title: COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver.
abstract: The aim was to examine the role of cyclooxygenase (COX)-2-mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high-fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co-treated with vehicle (HFa), or a selective COX-2 inhibitor celecoxib (HFa-Cel) or mesulid (HFa-Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12-week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa-Cel, and HFa-Mes. Time-dependent increases in plasma insulin, glucose, 8-isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The enhanced COX-2 and tumor necrosis factor-alpha (TNF-alpha) but attenuated PPAR-gamma and C/EBP-alpha mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa-Cel and HFa-Mes. Our findings suggest that COX-2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.
authors.affiliation: Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan. pshsieh@hotmail.com
authors.forename: Po-Shiuan
authors.initials: PS
authors.lastname: Hsieh
authors.forename: Jong-Shiaw
authors.initials: JS
authors.lastname: Jin
authors.forename: Chih-Fan
authors.initials: CF
authors.lastname: Chiang
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Chan
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chen
authors.forename: Kuang-Chung
authors.initials: KC
authors.lastname: Shih
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D050156:Adipogenesis; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D000068579:Celecoxib; D048429:Cell Size; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D015434:Panniculitis / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D052246:Cyclooxygenase 2 Inhibitors; D007328:Insulin; D020738:Leptin; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D000068579:Celecoxib; C012655:nimesulide