Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic Capacity in Diabetes Susceptibility

Abstract

Obesity is a strong risk factor for the development of type 2 diabetes. We have previously reported that in adipose tissue of obese (ob/ob) mice, the expression of adipogenic genes is decreased. When made genetically obese, the BTBR mouse strain is diabetes susceptible and the C57BL/6J (B6) strain is diabetes resistant. We used DNA microarrays and RT-PCR to compare the gene expression in BTBR-ob/ob versus B6-ob/ob mice in adipose tissue, liver, skeletal muscle, and pancreatic islets. Our results show: 1) there is an increased expression of genes involved in inflammation in adipose tissue of diabetic mice; 2) lipogenic gene expression was lower in adipose tissue of diabetes-susceptible mice, and it continued to decrease with the development of diabetes, compared with diabetes-resistant obese mice; 3) hepatic expression of lipogenic enzymes was increased and the hepatic triglyceride content was greatly elevated in diabetes-resistant obese mice; 4) hepatic expression of gluconeogenic genes was suppressed at the prediabetic stage but not at the onset of diabetes; and 5) genes normally not expressed in skeletal muscle and pancreatic islets were expressed in these tissues in the diabetic mice. We propose that increased hepatic lipogenic capacity protects the B6-ob/ob mice from the development of type 2 diabetes. Diabetes 52:688 -700, 2003

Genes for systemic vascular complications are differentially expressed in the livers of Type 2 diabetic patients

“…For example, up-regulation of Rad (a Ras-oncogene associated with diabetes), heat shock 70kD protein, and receptors for PDGF and endothelin, and down-regulation of general transcription and translation factors, and of cadherin and MHC have been observed in the skeletal muscle of insulin-resistant Pima Indians [7] and in Type 2 diabetic patients [8]. In addition, up-regulation of epidermal growth factor receptor and down-regulation of fatty acid-associated enzymes, fibronectin, VCAM1, MHC, plasminogen, SOD2, FMO5 and complement C3 have been observed in the liver of ob/ob mice [10,11,12].…”

“…More recently, microarray profiling of skeletal muscle tissue of Type 2 diabetic patients [7,8] and of healthy humans treated with insulin [9] has been reported. Although the liver is central for glucose homeostasis, microarray profiling of diabetic liver has been done only in Ob/Ob mice, a genetically obese rodent model of diabetes [10,11,12]. We have now used it to clarify the transcriptional alterations in the liver that are associated with the pathophysiology of Type 2 diabetes.…”

A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet

“…Benefits of enhanced triglyceride storage on insulin sensitivity have also been demonstrated in myocytes (38). Similarly, it has been suggested that differences in hepatic lipogenesis underlie the resistance of C57Bl/6J-ob/ob mice to diabetes by comparison with BTBR-ob/ob mice (39). Future studies will be required to define changes in hepatic flux of lipid metabolites induced by a CDD.…”

Glucose-stimulated Expression of Txnip Is Mediated by Carbohydrate Response Element-binding Protein, p300, and Histone H4 Acetylation in Pancreatic Beta Cells

“…In addition, Txnip deficiency was also able to rescue severely obese and insulin-resistant BTBRob/ob mice lacking leptin from diabetes, as demonstrated by our double-mutant congenic BTBRlep ob/ob txnip hcb/hcb (BTBR.ob/hcb) mice (9). BTBRob/ob mice are considered one of the most stringent models of type 2 diabetes, since, unlike B6ob/ob BTBRob/ob mice typically develop severe diabetes already at 6 weeks of age and completely decompensate at around 10 weeks (10). In contrast, Txnip-deficient BTBR.ob/ hcb mice remained normoglycemic for over 6 months.…”