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

Abstract

ABSTRACT: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 obesityassociated 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 (IC 50 ) 0.04 mM] and EP3 (L-798106 100 mg/kg, IC 50 0.5 mM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF-a 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 (250%) 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 NFkB and hypoxia-inducible factor-1a 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 obesityinduced adipose tissue inflammation and insulin resistance. FASEB J. 30, 2282FASEB J. 30, -2297FASEB J. 30, (2016 Adipose tissue (AT) inflammation has been suggested to play a central role in the pathogenesis of many obesityassociated complications, including insulin resistance (1), type 2 diabetes (2, 3), atherosclerosis (2-4), and nonalcoholic fatty liver disease (1). However, the underlying mechanisms of this process remain elusive.Adipocytes in an obesity setting are characterized by hypertrophy and hypoxia, and they are important sources of inflammation (5-7). This inflammation is mediated by the production of a substantial number of cytokines and chemokines, including TNF-a (3, 5), IL-6 (8), monocyte chemotactic protein-1 (MCP-1) (9), and RANTES (10). These cytokines and chemokines are crucially involved in the initiation of the adipocyte-mediated inflammatory response in obese individuals. The capacity of the constitutive and regulated release of immune mediators from adipocytes demonstrates a causal link between the biology of adipocytes and immune cells, such as macrophages and T cells. Moreover, the synergistic effect of inflamed

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice

“…Our results showed that StAR overexpression increased Ser473 phosphorylation of Akt both in muscle and epididymal adipose tissue, while reduced the level of pIRS1 Ser307 in muscle of obese mice, indicating StAR could protect obese mice against the progress of type 2 diabetes, and improve the impairment of insulin signaling pathway. Recent findings have revealed a relationship between adipocyte hypertrophy and systemic low grade inflammation [Chan et al, 2016]. Recent findings have revealed a relationship between adipocyte hypertrophy and systemic low grade inflammation [Chan et al, 2016].…”

Glabridin attenuates antiadipogenic activity induced by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin in murine 3T3‐L1 adipocytes

“…Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. PGE 2 plays a major role in inducing macrophage recruitment during adipocyte lipolysis (Chan, Hsiao, Chang, Wabitsch, & Hsieh, ). In the present study, the addition of 10 n m TCDD enhanced PGE 2 production (Figure A).…”

The Role of Adipocyte Hypertrophy and Hypoxia in the Development of Obesity-Associated Adipose Tissue Inflammation and Insulin Resistance

“…In addition, our recent study [63] has further demonstrated that COX-2 mediated PGE 2 EP3 signaling during the development of adipocyte hypertrophy and hypoxia is important to recruit and interact with adipose immune cells to amplify the inflammatory responses in adipose tissue, which is also causally linked to the development of systemic insulin resistance.…”