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

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Lipid accumulation in nonadipose tissues is closely related to the development of type 2 diabetes in obese subjects. We examined the potential preventive effect of peroxisome proliferator-activated receptor (PPAR)-␣ and PPAR-␥ stimulation on the development of diabetes in obese diabetes-prone OLETF rats. I ncreasing evidence suggests that lipid accumulation in nonadipose tissues, such as skeletal muscle and pancreatic islet, is causally related to the development of type 2 diabetes in obese individuals (1,2). Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear transcription factors that regulate lipid metabolism (3). Thiazolidinedione (TZD), a high-affinity ligand for PPAR-␥, is now widely used as an insulin-sensitizing drug (4) and has been shown to reduce fat accumulation in skeletal muscle (5). TZD has also been suggested to reduce fat accumulation in other nonadipose tissues such as islets and heart (6). However, these favorable effects of TZD on nonadipose tissues may not arise directly from PPAR-␥ activation in these tissues. PPAR-␥ is highly expressed in adipose tissue, but its expression is low in nonadipose tissues such as skeletal muscle or pancreatic ␤-cells (7). Therefore, it has been suggested that TZD improves muscle insulin action and prevents apoptosis of pancreatic ␤-cells by sequestering lipids in adipose tissue (8) or by increasing production of adiponectin (9), an adipocytokine that has been shown to increase insulin sensitivity (10).The role of PPAR-␣ in the regulation of intracellular lipid homeostasis in nonadipose tissues may be more straightforward. Normally, it is expressed in nonadipose tissues at relatively high levels compared with PPAR-␥ (11). PPAR-␣ is a transcription factor that has been shown to upregulate fatty acid oxidative enzymes mainly in the liver (12), but recent studies have indicated that it also increases fatty acid oxidation in skeletal muscle (13). It was also reported that PPAR-␣ stimulators increase insulin sensitivity and reduce adiposity (14) and lipid accumulation in skeletal muscle (5). The expression of PPAR-␣ and enzymes of fatty acid oxidation is markedly reduced in the fat-laden dysfunctional islets of obese prediabetic Zucker diabetic fatty (fa/fa) rats (15). It is unknown, however, whether PPAR-␣ stimulators can prevent ␤-cell destruction and diabetes in diabetes-prone animals. The present study was therefore undertaken to examine the potential preventive effects of PPAR-␣ stimulation on the development of diabetes in Otsuka Long Evans Tokushima Fatty (OLETF) rats, an animal model of obesity and diabetes. RESEARCH DESIGN AND METHODS Animals.Male OLETF rats and their lean nondiabetic counterparts, LongEvans Tokushima Otsuka (LETO) rats, were supplied at 4 weeks of age by the Otsuka Pharmaceutical Company (Tokushima, Japan). The rats were maintained at an ambient temperature (22 Ϯ 1°C) with 12:12-h light-dark cycles and free access to water and rat food. All procedures were approved by the Institutional Animal Care ...

Fatty liver is common in obese subjects with insulin resistance. Hepatic expression of sterol regulatory element binding protein-1c (SREBP-1c), which plays a major role in hepatic steatosis, is regulated by multiple factors, including insulin, adenosine monophosphate-activated protein kinase (AMPK), liver X receptors (LXRs), and specificity protein 1. Alpha-lipoic acid (ALA), a naturally occurring antioxidant, has been shown to decrease lipid accumulation in skeletal muscle by activating AMPK. Here we show that ALA decreases hepatic steatosis and SREBP-1c expression in rats on a high fat diet or given an LXR agonist. ALA increased AMPK phosphorylation in the liver and in cultured liver cells, and dominant-negative AMPK partially prevented ALA-induced suppression of insulin-stimulated SREBP-1c expression. ALA also inhibited DNAbinding activity and transcriptional activity of both specificity protein 1 and LXR. Conclusion: These results show that ALA prevents fatty liver disease through multiple mechanisms, and suggest that ALA can be used to prevent the development and progression of nonalcoholic fatty liver disease in patients with insulin resistance.