Identification of genes contributing to the obese yellowAvyphenotype: caloric restriction, genotype, diet × genotype interactions

2004 ◽  
Vol 18 (3) ◽  
pp. 316-324 ◽  
Author(s):  
Jim Kaput ◽  
Karin G. Klein ◽  
Eric J. Reyes ◽  
Warren A. Kibbe ◽  
Craig A. Cooney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Quantitative Trait Loci ◽  
Caloric Restriction ◽  
Quantitative Trait ◽  
Obesity And Diabetes ◽  
Ion Imbalance ◽  
Ad Libitum

The incidence and severity of obesity and type 2 diabetes are increasing in Western societies. The progression of obesity to type 2 diabetes is gradual with overlapping symptoms of insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemias, ion imbalance, and inflammation; this complex syndrome has been called diabesity. We describe here comparisons of gene expression in livers of A/ a (agouti) vs. Avy/ A (obese yellow) segregants (i.e., littermates) from BALB/cStCrlfC3H/Nctr × VYWffC3Hf/Nctr- Avy/ a matings in response to 70% and 100% of ad libitum caloric intakes of a reproducible diet. Twenty-eight ( 28 ) genes regulated by diet, genotype, or diet × genotype interactions mapped to diabesity quantitative trait loci. A subset of the identified genes is linked to abnormal physiological signs observed in obesity and diabetes.

scholarly journals Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats

2005 ◽  
Vol 34 (2) ◽  
pp. 299-315 ◽  
Author(s):  
Young Ho Suh ◽  
Younyoung Kim ◽  
Jeong Hyun Bang ◽  
Kyoung Suk Choi ◽  
June Woo Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Zucker Diabetic Fatty Rats ◽  
Zdf Rats

Insulin resistance occurs early in the disease process, preceding the development of type 2 diabetes. Therefore, the identification of molecules that contribute to insulin resistance and leading up to type 2 diabetes is important to elucidate the molecular pathogenesis of the disease. To this end, we characterized gene expression profiles from insulin-sensitive tissues, including adipose tissue, skeletal muscle, and liver tissue of Zucker diabetic fatty (ZDF) rats, a well characterized type 2 diabetes animal model. Gene expression profiles from ZDF rats at 6 weeks (pre-diabetes), 12 weeks (diabetes), and 20 weeks (late-stage diabetes) were compared with age- and sex-matched Zucker lean control (ZLC) rats using 5000 cDNA chips. Differentially regulated genes demonstrating > 1.3-fold change at age were identified and categorized through hierarchical clustering analysis. Our results showed that while expression of lipolytic genes was elevated in adipose tissue of diabetic ZDF rats at 12 weeks of age, expression of lipogenic genes was decreased in liver but increased in skeletal muscle of 12 week old diabetic ZDF rats. These results suggest that impairment of hepatic lipogenesis accompanied with the reduced lipogenesis of adipose tissue may contribute to development of diabetes in ZDF rats by increasing lipogenesis in skeletal muscle. Moreover, expression of antioxidant defense genes was decreased in the liver of 12-week old diabetic ZDF rats as well as in the adipose tissue of ZDF rats both at 6 and 12 weeks of age. Cytochrome P450 (CYP) genes were also significantly reduced in 12 week old diabetic liver of ZDF rats. Genes involved in glucose utilization were downregulated in skeletal muscle of diabetic ZDF rats, and the hepatic gluconeogenic gene was upregulated in diabetic ZDF rats. Genes commonly expressed in all three tissue types were also observed. These profilings might provide better fundamental understanding of insulin resistance and development of type 2 diabetes.

scholarly journals Docking protein 1 and free fatty acids are associated with insulin resistance in patients with type 2 diabetes mellitus

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110482
Author(s):  
Xiaoqin Ha ◽  
Xiaoling Cai ◽  
Huizhe Cao ◽  
Jie Li ◽  
Bo Yang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Effective Means ◽  
Model Assessment ◽  
High Concentration ◽  
Obesity And Diabetes ◽  
Docking Protein

Objective Insulin resistance (IR) is a key defect in type 2 diabetes mellitus (T2DM); therefore, effective means of ameliorating IR are sought. Methods We performed a retrospective cohort study of 154 patients with T2DM and 39 with pre-diabetes (pre-DM). The effects of IR and a high concentration of FFA on gene expression were determined using microarray analysis and quantitative reverse transcription polymerase chain reaction (RT-qPCR) in patients with T2DM or pre-DM. Results Serum FFA concentration and homeostasis model assessment of IR (HOMA-IR) were significantly higher in patients with T2DM but no obesity and in those with pre-DM than in controls. HOMA-IR was significantly associated with T2DM. RT-qPCR showed that the expression of FBJ murine osteosarcoma viral oncogene homolog ( FOS) and AE binding protein 1 ( AEBP1) was much lower in the circulation of participants with obesity and diabetes. RT-qPCR showed that the expression of docking protein 1 ( DOK1) was significantly lower in the blood of participants with diabetes but no obesity and in those with pre-DM than in controls. Conclusions FFA and DOK1 are associated with IR in patients with T2DM but no obesity or pre-DM. The downregulation of DOK1 might inhibit lipid synthesis and induce lipolysis, inducing or worsening IR.

scholarly journals Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Denise E. Lackey ◽  
Felipe C. G. Reis ◽  
Roi Isaac ◽  
Rizaldy C. Zapata ◽  
Dalila El Ouarrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Target Genes ◽  
Obese Mice ◽  
Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

A gene expression signature for insulin resistance

2011 ◽  
Vol 43 (3) ◽  
pp. 110-120 ◽  
Author(s):  
Nicky Konstantopoulos ◽  
Victoria C. Foletta ◽  
David H. Segal ◽  
Katherine A. Shields ◽  
Andrew Sanigorski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Large Scale ◽  
Gene Expression Signature ◽  
Channel Blockers ◽  
Expression Signature ◽  
Insulin Resistant ◽  
Novel Strategy

Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made “insulin resistant” by treatment with tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone (“resensitized”). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, β-adrenergic antagonists, β-lactams, and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study ( n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels; P < 0.001). These findings show that GES technology can be used for both the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

scholarly journals Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity

2016 ◽  
Vol 135 (8) ◽  
pp. 869-880 ◽  
Author(s):  
Satria P. Sajuthi ◽  
Neeraj K. Sharma ◽  
Jeff W. Chou ◽  
Nicholette D. Palmer ◽  
David R. McWilliams ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Quantitative Trait Loci ◽  
African Americans ◽  
Muscle Tissue ◽  
Quantitative Trait ◽  
Tissue Expression ◽  
Expression Quantitative Trait Loci ◽  
Trait Loci ◽  
Diabetes And Obesity

scholarly journals Leveraging IgG N-glycosylation quantitative-trait loci to characterize the relationship between Type 2 Diabetes and hypertension: A network with bidirectional mendelian randomization study

2020 ◽  
Author(s):  
Di Liu ◽  
Jie Zhang ◽  
Xiaoyu Zhang ◽  
Qiuyue Tian ◽  
Xiaoni Meng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Quantitative Trait Loci ◽  
Quantitative Trait ◽  
Mendelian Randomization ◽  
Hypertension Risk ◽  
Bidirectional Regulation ◽  
A Genome ◽  
Trait Loci ◽  
The Relationship

Abstract Background: The relationship between IgG N-glycosylation, type 2 diabetes (T2D) and hypertension is not well understood.Methods: A genome-wide association study (GWAS) of IgG N-glycosylation traits from 536 individuals was performed and 1203 IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) variants targeting 24 IgG N-glycosylation were mapped traits after multi-testing correction. Network with bidirectional mendelian randomization (MR) analysis was performed to examine the causal association between IgG N-glycosylation, T2D and hypertension.Results: By linking IgG N-glycan-QTL variants with GWAS results for T2D and hypertension, 19 putatively causal IgG N-glycans for T2D and 21 putatively causal IgG N-glycans for hypertension were identified. IgG N-glycan-QTL determined IgG N-glycosylation to higher T2D was associated with higher hypertension risk (β [95% CI] =1.234 [0.939-1.529], P <0.001). In addition, IgG N-glycan-QTL determined IgG N-glycosylation to higher hypertension was associated with higher T2D risk (β [95% CI] =0.753 [0.140-1.3669], P =0.016). No evidence of pleiotropic bias was detected in MR-Egger analysis.Conclusions: Overall, our study showed that IgG N-Glycosylation-QTLs determined T2D is associated with higher hypertension risk, and vice versa, performing bidirectional regulation through IgG N-Glycosylation.

scholarly journals Differential Endocrine Responses to Rosiglitazone Therapy in New Mouse Models of Type 2 Diabetes

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 919-926 ◽  
Author(s):  
Edward H. Leiter ◽  
Peter C. Reifsnyder ◽  
Weidong Zhang ◽  
Huei-ju Pan ◽  
Qiang Xiao ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Quantitative Trait Loci ◽  
Mouse Models ◽  
Quantitative Trait ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Plasminogen Activator Inhibitor 1 ◽  
Trait Loci ◽  
Pai 1

Polygenic mouse models for obesity-induced type 2 diabetes (T2D) more accurately reflect the most common manifestations of the human disease. Two inbred mouse strains (NON/Lt and NZO/HlLt) separately contributed T2D susceptibility- conferring quantitative trait loci to F1 males. Although chronic administration of rosiglitazone (Rosi) in diet (50 mg/kg) effectively suppressed F1 diabetes, hepatosteatosis was an undesired side effect. Three recombinant congenic strains (designated RCS1, -2, and -10) developed on the NON/Lt background carry variable numbers of these quantitative trait loci that elicit differential weight gain and male glucose intolerance syndromes of variable severity. We previously showed that RCS1 and -2 mice responded to chronic Rosi therapy without severe steatosis, whereas RCS10 males were moderately sensitive. In contrast, another recombinant congenic strain, RCS8, responded to Rosi therapy with the extreme hepatosteatosis observed in the F1. Longitudinal changes in multiple plasma analytes, including insulin, the adipokines leptin, resistin, and adiponectin, and plasminogen activator inhibitor-1 (PAI-1) allowed profiling of the differential Rosi responses in steatosis-exacerbated F1 and RCS8 males vs. the resistant RCS1 and RCS2 or moderately sensitive RCS10. Of these biomarkers, PAI-1 most effectively predicted adverse drug responses. Unexpectedly, mean resistin concentrations were higher in Rosi-treated RCS8 and RCS10. In summary, longitudinal profiling of multiple plasma analytes identified PAI-1 as a useful biomarker to monitor for differential pharmacogenetic responses to Rosi in these new mouse models of T2D.

scholarly journals Mild Caloric Restriction Decreases Insulin Requirements in Patients With Type 2 Diabetes and Severe Insulin Resistance

Medicine ◽  
2015 ◽  
Vol 94 (30) ◽  
pp. e1160 ◽  
Author(s):  
Cristina Adelia Meehan ◽  
Elaine Cochran ◽  
Megan Mattingly ◽  
Phillip Gorden ◽  
Rebecca J. Brown
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Caloric Restriction ◽  
Severe Insulin Resistance ◽  
Insulin Requirements
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