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‐α (TNF‐α) but attenuated PPAR‐γ and C/EBP‐α 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.

Celecoxib attenuates liver steatosis and inflammation in non-alcoholic steatohepatitis induced by high-fat diet in rats

“…The products of lipid peroxidation can mediate inflammatory recruitment by activating NF-κB and COX-2 (19,20). Studies have revealed that COX-2 activation in fat inflammation is crucial to the development of insulin resistance and fatty liver in high-fat-induced obese rats (21). COX-2 accumulation may be an important aspect of NASH that should receive considerable attention as a possible target for therapy.…”

Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

“…Increased levels of PGE correlate with TG accumulation in the liver (Hsieh et al 2009, Ii et al 2009, Henkel et al 2012. In agreement with these data, we found that decreased levels of PGE and COX2 in the PH groups evidenced an alteration in the proinflammatory mediators that could be preventing liver fat accumulation.…”

“…As mentioned before, the proinflammatory process is involved in the development of NAFLD (Day & James 1998) and prostaglandins, and COX2 play a role in lipid metabolism and lipid accumulation in the liver , Hsieh et al 2009, Ii et al 2009). Increased levels of PGE correlate with TG accumulation in the liver (Hsieh et al 2009, Ii et al 2009, Henkel et al 2012.…”

Cytosolic phospholipase A2: physiological function and role in disease

“…An extension of this work showed that cPLA 2 ␣ KO mice are protected from fatty liver damage induced by a high-fat diet ( 139 ). Mice with cPLA 2 ␣ defi ciency have lower serum PGE 2 levels, which may afford protection because the administration of PGE 2 enhances hepatic triacylglycerol content, whereas inhibition of COX-2 prevents fat deposition in rodents ( 137,141 ). Obesity is associated with development of nonalcoholic fatty liver disease with pathological manifestations including nonalcoholic steatohepatitis, fi brosis, or cirrhosis.…”