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Adipose tissue gene expression profiles of lean, insulin resistant, obese, and diabetic mice.

ABSTRACT: The expression of adipogenic genes is decreased in obesity and diabetes mellitus Samuel T. Nadler*, Jonathan P. Stoehr*, Kathryn L. Schueler*, Gene Tanimoto, Brian S. Yandell, and Alan D. Attie*,§ Departments of * Biochemistry, and Statistics and Horticulture, University of Wisconsin, Madison, WI, 53706; and Affymetrix, Inc., Santa Clara, CA 95051 Communicated by Neal L. First, University of Wisconsin, Madison, WI, July 13, 2000 (received for review April 3, 2000) Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role in diabetes has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences in gene expression in adipose tissue from lean, obese, and obese-diabetic mice. The expression level of over 11,000 transcripts was analyzed, and 214 transcripts showed significant differences between lean and obese mice. Surprisingly, the expression of genes normally associated with adipocyte differentiation were down-regulated in obesity. Not all obese individuals will become diabetic; many remain normoglycemic despite profound obesity. Understanding the transition to obesity with concomitant diabetes will provide important clues to the pathogenesis of type 2 diabetes. Therefore, we examined the levels of gene expression in adipose tissue from five groups of obese mice with varying degrees of hyperglycemia, and we identified 88 genes whose expression strongly correlated with diabetes severity. This group included many genes that are known to be involved in signal transduction and energy metabolism as well as genes not previously examined in the context of diabetes. Our data show that a decrease in expression of genes normally involved in adipogenesis is associated with obesity, and we further identify genes important for subsequent development of type 2 diabetes mellitus. Keywords: Genetic modifications and strain difference

ORGANISM(S): Mus musculus

PROVIDER: GSE2952 | GEO | 2005/07/18

SECONDARY ACCESSION(S): PRJNA92427

REPOSITORIES: GEO

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Project description:The expression of adipogenic genes is decreased in obesity and diabetes mellitus ; Samuel T. Nadler*, Jonathan P. Stoehr*, Kathryn L. Schueler*, Gene Tanimoto, Brian S. Yandell, and Alan D. Attie*,Â§ ; Departments of * Biochemistry, and Statistics and Horticulture, University of Wisconsin, Madison, WI, 53706; and Affymetrix, Inc., Santa Clara, CA 95051 ; Communicated by Neal L. First, University of Wisconsin, Madison, WI, July 13, 2000 (received for review April 3, 2000) ; Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role in diabetes has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences in gene expression in adipose tissue from lean, obese, and obese-diabetic mice. The expression level of over 11,000 transcripts was analyzed, and 214 transcripts showed significant differences between lean and obese mice. Surprisingly, the expression of genes normally associated with adipocyte differentiation were down-regulated in obesity. Not all obese individuals will become diabetic; many remain normoglycemic despite profound obesity. Understanding the transition to obesity with concomitant diabetes will provide important clues to the pathogenesis of type 2 diabetes. Therefore, we examined the levels of gene expression in adipose tissue from five groups of obese mice with varying degrees of hyperglycemia, and we identified 88 genes whose expression strongly correlated with diabetes severity. This group included many genes that are known to be involved in signal transduction and energy metabolism as well as genes not previously examined in the context of diabetes. Our data show that a decrease in expression of genes normally involved in adipogenesis is associated with obesity, and we further identify genes important for subsequent development of type 2 diabetes mellitus. Experiment Overall Design: For obesity study, lean samples include C57BL/6J lean, (C57BL/6J X BTBR) F1 and BTBR lean, obese sampples incluse C57BL/6J-ob/ob, (C57BL/6J X BTBR) F2-ob/ob and BTBR-ob/ob. All samples are subjected to Mu11K A and B arrays. Experiment Overall Design: For diabetes study, B6-ob/ob, (C57BL/6J X BTBR) F2-ob/ob low glucose, (C57BL/6J X BTBR) F2-ob/ob medium glucose, (C57BL/6J X BTBR) F2-ob/ob high glucose, and BTBR-ob/ob samples were analyzed for genes whose expression levels changes correlated with the plasma glucose levels in these mice. All samples are subjected to Mu11K A and B arrays.

Project description:Patients with long-duration diabetes develop cardiovascular complications resulting in highly increased mortality and complications which affect the kidneys, eyes and peripheral nerves associated with high morbidity. Among the diabetic complications, damage in the eye, diabetic retinopathy, is the most common microvascular complication of diabetes. Diabetic retinopathy is a leading cause of vision-loss globally. It is characterized by a number of different patho-mechanisms including changes in vascular permeability, capillary degeneration, and finally at a late stage overshooting formation of new blood vessels. This expression analysis focused on the use of different experimental models for Diabetes Mellitus and its complications (for a review see 1: Al-Awar et al: Experimental Diabetes Mellitus in Different Animal Models. J Diabetes Res. 2016; doi: 10.1155/2016/9051426). By that, we wanted to uncover the relative contributions of systemic hyperinsulinaemia and/or hyperglycemia to molecular regulations. The following models have been used: As insulinopenic, hyperglycemic model reflecting Type 1 diabetes, male STZ-Wistar rats (60mg/kg BW; i.p.) were used. Wistar rats without STZ injection served as non-diabetic controls. Male obese ZDF rats (Fa/Fa) were used as type-2 diabetes model characterized by persisting hyperglycemia and transient hyperinsulinemia. Male lean ZDF rats (Fa/-) served as non-diabetic controls. Male obese ZF rats (Fa/Fa) hyperglycemia were used reflecting euglycemia and severe insulin resistance. Male lean ZF rats (Fa/-) served as controls. ZDF and ZF rats were obtained in two genotypes, obese (genotype fa/fa) and lean littermates (genotype Fa/?). All rats were housed in standard cages under a normal light-dark cycle for 16 weeks. All animals had free access to food and water. ZF and Wistar rats received a standard chow (Ssniff R/M) and ZDF rats received Purina 5008 chow. A group size of n=8 were used for all study groups. Wistar rats were rendered type-1 like hyperglycemic and hypoinsulinemic via a single injection of streptocotocin (STZ, 60mg/kg; i.p.) at 7 weeks of age. Obese ZDF rats (fa/fa) develop spontaneously a type-2 diabetes phenotype with persisting hyperglycemia and transient hyperinsulinemia (hyperglycemic, hypoinsulinemic). Obese ZF rats (fa/fa) develop insulin resistance with permanent hyperinsulinemia without concomitant hyperglycemia and no overt diabetes phenotype. Non STZ treated Wistar rats, lean ZDF littermates (Fa/?), and lean ZF littermates (Fa/?) served as controls. All groups were kept for 12 weeks on respective conditions together with appropriate age-matched controls. Unbiased gene expression analysis was performed per group using Affymetrix gene arrays.

Project description:Insulin resistance is necessary but not sufficient for the development of type 2 diabetes. Diabetes results when pancreatic beta-cells fail to compensate for insulin resistance by increasing insulin production through an expansion of beta-cell mass or increased insulin secretion. Communication between insulin target tissues and beta-cells may initiate this compensatory response. Correlated changes in gene expression between tissues can provide evidence for such intercellular communication. We profiled gene expression in six tissues of mice from an obesity-induced diabetes-resistant and a diabetes-susceptible strain before and after the onset of diabetes. We studied the correlation structure of mRNA abundance and identified 105 co-expression gene modules. We provide an interactive gene network model showing the correlation structure between the expression modules within and among the six tissues. This resource also provides a searchable database of gene expression profiles for all genes in six tissues in lean and obese diabetes-resistant and diabetes-susceptible mice, at 4 and 10 weeks of age. A cell cycle regulatory module in islets predicts diabetes susceptibility. The module predicts islet replication; we found a strong correlation between ^2 H_2 O incorporation into islet DNA /in vivo/ and the expression pattern of the cell cycle module. This pattern is highly correlated with that of several individual genes in insulin target tissues, including IGF2, which has been shown to promote beta-cell proliferation, suggesting that these genes may provide a link between insulin resistance and beta-cell proliferation. Keywords: time course, mouse strain comparison, effect of obesity, Type 2 diabetes is a disorder that involves an increased demand for insulin brought about by insulin resistance, together with a failure to compensate with sufficient insulin production. Although Insulin resistance occurs in most obese individuals, diabetes is generally forestalled through compensation with increased insulin. This increase in insulin occurs through an expansion of beta-cell mass and/or increased insulin secretion by individual beta-cells. Failure to compensate for insulin resistance leads to type 2 diabetes. One way to understand the pathophysiology of diabetes is to examine the coordinate changes in gene expression that occur in insulin-responsive tissues and pancreatic islets in obese animals that either compensate for insulin resistance or progress to type 2 diabetes. In each case, there are groups of genes that undergo changes in expression in a highly correlated fashion. By identifying groups of correlated transcripts (gene expression modules) during the compensation and development of diabetes, we can gain insight into potential pathways and regulatory networks in obesity-induced diabetes. We study two strains of mice that differ in obesity-induced diabetes susceptibility. In this study, we surveyed gene expression in six tissues of lean and obese C57BL/6 (B6) and BTBR mice aged 4 wks and 10 wks. B6 mice remain essentially non-diabetic at all ages, irrespective of obesity. When obese, BTBR mice become severely diabetic by 10 weeks of age. By analyzing the correlation structure of the genes under three contrast conditions, obesity, strain, and age, we identified gene expression modules associated with the onset of diabetes and provide an interactive co-expression network model of type 2 diabetes. We found a key module that is comprised of cell cycle regulatory genes. In the islet, the expression profile of these transcripts accurately predicts diabetes and is highly correlated with islet cell proliferation.

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Adipose tissue gene expression profiles of lean, insulin resistant, obese, and diabetic mice.

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