Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3 mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3 and EP3β mice. Moreover, both EP3 and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity.

These findings indicate an elevated peripheral proinflammatory response, and provide further support for low grade inflammation in GAD. Further research may identify an 'inflammatory signature' for diagnosis and treatment response, and guide the search for novel pharmacological interventions.

This meta-analysis evaluated the influence of dietary intake and blood level of vitamin A (total vitamin A, retinol or β-carotene) on total and hip fracture risk. Cohort studies published before July 2017 were selected through English-language literature searches in several databases. Relative risk (RR) with corresponding 95% confidence interval (CI) was used to evaluate the risk. Heterogeneity was checked by Chi-square and I2 test. Sensitivity analysis and publication bias were also performed. For the association between retinol intake and total fracture risk, we performed subgroup analysis by sex, region, case ascertainment, education level, age at menopause and vitamin D intake. R software was used to complete all statistical analyses. A total of 319,077 participants over the age of 20 years were included. Higher dietary intake of retinol and total vitamin A may slightly decrease total fracture risk (RR with 95% CI: 0.95 (0.91, 1.00) and 0.94 (0.88, 0.99), respectively), and increase hip fracture risk (RR with 95% CI: 1.40 (1.02, 1.91) and 1.29 (1.06, 1.57), respectively). Lower blood level of retinol may slightly increase total fracture risk (RR with 95% CI: 1.11 (0.94, 1.30)) and hip fracture risk (RR with 95% CI: 1.27 (1.05, 1.53)). In addition, higher β-carotene intake was weakly associated with the increased risk of total fracture (RR with 95% CI: 1.07 (0.97, 1.17)). Our data suggest that vitamin A intake and level may differentially influence the risks of total and hip fractures. Clinical trials are warranted to confirm these results and assess the clinical applicability.

Rationale: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes and obesity contributes to the development of atherosclerosis. PKCδ expression and activity in monocytes were increased by hyperlipidemia and diabetes with unknown consequences to atherosclerosis. Objective: To investigate the effect of PKCδ activation in macrophages on the severity of atherosclerosis. Methods and Results: PKCδ expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKCδ in macrophages were generated by breeding PKCδ flox/flox mice with LyzM-Cre and ApoE−/− mice (MPKCδKO/ApoE−/− mice) and studied in atherogenic (AD) and very high fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD fed mice had insulin resistance and mild diabetes. Surprisingly, MPKCδKO/ApoE−/− mice exhibited accelerated aortic atherosclerotic lesions by 2-fold vs. ApoE−/− mice on AD or HFD. Splenomegaly was observed in MPKCδKO/ApoE−/− mice on AD and HFD, but not on regular chow. Both the AD or HFD increased macrophage numbers in aortic plaques and spleen by 1.7 and 2-fold, respectively, in MPKCδKO/ApoE−/− vs. ApoE−/− mice due to decreased apoptosis (62%) and increased proliferation (1.9 fold), and not due to uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCδKO/ApoE−/− were associated with elevated phosphorylation levels of pro-survival cell signaling proteins, Akt and FoxO3a, with reduction of pro-apoptotic protein Bim associated with PKCδ induced inhibition of P85/PI3K. Conclusion: Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKCδ isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall.