‘Striking the Right Balance’ in Targeting PPARγ in the Metabolic Syndrome: Novel Insights from Human Genetic Studies

Gurnell, Mark

doi:10.1155/2007/83593

Cited by 23 publications

(18 citation statements)

References 130 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with reports from clinical studies [24], treatment of DIO mice on the HF/CH diet with rosiglitazone increased the body weight and decreased hyperinsulinemia demonstrating the drug's insulin sensitizing effects (data not shown). These changes in metabolic parameters were paralleled by changes in the pro-inflammatory state of the mice.…”

Section: Discussionsupporting

confidence: 90%

Kinetic Assessment and Therapeutic Modulation of Metabolic and Inflammatory Profiles in Mice on a High-Fat and Cholesterol Diet

Engstrom¹,

Bober²,

Chen³

et al. 2010

PPAR Research

View full text Add to dashboard Cite

The kinetics of metabolic and inflammatory parameters associated with obesity were evaluated in a murine diet-induced obesity (DIO) model using a diet high in fat and cholesterol. Cellular infiltration and mediator production were assessed and shown to be therapeutically modulated by the PPARgamma agonist rosiglitazone. C57BL/6 mice were maintained on a 45% fat/ 0.12% cholesterol (HF/CH) or Chow diet for 3, 6, 16, or 27 weeks. Flow cytometry was employed to monitor peripheral blood monocytes and adipose tissue macrophages (ATM). Gene expression and protein analysis methods were used to evaluate mediator production from total epididymal fat (EF), stromal vascular fraction (SVF), and sorted SVF cells. To investigate therapeutic intervention, mice were fed a HF/CH diet for 12 weeks and then a diet formulated with rosiglitazone (5 mg/kg) for an additional 6 weeks. A HF/CH diet correlated with obesity and a dramatic proinflammatory state. Therapeutic intervention with rosiglitazone attenuated the HF/CH induced inflammation. In addition, a novel population was found that expressed the highest levels of the pro-inflammatory mediators CCL2 and IL-6.

show abstract

Section: Discussionsupporting

confidence: 90%

Kinetic Assessment and Therapeutic Modulation of Metabolic and Inflammatory Profiles in Mice on a High-Fat and Cholesterol Diet

Engstrom¹,

Bober²,

Chen³

et al. 2010

PPAR Research

View full text Add to dashboard Cite

show abstract

“…This mutation has previously been shown to cause severe insulin-resistant diabetes and partial lipodystrophy [32], [33], [34]. The proband’s age at diagnosis was 38 years; she was included in our study because a family member was diagnosed at age 28 years.…”

Section: Resultsmentioning

confidence: 99%

Exome Sequencing and Genetic Testing for MODY

et al. 2012

View full text Add to dashboard Cite

ContextGenetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive.ObjectiveThe aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results.Research Design and MethodsWe performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism.ResultsOn average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0–4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes.ConclusionOur results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.

show abstract

“…48 Obese and insulin-resistant patients treated with rosiglitazone gain some weight as a consequence of the treatment. 85 However, their insulin resistance decreases probably due to a lowering of circulating free fatty acid levels. The latter may be related to increased SCD1 mRNA levels and subsequent enhanced fat storage.…”

mentioning

confidence: 99%

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

2008

View full text Add to dashboard Cite

The prevalence of obesity and related metabolic disorders increases rapidly in western societies. A proper choice of foods may now prevent or delay many of the health consequences related to these disorders. In this respect, replacing dietary saturated fatty acids (SFAs) by cis-monounsaturated fatty acids (cis-MUFAs) has beneficial effects. In addition to diet-derived cis-MUFAs, the human body can also generate cis-MUFAsfrom SFAs through the action of stearoyl-CoA desaturases (SCDs). SCDs may play an adverse role in obesity and obesity-related insulin resistance. Here, we review the current knowledge on the molecular aspects and the role of SCD1 in obesity and the metabolic syndrome (MS). In mice, many studies have suggested a negative role for SCD1 in the development of obesity and insulin resistance. In humans, however, evidence is less convincing. If anything, increased, rather than decreased, levels of SCD1 mRNA levels are negatively associated with MS-related diseases such as insulin resistance. However, an unequivocal conclusion is currently not possible as the number of human studies is limited. Therefore, more human studies are needed at the molecular as well as at the physiological level to understand the true role of SCD1 during the development of obesity and the MS.

show abstract

‘Striking the Right Balance’ in Targeting PPARγ in the Metabolic Syndrome: Novel Insights from Human Genetic Studies

Cited by 23 publications

References 130 publications

Kinetic Assessment and Therapeutic Modulation of Metabolic and Inflammatory Profiles in Mice on a High-Fat and Cholesterol Diet

Kinetic Assessment and Therapeutic Modulation of Metabolic and Inflammatory Profiles in Mice on a High-Fat and Cholesterol Diet

Exome Sequencing and Genetic Testing for MODY

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

Contact Info

Product

Resources

About