No abstract

Mesenchymal cells are able to differentiate into several distinct cell types, including osteoblasts and adipocytes. The commitment to a particular lineage may be regulated by specific transcription factors. Peroxisome proliferator-activated receptor-␥ (PPAR␥), acting in conjunction with CCAAT/enhancer-binding protein-␣, has been suggested as a key regulator of adipogenic differentiation. Previous studies have shown that the activation of PPAR␥ in osteoblasts suppresses osteoblast differentiation and the expression of osteocalcin, an osteoblast-specific protein. However, the mechanism of this inhibition remains unclear. We investigated the effect of PPAR␥ activation on the expression of osteocalcin and analyzed the molecular mechanism. Mouse osteoblastic MC3T3-E1 cells expressed PPAR␥, which was transcriptionally active, whereas rat osteosarcoma ROS 17/2.8 cells did not. Treatment of MC3T3-E1 osteoblasts and ROS 17/2.8 cells stably transfected with PPAR␥2 with the PPAR␥ activator 15-deoxy-⌬ 12,14 -prostaglandin J 2 inhibited the mRNA expression of osteocalcin and Runx2, the latter of which is a key transcription factor in osteoblast differentiation. This decreased expression of osteocalcin and Runx2 was partly explained by the decreased level of Runx2 resulting from the suppressed transcription from the Runx2 promoter. However, in addition to this indirect effect, the activation of PPAR␥ by 15-deoxy-⌬ 12,14 -prostaglandin J 2 directly suppressed the Runx2-mediated induction of the activities of the osteocalcin promoter and the artificial promoter p6OSE2, which contains six tandem copies of osteoblast-specific element-2, the Runx2-binding promoter sequence. This inhibition was mediated by a physical interaction between PPAR␥ and Runx2 and the subsequent repression of the transcriptional activity at the osteoblast-specific element-2 sequence. Thus, this study demonstrates that the activation of PPAR␥ inhibits osteocalcin expression both by suppressing the expression of Runx2 and by interfering with the transactivation ability of Runx2.Mesenchymal cells are able to differentiate into several distinct cell types, including osteoblasts and adipocytes (1-3). The mechanisms directing the cells along a particular lineage and the suppression of alternative pathways are not well established, although signals derived from the extracellular environment and several key transcription factors have been identified (4 -8).Peroxisome proliferator-activated receptors (PPARs) 1 are a family of ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily (9, 10). PPAR␥ is abundantly expressed in both white and brown adipose tissue and has been known to play a critical role in the regulation of adipocyte differentiation (10). The transfection of fibroblastic cells with PPAR␥2 and its subsequent activation with ligand have been shown to be sufficient to initiate adipogenesis (11). Moreover, determined myoblasts with no inherent adipogenic potential can be induced to transdifferentiate into mature adipo...

Resistin is an adipocyte-derived peptide that might play a role in obesity and insulin resistance. However, its role in humans is largely unclear. Although many studies have measured the expression of human resistin in tissues, the circulating concentrations of resistin and its relation to metabolic parameters in humans are unknown. We developed an ELISA for human resistin and measured plasma concentrations in aged individuals with or without type 2 diabetes mellitus. To validate the results of plasma resistin concentrations in our subjects, plasma adiponectin concentrations were also determined, which were higher in nondiabetic subjects than in type 2 diabetic patients and correlated with the homeostasis model assessment for insulin resistance (HOMA-IR). Log-transformed plasma resistin concentrations (log-resistin) were higher in diabetic patients compared with normal individuals (0.50 +/- 0.39 vs. 0.28 +/- 0.51 ng/ml; P < 0.001), and this difference was significant after controlling for gender and body mass index. Log-resistin did not show a significant correlation with HOMA-IR, waist circumference, body mass index, blood pressure, or total cholesterol. The plasma glucose concentration was an independent factor associated with log-resistin. In conclusion, plasma resistin concentrations are elevated in patients with type 2 diabetes, but are not associated with insulin resistance or obesity.