COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver.
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.
Hsieh
Po-Shiuan
PS
Department of Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan. pshsieh@hotmail.com
Jin
Jong-Shiaw
JS
Chiang
Chih-Fan
CF
Chan
Pei-Chi
PC
Chen
Chih-Hao
CH
Shih
Kuang-Chung
KC
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
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