Fenofibrate is a drug that has been suggested to inhibit weight gain by increasing the catabolism of fatty acid in the hepatic mitochondria. We hypothesized that fenofibrate induces an increase in energy expenditure in the hepatic mitochondria, which results in the reduction of adipose tissue. In this study we measured hepatic uncoupling protein (UCP)-2, -3, core temperatures and abdominal fat composition with MRI in Otsuka Long-Evans Tokushima Fatty rats. The fenofibrate group (n=7) was fed fenofibrate (320 mg/kg) mixed chow. The control group (n=7) was fed chow only. The body weight (531.6+/-7.6 g) of the fenofibrate group was significantly lower than that (744.3+/-14.9 g) of the control group (p<0.005). The areas of visceral and subcutaneous fat in the fenofibrate group (11.0+/-0.9 cm2, 4.2+/-0.3 cm2) were significantly less than those in the control group (21.0+/-0.7 cm2, 7.4+/-0.4 cm2) (p=0.046, respectively). The esophageal and rectal temperatures of the fenofibrate group (37.7+/-0.1 degrees C, 33.1+/-0.2 degrees C) were significantly higher than those of the control group (37.3+/-0.1 degrees C, 32.2+/-0.1 degrees C) (p=0.025, p=0.005). There was de novo expression of UCP-3 in the liver of the fenofibrate group. These data suggest that increased energy dissipation, via hepatic UCP-3 by fenofibrate, contribute to decreased weight gain in obese rats.
Rats, Inbred OLETF ; Rats ; Procetofen/*pharmacology ; Obesity/*physiopathology ; Muscle, Skeletal/drug effects/physiopathology ; Liver/drug effects/*physiopathology ; Energy Metabolism/*drug effects ; Body Weight/*drug effects ; Body Temperature/*drug effects ; Antilipemic Agents/administration & dosage ; Animals ; Adipose Tissue/*drug effects

Peroxisome proliferator-activated receptor alpha (PPARalpha) activation in rodents is thought to improve insulin sensitivity by decreasing ectopic lipids in non-adipose tissues. Fenofibrate, a lipid-modifying agent that acts as a PPARalpha agonist, may prevent adipocyte hypertrophy and insulin resistance by increasing intracellular lipolysis from adipose tissue. Consistent with this hypothesis, fenofibrate decreased visceral fat mass and adipocyte size in high fat diet-fed obese mice, and concomitantly increased the expression of PPARalpha target genes involved in fatty acid beta-oxidation in both epididymal adipose tissue and differentiated 3T3-L1 adipocytes. However, mRNA levels of adipose marker genes, such as leptin and TNFalpha, were decreased in epididymal adipose tissue by fenofibrate treatment. Fenofibrate not only reduced circulating levels of free fatty acids and triglycerides, but also normalized hyperinsulinemia and hyperglycemia in obese mice. Blood glucose levels of fenofibrate-treated mice were significantly reduced during intraperitoneal glucose tolerance test compared with obese controls. These results suggest that fenofibrate-induced fatty acid beta-oxidation in visceral adipose tissue may be one of the major factors leading to decreased adipocyte size and improved insulin sensitivity.
3T3 Cells ; Adipocytes/cytology/*drug effects ; Animals ; Antilipemic Agents/*pharmacology ; Blood Glucose ; Body Weight ; Cell Enlargement/*drug effects ; Dietary Fats ; Gene Expression Regulation/drug effects ; Glucose Tolerance Test ; Insulin/blood ; *Insulin Resistance ; Leptin/genetics ; Lipids/blood ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; PPAR alpha/*metabolism ; Procetofen/*pharmacology ; Tumor Necrosis Factor-alpha/genetics

To determine whether the PPARalpha agonist fenofibrate regulates obesity and lipid metabolism with sexual dimorphism, we examined the effects of fenofibrate on body weight, white adipose tissue (WAT) mass, circulating lipids, and the expression of PPARalpha target genes in both sexes of high fat diet-fed C57BL/6J mice. Both sexes of mice fed a high-fat diet for 14 weeks exhibited increases in body weight, visceral WAT mass, as well as serum triglycerides and cholesterol, although these effects were more pronounced among males. Feeding a high fat diet supplemented with fenofibrate (0.05% w/w) reduced all of these effects significantly in males except serum cholesterol level. Females on a fenofibrate-enriched high fat diet had reduced serum triglyceride levels, albeit to a smaller extent compared to males, but did not exhibit decreases in body weight, WAT mass, and serum cholesterol. Fenofibrate treatment resulted in hepatic induction of PPAR alpha target genes encoding enzymes for fatty acid beta-oxidation, the magnitudes of which were much higher in males compared to females, as evidenced by results for acyl-CoA oxidase, a first enzyme of the beta-oxidation system. These results suggest that observed sexually dimorphic effects on body weight, WAT mass and serum lipids by fenofibrate may involve sexually related elements in the differential activation of PPARalpha.
Adipose Tissue/drug effects/metabolism ; Animals ; Body Composition/drug effects ; Body Weight/drug effects ; Diet ; Dietary Fats/pharmacology ; Female ; Gene Expression Regulation/drug effects ; Lipids/blood/*metabolism ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/*metabolism/pathology ; Organ Weight/drug effects ; Procetofen/*pharmacology ; Receptors, Cytoplasmic and Nuclear/*agonists ; *Sex Characteristics ; Time Factors ; Transcription Factors/*agonists