No abstract

OBJECTIVE-Adiponectin is an important adipocytokine that improves insulin action and reduces atherosclerotic processes. The plasma adiponectin level is paradoxically reduced in obese individuals, but the underlying mechanism is unknown. This study was undertaken to test the hypothesis that mitochondrial function is linked to adiponectin synthesis in adipocytes.RESEARCH DESIGN AND METHODS-We examined the effects of rosiglitazone and the measures that increase or decrease mitochondrial function on adiponectin synthesis. We also examined the molecular mechanism by which changes in mitochondrial function affect adiponectin synthesis.RESULTS-Adiponectin expression and mitochondrial content in adipose tissue were reduced in obese db/db mice, and these changes were reversed by the administration of rosiglitazone. In cultured adipocytes, induction of increased mitochondrial biogenesis (via adenoviral overexpression of nuclear respiratory factor-1) increased adiponectin synthesis, whereas impairment in mitochondrial function decreased it. Impaired mitochondrial function increased endoplasmic reticulum (ER) stress, and agents causing mitochondrial or ER stress reduced adiponectin transcription via activation of c-Jun NH 2 -terminal kinase (JNK) and consequent induction of activating transcription factor (ATF)3. Increased mitochondrial biogenesis reversed all of these changes.CONCLUSIONS-Mitochondrial function is linked to adiponectin synthesis in adipocytes, and mitochondrial dysfunction in adipose tissue may explain decreased plasma adiponectin levels in obesity. Impaired mitochondrial function activates a series of mechanisms involving ER stress, JNK, and ATF3 to decrease adiponectin synthesis. Diabetes

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...