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Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance [skeletal muscle]

ABSTRACT: Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis –in large parts- through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE53754 | GEO | 2014/10/15

SECONDARY ACCESSION(S): PRJNA232813

REPOSITORIES: GEO

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Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance [abdominal fat]

Project description:Obesity-related insulin resistance represents the core component of the so-called Metabolic Syndrome, ultimately promoting glucose intolerance, pancreatic beta cell failure, and overt type 2 diabetes 1 2. Based on substantial side effects of existing pharmacological approaches, efficient and safe insulin sensitization and glucose control remain critical therapeutic aims to prevent diabetic late complications 3. Here, we identify Transforming Growth Factor beta-like Stimulated Clone (TSC) 22 D4 as a critical molecular determinant of insulin signaling and glucose handling. Hepatocyte-specific inactivation of TSC22D4 enhanced insulin signaling in liver and skeletal muscle, while hepatic TSC22D4 overexpression blunted insulin tissue responses. Consequently, hepatic TSC22D4 inhibition both prevented and reversed hyperglycemia, glucose intolerance, and insulin resistance in various diabetes mouse models, respectively. TSC22D4 was found to exert its effects on systemic glucose homeostasis - in large parts - through the transcriptional regulation of the small secretory protein lipocalin (LCN) 13 as demonstrated by chromatin recruitment and genetic rescue experiments in vivo. As hepatic TSC22D4 levels were found to be elevated in human diabetic patients, correlating with decreased insulin sensitivity and hyperglycemia, our results establish the inhibition of TSC22D4 as an attractive insulin sensitizing option in diabetes therapy.

2014-10-15 | GSE53753 | GEO

Transforming growth factor beta-like stimulated clone 22 D4 promotes diabetic hyperglycemia and insulin resistance [abdominal fat]

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Cachexia-inducible Transforming growth factor-beta1 stimulated Clone-22 D4 controls acute hepatic lipid homeostasis.

2012-09-01 | GSE33324 | GEO

Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients [transcriptome analysis]

Project description:Type 2 diabetes is a complex disease associated with many underlying pathomechanisms. Epigenetic regulation of gene expression by DNA methylation has become increasingly recognized as an important component in the etiology of type 2 diabetes. We performed genome-wide methylome and transcriptome analysis in liver from severely obese patients with or without type 2 diabetes to discover aberrant pathways underlying the development of insulin resistance. We identified hypomethylation of five key genes involved in hepatic glycolysis, de novo lipogenesis and insulin resistance with concomitant increased mRNA expression and protein content. The CpG-site within the ATF-motif was hypomethylated in four of these genes in liver of non-diabetic and type 2 diabetic obese patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. In conclusion, severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome and genes controlling glucose and lipid metabolism are hypomethylated at a regulatory site. Thus, obesity may epigenetically reprogram the liver towards increased lipid production and exacerbate the development of insulin resistance. To better understand the molecular mechanisms underlying the development of hepatic insulin resistance and type 2 diabetes at a molecular level, we performed a genome-wide methylome and transcriptome analysis of liver from non-obese metabolically healthy, obese non-diabetic and obese type 2 diabetic patients. Distinct DNA methylation and gene expression profiles were identified in liver from the obese and type 2 diabetic patients compared with the non-obese participants.

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2016-06-29 | E-GEOD-79008 | biostudies-arrayexpress

Cachexia-inducible Transforming growth factor-beta1 stimulated Clone-22 D4 controls acute hepatic lipid homeostasis.

Project description:To explore the molecular basis for TSC22D4 function in hepatic lipid homeostasis in vivo TSC22D4 was knocked down in the mouse liver using adenovirus and performed genome wide expression analysis. 1x10^9 plaque-forming units (pfu) per recombinant virus were administered via tail vein injection. Mice (C57Bl/6) were sacrificed 7 days after infection. Hepatic RNA was isolated and used for whole genome expression analysis.

2012-09-01 | E-GEOD-33324 | biostudies-arrayexpress

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