Pregnancy in Obese Mice Protects Selectively against Visceral Adiposity and Is Associated with Increased Adipocyte Estrogen Signalling

Maternal obesity is linked with increased adverse pregnancy outcomes for both mother and child. The metabolic impact of excessive fat within the context of pregnancy is not fully understood. We used a mouse model of high fat (HF) feeding to induce maternal obesity to identify adipose tissue-mediated mechanisms driving metabolic dysfunction in pregnant and non-pregnant obese mice. As expected, chronic HF-feeding for 12 weeks preceding pregnancy increased peripheral (subcutaneous) and visceral (mesenteric) fat mass. However, unexpectedly at late gestation (E18.5) HF-fed mice exhibited a remarkable normalization of visceral but not peripheral adiposity, with a 53% reduction in non-pregnant visceral fat mass expressed as a proportion of body weight (P<0.001). In contrast, in control animals, pregnancy had no effect on visceral fat mass proportion. Obesity exaggerated glucose intolerance at mid-pregnancy (E14.5). However by E18.5, there were no differences, in glucose tolerance between obese and control mice. Transcriptomic analysis of visceral fat from HF-fed dams at E18.5 revealed reduced expression of genes involved in de novo lipogenesis (diacylglycerol O-acyltransferase 2--Dgat2) and inflammation (chemokine C-C motif ligand 20--Ccl2) and upregulation of estrogen receptor α (ERα) compared to HF non pregnant. Attenuation of adipose inflammation was functionally confirmed by a 45% reduction of CD11b+CD11c+ adipose tissue macrophages (expressed as a proportion of all stromal vascular fraction cells) in HF pregnant compared to HF non pregnant animals (P<0.001). An ERα selective agonist suppressed both de novo lipogenesis and expression of lipogenic genes in adipocytes in vitro. These data show that, in a HF model of maternal obesity, late gestation is associated with amelioration of visceral fat hypertrophy, inflammation and glucose intolerance, and suggest that these effects are mediated in part by elevated visceral adipocyte ERα signaling

Thromboprophylaxis after Knee Arthroscopy and Lower-Leg Casting

Background The use of thromboprophylaxis to prevent clinically apparent venous thromboembolism after knee arthroscopy or casting of the lower leg is disputed. We compared the incidence of symptomatic venous thromboembolism after these procedures between patients who received anticoagulant therapy and those who received no anticoagulant therapy. Methods We conducted two parallel, pragmatic, multicenter, randomized, controlled, open-label trials with blinded outcome evaluation: the POT-KAST trial, which included patients undergoing knee arthroscopy, and the POT-CAST trial, which included patients treated with casting of the lower leg. Patients were assigned to receive either a prophylactic dose of low-molecular-weight heparin (for the 8 days after arthroscopy in the POT-KAST trial or during the full period of immobilization due to casting in the POT-CAST trial) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism and major bleeding within 3 months after the procedure. Results In the POT-KAST trial, 1543 patients underwent randomization, of whom 1451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, -0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, -0.6 to 0.7). In the POT-CAST trial, 1519 patients underwent randomization, of whom 1435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, -0.4 percentage points; 95% CI, -1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection. Conclusions The results of our trials showed that prophylaxis with low-molecular-weight heparin for the 8 days after knee arthroscopy or during the full period of immobilization due to casting was not effective for the prevention of symptomatic venous thromboembolism. (Funded by the Netherlands Organization for Health Research and Development; POT-KAST and POT-CAST ClinicalTrials.gov numbers, NCT01542723 and NCT01542762 , respectively.)