Dataset Information

Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice

ABSTRACT: Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor deficient (db/db) obese mice on a C57BL/6×C57BLKS mixed genetic background. Furthermore, shRNA mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9wt db/db and Aqp9-/- db/db mice did not differ in body weight and liver TAG contents. On the C57BL/6 genetic background we observed elevated plasma glucose in Aqp9-/- db/db mice (+ 1.1 mM, life-time average) while plasma insulin concentration was reduced at time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9wt db/db and Aqp9-/- db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%), glucose (+24%) and reduction in threonate (all at q<0.1) in Aqp9-/- db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP9 in glycerol metabolism of obese C57BL/6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis.

INSTRUMENT(S): LECO Pegasus III

SUBMITTER: Michael Rutzler

PROVIDER: MTBLS219 | MetaboLights | 2015-09-28

REPOSITORIES: MetaboLights

ACCESS DATA

Dataset's files

Source:

Items per page:

1 - 5 of 9

Publications

Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice.

Spegel Peter P Chawade Aakash A Nielsen Søren S Kjellbom Per P Rützler Michael M

Physiological reports 20150901 9

Deletion of the glycerol channel aquaporin-9 (Aqp9) reduces postprandial blood glucose levels in leptin receptor-deficient (db/db) obese mice on a C57BL/6 × C57BLKS mixed genetic background. Furthermore, shRNA-mediated reduction of Aqp9 expression reduces liver triacylglycerol (TAG) accumulation in a diet-induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57BL/6 background. Aqp9(wt) db/db and Aqp9(-/-) db/db ...[more]

PMID: 26416971

Similar Datasets

Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types. Comparison of wildtype mouse liver function versus Ugcg-deficient

Project description:Little is known about the role of the transcription factor PPARÃ?/d in liver. Here we set out to better elucidate the function of PPARÃ?/d in liver by comparing the effect of PPARa and PPARÃ?/d deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARa and PPARÃ?/d deletion was similar, whereas in fasted state the effect of PPARa deletion was much more pronounced, consistent with the pattern of gene expression of PPARa and PPARÃ?/d. Minor overlap was found between PPARa- and PPARÃ?/d-dependent gene regulation in liver. Pathways upregulated by PPARÃ?/d deletion were connected to innate immunity. Pathways downregulated by PPARÃ?/d deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPARÃ?/d-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARÃ?/d target genes. In contrast to PPARa-/- mice, no changes in plasma FFA, plasma Ã?-hydroxybutyrate, liver triglycerides and liver glycogen were observed in PPARÃ?/d-/- mice. Our data indicate a role for PPARÃ?/d in hepatic glucose utilization and lipoprotein metabolism but not in the adaptive response to fasting. Keywords: Analysis of target gene regulation by using microarrays Pure-bred Sv129 PPARÎ± -/- mice and corresponding wildtype mice were used. Male mice (n=4-5 per group) were either fed or fasted for 24 hours. At the end of the experiment, mice were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%). Blood was collected by orbital puncture, after which the mice were sacrificed by cervical dislocation. Livers were dissected, snap frozen in liquid nitrogen and kept at -80ÂºC until further analysis. For RNA analyses, tissue from the same part of the liver lobe was used.

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.

			Action	DRS
	MTBLS219	Other
	FILES	Other
	a_MTBLS219_liver_aqp9_ko.txt	Txt
	a_MTBLS219_plasma_aqp9_ko.txt	Txt
	i_Investigation.txt	Txt