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 ...