY rats. A Interferon-induced protein with tetra-tricopepetide repeats (Ifit 1: 1369836_at); B Interferon-inducible GTPase (Iigp 1: 1377950_at); C Phospholipade A2 activating protein (Plaa: 1396714_at); D Chemokine C-X-C motif ligand 14 (Cxcl14: 1388485_at); E Sialic acid binding Ig-like lectin 5 (Siglec5: 1385465_at); F Secretory phospholipase A group IIA (sPla2: 168128_at). The Y-axis represents raw, non-normalized probe set intensities, and the x-axis animal age. Data represent means and error bars 1 SD of the mean. Closed circles = GK; open circles = WKY). * = P<0.05; ** = P<0.001.

Mentions: This functional category of differentially regulated genes (103 probe sets) demonstrates significant differences between the GK and WKY populations with respect to the number of immune cells and inflammation in adipose tissue. Of the 103 probe sets, 73 were higher in WKY as compared to GK animals, while 30 were higher in GK animals. Selected examples of genes in this category are presented in Figure 7. Figures 7A and B show the expression patterns of interferon-induced protein with tetratricopeptide repeats 1 (Ifit1) and interferon-inducible GTPase (Iigp1). Both of these interferon-induced genes are much higher in the adipose tissue of diabetic GK animals than in control WKY rats at all ages. The expression of both of these genes was also much higher at all ages in the livers of these animals. The high expression of these interferon-induced genes suggests that the previously reported chronic natural immune activation in the liver of GK population extends as well to adipose tissue. In addition to suggesting a heightened inflammatory state in these animals, excessive circulating concentrations of interferon are also associated with insulin resistance [26], [27]. Similarly, phospholipase A2, activating protein (Plaa) expression is higher at all ages in the adipose tissue of the GK population (Figure 7C). Pro-inflammatory eicosanoids are released from membrane phospholipids by the action of phospholipase A2 (PLA2), which is activated by PLAA [28]. The expression of Plaa was higher at all ages in the livers of these animals as well. A fourth example of a gene suggesting chronic inflammation in the GK rats is chemokine C-X-C motif ligand 14 (Cxcl14). In the presence of prostaglandins, CXCL14 can both attract and activate a variety of immune cells. It was previously demonstrated that disruption of Cxcl14 greatly reduced obesity-induced insulin resistance in mice, and that restoring the gene restored the insulin resistance [29]. Figure 7D shows that Cxcl14 is chronically higher in GK when compared with WKY. Like the previous three examples, Cxcl14 is also elevated in the livers of these animals. In contrast to the expression of genes suggesting inflammation, aspects of the data suggest that there are actually more immune cells in the larger adipose tissue mass of the WKY population. For example, the expression of sialic acid binding Ig-like lectin 5 (Siglec5) which is primarily expressed by neutrophils [30] is higher as early as 4 weeks in the WKY population and increases with age, while the expression in adipose tissue of the GK diabetic animals remains rather low throughout the 20 week experimental time period (Figure 7E). In addition, the expression of secretory phospholipase A2, group IIA (sPla2) which in adipose tissue is likely associated with macrophages [31], increases with age in both groups but is significantly higher at all ages in WKY (Figure 7F). Similarly the expression of other genes such as Tnf receptor-associated factor 6 (Traf6), caspase recruitment domain family, member 9 (Card9) and integrin alpha M (Itgam), a macrophage marker, are also more highly expressed in the adipose tissue of WKY relative to GK (Table S2). The sum of these data suggest that while markers of immune cells in general are higher in the WKY population, which is consistent with their greater amount of adipose tissue, markers suggesting inflammation are higher in the GK population.


Adipose tissue deficiency and chronic inflammation in diabetic Goto-Kakizaki rats.

Xue B, Sukumaran S, Nie J, Jusko WJ, Dubois DC, Almon RR - PLoS ONE (2011)

Examples of genes related to immune function.Expression of probe sets related to immune function/inflammation in adipose tissue as a function of age in GK and WKY rats. A Interferon-induced protein with tetra-tricopepetide repeats (Ifit 1: 1369836_at); B Interferon-inducible GTPase (Iigp 1: 1377950_at); C Phospholipade A2 activating protein (Plaa: 1396714_at); D Chemokine C-X-C motif ligand 14 (Cxcl14: 1388485_at); E Sialic acid binding Ig-like lectin 5 (Siglec5: 1385465_at); F Secretory phospholipase A group IIA (sPla2: 168128_at). The Y-axis represents raw, non-normalized probe set intensities, and the x-axis animal age. Data represent means and error bars 1 SD of the mean. Closed circles = GK; open circles = WKY). * = P<0.05; ** = P<0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045458&req=5

pone-0017386-g007: Examples of genes related to immune function.Expression of probe sets related to immune function/inflammation in adipose tissue as a function of age in GK and WKY rats. A Interferon-induced protein with tetra-tricopepetide repeats (Ifit 1: 1369836_at); B Interferon-inducible GTPase (Iigp 1: 1377950_at); C Phospholipade A2 activating protein (Plaa: 1396714_at); D Chemokine C-X-C motif ligand 14 (Cxcl14: 1388485_at); E Sialic acid binding Ig-like lectin 5 (Siglec5: 1385465_at); F Secretory phospholipase A group IIA (sPla2: 168128_at). The Y-axis represents raw, non-normalized probe set intensities, and the x-axis animal age. Data represent means and error bars 1 SD of the mean. Closed circles = GK; open circles = WKY). * = P<0.05; ** = P<0.001.
Mentions: This functional category of differentially regulated genes (103 probe sets) demonstrates significant differences between the GK and WKY populations with respect to the number of immune cells and inflammation in adipose tissue. Of the 103 probe sets, 73 were higher in WKY as compared to GK animals, while 30 were higher in GK animals. Selected examples of genes in this category are presented in Figure 7. Figures 7A and B show the expression patterns of interferon-induced protein with tetratricopeptide repeats 1 (Ifit1) and interferon-inducible GTPase (Iigp1). Both of these interferon-induced genes are much higher in the adipose tissue of diabetic GK animals than in control WKY rats at all ages. The expression of both of these genes was also much higher at all ages in the livers of these animals. The high expression of these interferon-induced genes suggests that the previously reported chronic natural immune activation in the liver of GK population extends as well to adipose tissue. In addition to suggesting a heightened inflammatory state in these animals, excessive circulating concentrations of interferon are also associated with insulin resistance [26], [27]. Similarly, phospholipase A2, activating protein (Plaa) expression is higher at all ages in the adipose tissue of the GK population (Figure 7C). Pro-inflammatory eicosanoids are released from membrane phospholipids by the action of phospholipase A2 (PLA2), which is activated by PLAA [28]. The expression of Plaa was higher at all ages in the livers of these animals as well. A fourth example of a gene suggesting chronic inflammation in the GK rats is chemokine C-X-C motif ligand 14 (Cxcl14). In the presence of prostaglandins, CXCL14 can both attract and activate a variety of immune cells. It was previously demonstrated that disruption of Cxcl14 greatly reduced obesity-induced insulin resistance in mice, and that restoring the gene restored the insulin resistance [29]. Figure 7D shows that Cxcl14 is chronically higher in GK when compared with WKY. Like the previous three examples, Cxcl14 is also elevated in the livers of these animals. In contrast to the expression of genes suggesting inflammation, aspects of the data suggest that there are actually more immune cells in the larger adipose tissue mass of the WKY population. For example, the expression of sialic acid binding Ig-like lectin 5 (Siglec5) which is primarily expressed by neutrophils [30] is higher as early as 4 weeks in the WKY population and increases with age, while the expression in adipose tissue of the GK diabetic animals remains rather low throughout the 20 week experimental time period (Figure 7E). In addition, the expression of secretory phospholipase A2, group IIA (sPla2) which in adipose tissue is likely associated with macrophages [31], increases with age in both groups but is significantly higher at all ages in WKY (Figure 7F). Similarly the expression of other genes such as Tnf receptor-associated factor 6 (Traf6), caspase recruitment domain family, member 9 (Card9) and integrin alpha M (Itgam), a macrophage marker, are also more highly expressed in the adipose tissue of WKY relative to GK (Table S2). The sum of these data suggest that while markers of immune cells in general are higher in the WKY population, which is consistent with their greater amount of adipose tissue, markers suggesting inflammation are higher in the GK population.

Bottom Line: Systemic inflammation was reflected by chronically elevated white blood cell counts.Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes.This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America.

ABSTRACT
Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.

Show MeSH
Related in: MedlinePlus