We examined the involvement of adipocyte cyclooxygenase‐2 (COX‐2) and prostaglandin E ₂ (PGE2)‐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 (IC ₅₀ ) ã 0.04 μM] and EP3 (L‐798106 100 μg/kg, IC ₅₀ ã 0.5 μM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX‐2 and EP3 gene expressions and the AT TNF‐α 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 NF‐ k B and hypoxia‐inducible factor‐1α 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. FASEB J. 30, 2282–2297 (2016). www.fasebj.org

Obesity and insulin resistance are two major risk factors for the development of metabolic syndrome, type 2 diabetes and associated cardiovascular diseases (CVDs). Cyclooxygenase (COX), a rate-limiting enzyme responsible for the biosynthesis of prostaglandins (PGs), exists in two isoforms: COX-1, the constitutive form, and COX-2, mainly the inducible form. COX-2 is the key enzyme in eicosanoid metabolism that converts eicosanoids into a number of PGs, including PGD₂, PGE₂, PGF_2α, and prostacyclin (PGI₂), all of which exert diverse hormone-like effects via autocrine or paracrine mechanisms. The COX-2 gene and immunoreactive proteins have been documented to be highly expressed and elevated in adipose tissue (AT) under morbid obesity conditions. On the other hand, the environmental stress-induced expression and constitutive over-expression of COX-2 have been reported to play distinctive roles under different pathological and physiological conditions; i.e., over-expression of the COX-2 gene in white AT (WAT) has been shown to induce de novo brown AT (BAT) recruitment in WAT and then facilitate systemic energy expenditure to protect mice against high-fat diet-induced obesity. Hepatic COX-2 expression was found to protect against diet-induced steatosis, obesity, and insulin resistance. However, COX-2 activation in the epidydimal AT is strongly correlated with the development of AT inflammation, insulin resistance, and fatty liver in high-fat-diet-induced obese rats. This review will provide updated information regarding the role of COX-2-derived signals in the regulation of energy metabolism and the pathogenesis of obesity and MS.

Osteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone. In total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up. At the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601–0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without. Patients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.

The prevalence of type 2 diabetes mellitus (T2DM) is higher in patients who have liver diseases such as nonalcoholic fatty liver disease, chronic viral hepatitis, hemochromatosis, alcoholic liver disease and cirrhosis. It is suggested that there is a pathogenic link between the presence of T2DM and the severity of liver injury. However, evidence related to the impact of hepatic inflammation on the development of T2DM has not yet emerged. This article provides an overview of the evidence for an increased prevalence of diabetes in a range of liver diseases, the impact of liver diseases on insulin resistance and β cell dysfunction, and the potential mechanisms whereby coexistent liver diseases exacerbate the development of T2DM.