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

Many transcription coactivators interact with nuclear receptors in a ligandThe nuclear receptor superfamily is a group of proteins that regulate, in a ligand-dependent manner, transcriptional initiation of target genes by binding to specific DNA sequences named hormone response elements (reviewed in reference 23). Functional analysis of nuclear receptors has shown that there are two major activation domains. The N-terminal domain (AF1) contains a ligand-independent activation function, whereas the ligand-binding domain (LBD) exhibits ligand-dependent transactivation function (AF2). The AF2 core region, located at the extreme C terminus of the receptor LBDs, is conserved among nuclear receptors and undergoes a major conformational change upon ligand binding (23). This region has been shown to play a critical role in mediating transactivation by serving as a ligand-dependent interaction interface with many different coactivators (reviewed in reference 9). These coactivators, including the p160 family members (i.e., SRC-1, SRC-2/GRIP1/TIF2, and SRC-3/ACTR/pCIP/AIB1/ RAC3/TRAM1), CBP/p300, p/CAF, TRAP/DRIP, activating signal cointegrator 2 (ASC-2), and many others, bridge nuclear receptors and the basal transcription apparatus and/or remodel the chromatin structures (9).Chromatin, the physiological template of all eukaryotic genetic information, undergoes a diverse array of posttranslational modifications that largely impinge on histone amino termini, thereby regulating access to the underlying DNA (reviewed in reference 12). SRC-1 and the p160 family member ACTR, along with CBP and p300, were recently shown to contain histone acetyltransferase (HAT) activities and associate with yet another HAT protein, p/CAF (9). In contrast, SMRT and N-CoR, nuclear receptor corepressors, form complexes with Sin3 and histone deacetylase proteins (9). These results are consistent with the notion that the acetylation of histones destabilizes nucleosomes and relieves transcriptional repression by allowing transcription factors to access recognition elements, whereas deacetylation of the histones stabilizes the repressed state. More recently, the histone arginine methyltransferases CARM1 and PRMT1 were newly defined as transcriptional coactivators of nuclear receptors (4, 40). NSD1 and

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