Dataset Information

Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men.

ABSTRACT:

Context

Lipin-1 functions in adipocyte triglyceride biosynthesis and in the regulation of gene expression, both of which may influence metabolic homeostasis.

Objective

Our objective was to determine whether variations in adipose tissue lipin-1 expression levels influence insulin sensitivity and gene expression in young healthy human subjects.

Design and subjects

In 56 healthy young men (22.6 +/- 3.2 yr; 26.4 +/- 4.1 kg/m2) we determined insulin sensitivity by a euglycemic-hyperinsulinemic clamp, and whole body oxygen consumption and respiratory quotient by indirect calorimetry. We performed gene expression analysis in adipose tissue samples from human subjects and from lipin-1 transgenic mice using quantitative RT-PCR.

Results

In healthy young men, lipin-1 expression was positively correlated with insulin sensitivity (R2 = 0.22; P < 0.01), insulin-stimulated respiratory quotient (R2 = 0.16; P < 0.01), and maximal oxygen consumption during exercise (R2 = 0.16; P < 0.01). Lipin-1 mRNA levels were also correlated with expression of genes involved in lipid oxidation, uptake, and lipolysis, both in humans and in lipin-1 transgenic mice. The strongest correlation occurred between lipin-1 and peroxisome proliferator-activated receptor alpha (R2 = 0.74; P < 1 x 10(-7)), a nuclear receptor with a key role in fatty acid oxidation.

Conclusion

Lipin-1 expression levels in adipose tissue of healthy young subjects and in mice are correlated with a favorable metabolic profile and expression of fatty acid oxidation genes.

SUBMITTER: Donkor J

PROVIDER: S-EPMC2190746 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men.

Donkor Jimmy J Sparks Lauren M LM Xie Hui H Smith Steven R SR Reue Karen K

The Journal of clinical endocrinology and metabolism 20071009 1

<h4>Context</h4>Lipin-1 functions in adipocyte triglyceride biosynthesis and in the regulation of gene expression, both of which may influence metabolic homeostasis.<h4>Objective</h4>Our objective was to determine whether variations in adipose tissue lipin-1 expression levels influence insulin sensitivity and gene expression in young healthy human subjects.<h4>Design and subjects</h4>In 56 healthy young men (22.6 +/- 3.2 yr; 26.4 +/- 4.1 kg/m2) we determined insulin sensitivity by a euglycemic-h ...[more]

PMID: 17925338

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Project description:ObjectiveNuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice.MethodsA novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated.ResultsWO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis.ConclusionsWO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.

Dataset Information

Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men.

Context

Objective

Design and subjects

Results

Conclusion

Publications

Adipose tissue lipin-1 expression is correlated with peroxisome proliferator-activated receptor alpha gene expression and insulin sensitivity in healthy young men.

Similar Datasets

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