Journal
FASEB JOURNAL
Volume 30, Issue 6, Pages 2282-2297Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201500127
Keywords
adipocyte hypertrophy; cyclooxygenase-2 activation; EP3
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Funding
- National Science Council (NSC) of the Republic of China [NSC 101-2320-B-016-001-MY3]
- Tri-Service General Hospital [TSGH-C103-007-S01]
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We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE(2))-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) approximate to 0.04 mu M] and EP3 (L-798106 100 mu g/kg, IC50 approximate to 0.5 mu M) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF- and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-B and hypoxia-inducible factor-1 transcription activation. These findings suggest that adipocyte COX-2 PGE(2)-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E-2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.
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