Objective Adipose tissue (AT) inflammation characterized by macrophage accumulation and secretion of inflammatory mediators is considered to play a critical role in the pathogenesis of obesity-linked metabolic disorders, in particular, insulin resistance. Although an intimate relationship exists between inflammation and metabolism, there is a lack of consistent therapeutic success in targeting inflammatory pathways to treat obesity-linked metabolic diseases suggesting that certain immunoregulatory genes can exert differential effects on metabolic regulation. The objective of this study is to determine the role of cyclooxygenase-2 (COX-2), an inducible inflammatory gene, abundantly upregulated in macrophages upon exposure to inflammatory stimuli, in modulating AT inflammation and systemic metabolic homeostasis in obesity.
Methods Wild type (WT) and COX-2 knock-out (COX-2-/-) mice were fed a standard chow diet (CD) or a high fat (HF, 45% fat calories) diet for 13 wk. The expression of macrophage and inflammatory markers were determined in visceral AT and macrophage-rich stromal cells collected from visceral AT. In addition, various metabolic tests including insulin and glucose tolerance tests and energy expenditure measurements were performed to determine the impact of COX-2 deletion in modulating metabolic homeostasis.
Results Consistent with its role in inducing an inflammatory response, deletion of COX-2 resulted in a decrease in markers of AT inflammation. For example, the markers of M1 pro-inflammatory macrophages were reduced and that of M2 anti-inflammatory macrophages were increased in the visceral AT of COX-2−/− compared to WT mice on a HF diet. Moreover, the mRNA expression of inflammatory genes such as MIP1α and TNFα was significantly lower (P<0.05) in COX-2−/− compared to WT mice. Although AT inflammation was reduced, COX-2 deletion led to impaired metabolic homeostasis. Notably, the total fat mass determined by EchoMRI was significantly higher (P<0.001) with a concomitant increase in visceral AT mass and plasma leptin levels (P<0.05) in COX-2−/− mice. In addition, the plasma total cholesterol was significantly higher (P<0.05) in COX-2−/− compared to WT mice on a HF diet. Moreover, COX-2−/− mice exhibit systemic insulin resistance and impaired glucose handling as analyzed by insulin and glucose tolerance tests. Further, the energy expenditure and locomotor activity determined using the metabolic cages were greatly reduced in COX-2−/− compared to WT mice.
Conclusion Taken together, deletion of COX-2 attenuated AT inflammation but increased adiposity and impaired metabolic homeostasis in a state of nutrient excess. Although inflammation is intricately linked to metabolism, our study suggests that a considerable discordance exists between these two processes and that COX-2 derived eicosanoids can exert differential effects in modulating inflammatory and metabolic processes.
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