Biomedical subjects

Dominique Langin

Publications and source records attributed to Dominique Langin.

39 records · Page 3Linked to original sources

PubMed2002

Regulation of human adipocyte gene expression by thyroid hormone.

Thyroid hormones are key regulators of metabolism. In adipose tissue, changes in thyroid status result in alterations of lipolytic capacity. The effects of these hormones are mediated by thyroid hormone receptors that modulate gene transcription. Very few target genes have been identified in adipose tissue. To investigate the effect of T(3) on gene expression in human adipocytes, primary cultures of human sc adipose tissue explants were treated with T(3). (32)P-labeled cDNA probes prepared from isolated adipocyte total RNA were hybridized to cDNA arrays representing 1,176 genes. Among the statistically significant variations in mRNA levels with more than 1.3-fold difference, 13 and 6 genes were positively and negatively regulated, respectively (n = 3). The genes encoded proteins that were involved in signal transduction, lipid metabolism, apoptosis, and inflammatory response. Using RT-competitive PCR, we showed a down-regulation of phosphodiesterase 3B, alpha(2A)-adrenergic receptor, and G protein alpha(i2) subunit mRNAs, and an up-regulation of beta(2)-adrenergic receptor mRNA. These regulations may explain the T(3)-mediated increase in catecholamine-induced lipolysis. The down-regulation of sterol regulatory element binding protein-1c, a transcription factor controlling lipogenic gene expression, may constitute a link between thyrotoxicosis and insulin resistance. Thus, these data suggest that T(3) modulates expression of genes with a wide range of function in human adipose tissue.

Adipocytes↗

PubMed2002

Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose.

Hormone-sensitive lipase (HSL) catalyzes the rate-limiting step in the mobilization of fatty acids from adipose tissue, thus determining the supply of energy substrates in the body. HSL mRNA was positively regulated by glucose in human adipocytes. Pools of stably transfected 3T3-F442A adipocytes were generated with human adipocyte HSL promoter fragments from -2,400/+38 to -31/+38 bp linked to the luciferase gene. A glucose-responsive region was mapped within the proximal promoter (-137 bp). Electromobility shift assays showed that upstream stimulatory factor (USF)-1 and USF2 and Sp1 and Sp3 bound to a consensus E-box and two GC-boxes in the -137-bp region. Cotransfection of the -137/+38 construct with USF1 and USF2 expression vectors produced enhanced luciferase activity. Moreover, HSL mRNA levels were decreased in USF1- and USF2-deficient mice. Site-directed mutagenesis of the HSL promoter showed that the GC-boxes, although contributing to basal promoter activity, were dispensable for glucose responsiveness. Mutation of the E-box led to decreased promoter activity and suppression of the glucose response. Analogs and metabolites were used to determine the signal metabolite of the glucose response. The signal is generated downstream of glucose-6-phosphate in the glycolytic pathway before the triose phosphate step.

3T3 Cells↗

PubMed2002

Understanding adipose tissue development from transgenic animal models.

The World Health Organization has recognized obesity as a health problem of pandemic proportions. Recent work led to major breakthroughs in the understanding of the molecular basis of adipose tissue development with the cloning and characterization of numerous genes involved in fat cell differentiation and metabolism. Transgenesis has proved very useful in establishing the physiological roles of these genes. Here we review transgenic models made to study adipose tissue's metabolic and trophic responses. Genetic modifications unexpectedly associated to alterations of adipose tissue development are also examined because of their potential involvement in obesity and energy balance regulation. After a description of the methodologies commonly used, we review the data obtained on transcription factors, metabolism, signal transduction, secreted products, and models of lipodystrophy. An overview of such integrative studies leads to a better understanding of the physiology of adipose tissue development. Alterations in expression levels of proteins involved at different steps of a regulatory pathway highlight the complementary roles of genes in the regulation of adipose tissue development. However, lack of phenotypes also illustrates the capacity of animals to set up adaptive mechanisms.

Adipose Tissue↗