In their comment, González-Ortiz et al. (1) cited their study (2) that reported that in a randomized, double-blind, placebo-controlled clinical trial of 12 overweight or obese male volunteers, of whom 6 received celecoxib for 4 weeks, the insulin sensitivity after celecoxib treatment was significantly higher compared with the basal estimation.
Our study demonstrated that expression of cyclooxygenase-2 (COX-2) in hepatocytes protects against adiposity, inflammation, and hepatic insulin resistance (IR) in mice fed a high-fat diet (HFD) and that DFU (a celecoxib analog) partially reversed the beneficial effects induced by COX-2–dependent prostaglandins (3). Contradictory results have been obtained in studies of transgenic mice (3) and humans (2).
COX-2–dependent prostaglandin E2 is considered a proinflammatory mediator that is involved in the pathogenesis of several diseases. Inflammation induces the expression of COX-2; however, hepatocytes fail to induce COX-2 regardless of the proinflammatory stimuli used. Thus, ectopic expression of COX-2 in hepatocytes constitutes a nonphysiological condition ideal to conduct mechanistic studies to evaluate the role of prostaglandins in liver pathogenesis.
Our previous results demonstrated reduced plasmatic levels of proinflammatory cytokines induced by lipopolysaccharide in COX-2 transgenic mice. These results agree with the data reported in our study (3) in which decreased expression of proinflammatory cytokines in white fat revealed protection against low-grade chronic inflammation. In addition, COX-2–dependent prostaglandin E2, acting via EP2/EP4 Gβγ dimers, enhanced insulin signaling through Akt phosphorylation. Also, AMPK was phosphorylated in hepatocytes expressing COX-2 under the HFD condition, and this induced fatty acid oxidation contributing to the beneficial effects of COX-2 against obesity.
Regarding the role of COX-2 inhibitors in the pathogenesis of obesity and IR, the results are controversial. Some studies reported that muscle and fat IR improved in rats fed HFD and treated with celecoxib. Others found that COX-2 inhibition exacerbated IR in skeletal muscle. Importantly, the concentrations of COX-2 inhibitors required to induce apoptosis are much higher than that required to inhibit COX-2 activity, and these compounds also have antiproliferative effects in cells lacking COX-2 (4). On the basis of these and other studies, it is assumed that the effects of COX-2 inhibitors are mediated through both COX-2–dependent and –independent pathways. Hence, OSU-03012, a non–cyclooxygenase-inhibiting celecoxib derivative, was used recently to induce apoptosis or to inhibit proliferation in different cells (5).
Our results agree with Vegiopoulos et al. (6), who reported that overexpression of COX-2 in adipose tissue induced browning, increased energy expenditure, and protected mice against obesity. Thus, the phenotype of two different models of COX-2 transgenic mice (adipose tissue and liver) exhibited the same behavior on obesity and insulin sensitivity. Finally, our recent publication (7) went into depth on the mechanism by which COX-2 improves insulin signaling through the modulation of microRNA-183 and IRS1.
Regarding the clinical trial by González-Ortiz et al. (2), it would be interesting to analyze the plasmatic levels of prostaglandins in these patients and the effect of celecoxib. We agree with González-Ortiz et al. (1) that more in-depth studies in humans should be performed in larger populations with longer interventions with different COX-2 inhibitors.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
