title: Long-term fenofibrate treatment impaired glucose-stimulated insulin secretion and up-regulated pancreatic NF-kappa B and iNOS expression in monosodium glutamate-induced obese rats: is that a latent disadvantage?
abstract: BACKGROUND
  Fenofibrate, a PPAR alpha agonist, has been widely used in clinics as lipid-regulating agent. PPAR alpha is known to be expressed in many organs including pancreatic beta cells and regulate genes involved in fatty acid metabolism. Some reports based on cell lines or animals have provided evidences that PPAR alpha agonists may affect (increased or suppressed) beta cell insulin secretion, and several studies are producing interesting but still debated results.
  
  
  METHODS
  In this research, we investigated the long term effects of fenofibrate on beta cell function in a metabolic syndrome animal model, monosodium glutamate (MSG) induced obese rats. Obese MSG rats were administered by gavage with fenofibrate at a dose of 100 mg/kg for 12 weeks. Oral glucose tolerance and insulin tolerance tests were performed to evaluate glucose metabolism and insulin sensitivity. We have used the hyperglycemic clamp technique to evaluate the capacity of beta cell insulin secretion. This technique provides an unbiased approach to understand the beta cell function in vivo. The changes of gene and protein expression in the pancreas and islets were also analyzed by Real-Time-PCR, Western blot and immunostaining.
  
  
  RESULTS
  Fenofibrate reduced the plasma lipid levels within a few days, and showed no beneficial effects on glucose homeostasis or insulin sensitivity in obese MSG rats. But the animals treated with fenofibrate exhibited significantly decreased fasting plasma insulin and impaired insulin secretory response to glucose stimulation. Further studies confirmed that fenofibrate increased MDA level and decreased total ATPase activity in pancreatic mitochondrion, accompanied by the upregulation of iNOS and NF-kappa B and TNF alpha expression in pancreatic islets of obese MSG rats.
  
  
  CONCLUSIONS
  Long-term fenofibrate treatment disrupted beta cell function, and impaired glucose-stimulated insulin secretion in obese MSG rats, perhaps to some extent associated with the activated inflammatory pathway and increased formation of oxidative products, especially the up-regulation of NF-kappa B and iNOS expression in islets.
authors: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No,1 Xiannongtan Street, Beijing 100050, PR China.
authors: Shuai-nan
authors: SN
authors: Liu
authors: Quan
authors: Q
authors: Liu
authors: Lin-yi
authors: LY
authors: Li
authors: Yi
authors: Y
authors: Huan
authors: Su-juan
authors: SJ
authors: Sun
authors: Zhu-fang
authors: ZF
authors: Shen
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D005947:Glucose / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008315:Malondialdehyde / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012970:Sodium Glutamate; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D016328:NF-kappa B; D008315:Malondialdehyde; D052247:Nitric Oxide Synthase Type II; D000251:Adenosine Triphosphatases; D005947:Glucose; D011345:Fenofibrate; D012970:Sodium Glutamate