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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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Hormone profiles.Plasma concentrations of A) corticosterone, B) leptin and C) adiponectin as a function of age in GK and WKY animals. 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-g005: Hormone profiles.Plasma concentrations of A) corticosterone, B) leptin and C) adiponectin as a function of age in GK and WKY animals. Data represent means and error bars 1 SD of the mean. Closed circles = GK; open circles = WKY). * = P<0.05; ** = P<0.001.

Mentions: Plasma concentrations of four hormones relevant to glucose homeostasis (insulin, corticosterone, leptin, and adiponectin) were measured in both populations of animals. As described previously [16] plasma insulin concentrations were similar in both populations of animals at 4 weeks of age (Figure S1). In WKYs, insulin increased modestly between 4 and 8 weeks of age and remained at a relatively constant level throughout the rest of the experimental period. In contrast, insulin increased dramatically (about 6-fold) in the GK population between 4 and 8 weeks, remained at this elevated level through 12 weeks, then began to decline such that by the end of the experimental period plasma insulin was marginally higher in WKY than in GK. Figure 5 presents plasma corticosterone, leptin, and adiponectin concentrations in these animals. Corticosterone, the natural glucocorticoid in the rat, is released from the adrenal gland in a distinct circadian pattern [20]. These animals were sacrificed close to the nadir of the corticosterone rhythm. The plasma corticosterone concentration in the WKY population was rather constant, with a mean value of 122.4±29.8 ng/ml, with no significant differences across age. In contrast, the corticosterone concentration in GK animals started at about 600 ng/ml at 4 weeks and declined asymptotically, yet was still significantly higher than the WKY animals even at 20 weeks. This result indicates that either the GK population has an unusually high plasma corticosterone concentration or that there is a disturbance in the endogenous circadian rhythm of these animals. Leptin is an adipokine produced by adipose tissue and is also released in a circadian fashion with peak plasma concentration during the late dark/active period and the nadir during the late light/inactive period [21]. Therefore, our time of sacrifice should yield intermediate leptin concentrations. In normal animals, leptin concentrations increase with increasing fat mass [22]–[24]. The plasma leptin concentration in our WKY population continually increased throughout the experiment and essentially mirrored the increase in adipose tissue in these animals. Given the lack of development of adipose tissue in the GK population, plasma leptin concentrations in GK animals were therefore unusually high. For example at 8 weeks both the WKY and GK populations had the same amount of adipose tissue yet the plasma leptin concentration was twice as high in the GK animals. Similarly, at 12 weeks the WKY population had about twice as much adipose tissue than the GK but plasma leptin concentration was still significantly higher in the GK animals. Only at 20 weeks, when the GK population appeared to be losing adipose tissue did the plasma leptin concentration begin to decline. Adiponectin is another adipokine, but in contrast to leptin, plasma concentrations have been reported to be inversely related to the amount of body fat [25]. Plasma concentrations of this hormone were higher in GK animals at all ages, and declined with age in both groups.


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)

Hormone profiles.Plasma concentrations of A) corticosterone, B) leptin and C) adiponectin as a function of age in GK and WKY animals. 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-g005: Hormone profiles.Plasma concentrations of A) corticosterone, B) leptin and C) adiponectin as a function of age in GK and WKY animals. Data represent means and error bars 1 SD of the mean. Closed circles = GK; open circles = WKY). * = P<0.05; ** = P<0.001.
Mentions: Plasma concentrations of four hormones relevant to glucose homeostasis (insulin, corticosterone, leptin, and adiponectin) were measured in both populations of animals. As described previously [16] plasma insulin concentrations were similar in both populations of animals at 4 weeks of age (Figure S1). In WKYs, insulin increased modestly between 4 and 8 weeks of age and remained at a relatively constant level throughout the rest of the experimental period. In contrast, insulin increased dramatically (about 6-fold) in the GK population between 4 and 8 weeks, remained at this elevated level through 12 weeks, then began to decline such that by the end of the experimental period plasma insulin was marginally higher in WKY than in GK. Figure 5 presents plasma corticosterone, leptin, and adiponectin concentrations in these animals. Corticosterone, the natural glucocorticoid in the rat, is released from the adrenal gland in a distinct circadian pattern [20]. These animals were sacrificed close to the nadir of the corticosterone rhythm. The plasma corticosterone concentration in the WKY population was rather constant, with a mean value of 122.4±29.8 ng/ml, with no significant differences across age. In contrast, the corticosterone concentration in GK animals started at about 600 ng/ml at 4 weeks and declined asymptotically, yet was still significantly higher than the WKY animals even at 20 weeks. This result indicates that either the GK population has an unusually high plasma corticosterone concentration or that there is a disturbance in the endogenous circadian rhythm of these animals. Leptin is an adipokine produced by adipose tissue and is also released in a circadian fashion with peak plasma concentration during the late dark/active period and the nadir during the late light/inactive period [21]. Therefore, our time of sacrifice should yield intermediate leptin concentrations. In normal animals, leptin concentrations increase with increasing fat mass [22]–[24]. The plasma leptin concentration in our WKY population continually increased throughout the experiment and essentially mirrored the increase in adipose tissue in these animals. Given the lack of development of adipose tissue in the GK population, plasma leptin concentrations in GK animals were therefore unusually high. For example at 8 weeks both the WKY and GK populations had the same amount of adipose tissue yet the plasma leptin concentration was twice as high in the GK animals. Similarly, at 12 weeks the WKY population had about twice as much adipose tissue than the GK but plasma leptin concentration was still significantly higher in the GK animals. Only at 20 weeks, when the GK population appeared to be losing adipose tissue did the plasma leptin concentration begin to decline. Adiponectin is another adipokine, but in contrast to leptin, plasma concentrations have been reported to be inversely related to the amount of body fat [25]. Plasma concentrations of this hormone were higher in GK animals at all ages, and declined with age in both groups.

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