Insulin resistance is a component of type 2 diabetes and often precedes pancreatic ␤-cell failure. Contributing factors include obesity and a central pattern of fat accumulation with a strong genetic component. The adipocyte secreted hormone resistin has been proposed as a link between the adipocyte and insulin resistance by inhibition of insulin-stimulated glucose uptake and/ or blocking adipocyte differentiation. Here we report that the G/G genotype of a single nucleotide polymorphism (SNP) in the promoter of the human resistin gene, ؊180C>G, had significantly increased basal promoter activity in adipocytes. These data were recapitulated in vivo, where G/G homozygotes had significantly higher resistin mRNA levels in human abdominal subcutaneous fat. A significant interaction was also found between the ؊180C>G SNP, a marker of oxidative stress (NAD[P]H quinone oxidoreductase mRNA) and homeostasis model assessment of insulin resistance. In addition, resistin mRNA was positively and independently correlated with insulin resistance and hepatic fat as measured by liver X-ray attenuation. These data implicate resistin in the pathophysiology of the human insulin resistance syndrome, an effect mediated by the ؊180C>G promoter SNP and potentially cellular oxidative stress.

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Transgenic mice bearing a transgene coding for a glucocorticoid receptor antisense mRNA that partially blocks glucocorticoid receptor expression were used to investigate the long-term effect of hypothalamic-pituitary-adrenal dysfunction on brain 5-hydroxytryptamine-2A (5-HT_2A) receptor expression. The brain 5-HT_2A receptor mRNA levels in transgenic mice were measured by in situ hybridization and compared to those in control mice. We also studied the effect of a 3-week treatment with fluoxetine on brain 5-HT_2A receptor expression in the transgenic mice. No difference in 5-HT_2A mRNA levels was observed between transgenic and control mice in cortical or striatal regions, and fluoxetine treatment was without effect. No difference in hypothalamic 5-HT_2A mRNA levels was observed between transgenic and control mice, while fluoxetine treatment increased these levels in both transgenic as well as in the hypothalamic ventromedial and paraventricular nuclei of control mice. 5-HT_2A receptor mRNA levels were similar in hippocampal CA1 and CA2 subregions of control and transgenic, but were lower in the CA3 and CA4 subregions of transgenic mice. Fluoxetine had no effect on 5-HT_2A mRNA levels of transgenic mice but reduced control mouse 5-HT_2A receptor mRNA levels in the CA3 subregion. These results suggest that impaired glucocorticoid receptor function can affect hippocampal 5-HT_2A receptor expression in transgenic mice and that this is not corrected by fluoxetine treatment.