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Translin KO mice display elevated adiposity

ABSTRACT: The high prevalence of obesity has focused attention on defining the pathophysiological processes that underlie susceptibility or resistance to its deleterious metabolic consequences. Mice lacking translin (Tsn), a gene implicated in a variety of biological functions from transcription to microRNA degradation, display extremely high levels of adiposity, comparable to those found in well-known genetic models of obesity, such as melanocortin 4 receptor or leptin knockout (KO) mice. Although translin KO mice display increased adiposity they retain normal glucose tolerance. In contrast, wild-type (WT) mice placed on a high-fat diet until they match translin KO adiposity levels are glucose intolerant, as expected. Conversely, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. The ability of translin KO mice to retain normal glucose tolerance in the face of massive tissue expansion may be due to three factors: preferential accumulation of subcutaneous fat, reduced levels of TNF mRNA in both adipose and hepatic tissue, and elevated levels of plasma adiponectin. Further studies aimed at defining the molecular bases for these phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.

ORGANISM(S): synthetic construct Mus musculus

PROVIDER: GSE114932 | GEO | 2020/04/10

REPOSITORIES: GEO

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Project description:In an effort to reduce hepatic glucose production and lower plasma glucose levels that are characteristics of diabetes, we have devised a treatment whereby we enhance glycolysis in the liver of a type 2 diabetic mouse model (KK/H1J). We achieve this by raising the levels of a potent regulator of glucose metabolism, fructose-2,6-bisphosphate (F26BP). Treating the mice in this way, we have demonstrated amelioration of the diabetic phenotype in terms of lowering plasma glucose and insulin levels. These treated mice also display reduced weight gain, reduced adiposity, and normalized plasma and hepatic lipid levels. These latter metabolic changes brought about by raising F26BP levels are counterintuitive. A concurrent increase in glycolysis and lipogenesis is expected, however, we observe an increase in glycolysis with a concurrent decrease in lipogenesis. Preliminary analysis of gene expression in these mice has revealed alterations in gene expression of several genes that support the therapeutic effect of raising F26BP levels. To further profile F26BP effects on hepatic gene expression, we have applied a comprehensive approach to identify sets of genes and thereby biological pathways that are differentially regulated when hepatic glycolysis is accelerated in diabetic mice. Comparing diabetic and treated animals, we hope to further clarify the molecular and genetic signature of type 2 diabetes and obesity and elucidate how this signature is affected by raising F26BP levels. Our study examining gene array as well as the hepatic proteome has identified multiple gene and protein expression changes. Of particular relevance, we note that fatty acid metabolism and cholesterol metabolism pathways are significantly down-regulated in diabetic mice treated with a PFK-2 mutant engineered to raise F26BP levels, which underlie the changes we see in the metabolic parameters. 6 KK/H1J mice, a polygenic model of type 2 diabetes and obesity, weighing approximately 35g were used in this study. 3 mice were injected with GFP control adenovirus and 3 mice were injected with bisphosphatase deficient PFK-2 adenovirus (BPD). Mice were followed for 7 days before livers were extracted. Total cellular RNA was extracted from each mouse and analyzed by microarray separately.

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Translin KO mice display elevated adiposity

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