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Background: Evidence suggests that people who are more responsive to psychological stress are at an increased risk of developing obesity. However, the biological mechanisms underlying this phenomenon are poorly understood. The cytokines leptin, interleukin-1 receptor antagonist (IL-1Ra) and interleukin-6 (IL-6) play a key role in fat metabolism and abnormal circulating levels of these proteins have been reported in obese people and in individuals subject to stress. Objective: This study investigated whether cytokine responses to acute mental stress are associated with adiposity in healthy young women. Design and Subjects: A laboratory study of 67 women, aged 18-25 years, recruited from University College London. Measurements: Height, weight and waist circumference were measured and body fat mass was estimated by bioelectrical impedance body composition analysis. Laboratory mental stress testing was carried out and blood pressure and heart rate were recorded at baseline, during two moderately challenging tasks (Stroop and speech) and during recovery 40-45 min post-stress. Blood samples taken at baseline, immediately post-stress and 45 min post-stress, were used for assessment of circulating cytokines. Saliva samples taken throughout the session were assessed for cortisol. Results: Women who had larger cytokine responses to stress were more abdominally obese than women with smaller cytokine stress responses. Specifically, there was a positive correlation between waist circumference and stress-induced increases in plasma levels of leptin (r ¼ 0.35, Po0.05) and IL-1Ra responses (r ¼ 0.29, Po0.05). There was also a significant positive correlation between prolonged diastolic blood pressure responses to stress and measures of total and abdominal obesity (r ¼ 0.28-0.33, Po0.05). Conclusion: Increased cytokine production could be a mechanism linking stress and abdominal obesity.

Uterine artery application of adenoviral vascular endothelial growth factor A (Ad.VEGF-A) gene therapy increases uterine blood flow and fetal growth in experimental animals with fetal growth restriction (FGR). Whether Ad.VEGF-A reduces lifelong cardiovascular disease risk imposed by FGR remains unknown. Here, pregnant guinea pigs fed 70% normal food intake to induce FGR received Ad.VEGF-A (1×10 viral particles, n = 15) or vehicle ( n = 10), delivered to the external surface of the uterine arteries, in midpregnancy. Ad libitum-fed controls received vehicle only ( n = 14). Litter size, gestation length, and perinatal mortality were similar in control, untreated FGR, and FGR+Ad.VEGF-A animals. When compared with controls, birth weight was lower in male but higher in female pups following maternal nutrient restriction, whereas both male and female FGR+Ad.VEGF-A pups were heavier than untreated FGR pups ( P < 0.05, ANOVA). Postnatal weight gain was 10-20% greater in female FGR+Ad.VEGF-A than in untreated FGR pups, depending on age, although neither group differed from controls. Maternal nutrient restriction reduced heart weight in adult female offspring irrespective of Ad.VEGF-A treatment but did not alter ventricular wall thickness. In males, postnatal weight gain and heart morphology were not affected by maternal treatment. Neither systolic, diastolic, mean arterial pressure, adrenal weight, nor basal or challenged plasma cortisol were affected by maternal undernutrition or Ad.VEGF-A in either sex. Therefore, increased fetal growth conferred by maternal uterine artery Ad.VEGF-A is sustained postnatally in FGR female guinea pigs. In this study, we did not find evidence for an effect of maternal nutrient restriction or Ad.VEGF-A therapy on adult offspring blood pressure.

Background Adenovirus (Ad) mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries of pregnant sheep increases uterine blood flow1. We recently demonstrated significantly increased fetal growth velocity following Ad. VEGF gene therapy in growth-restricted sheep fetuses2. Herein the subsequent effect on postnatal growth, metabolism and body composition in the same cohort was investigated. Methods Growth rate was determined weekly from birth until weaning in 31 lambs born following maternal administration of Ad. VEGF (n=16) or control saline (n=15) mid-pregnancy. At 7 weeks of age, following a 3 h fast, lambs were blood-sampled at −20, −10, 0, +5, +10, +15, +20, +25, +30, +45, +60, +90 and +120 min relative to an intravenous glucose bolus (0.25 g/kg). Plasma was analysed for insulin, glucose and non-esterified fatty acids (NEFA). At 12 weeks, lambs underwent necropsy and complete dissection. Results Postnatal growth velocity was increased in Ad. VEGF-treated lambs compared to controls (397 g/day vs 363 g/day, p=0.023). There was no difference in fractional growth rate, which was inversely related to birthweight (r=–0.910, p=<0.001) irrespective of treatment. Following glucose challenge, insulin area under the curve (AUC) was increased (p=0.04) and NEFA AUC increased (p=0.038) in Ad. VEGF versus saline groups. At necropsy there were no significant differences in perirenal fat or major organ weights. Conclusion Prenatal gene therapy for ovine fetal growth restriction results in enhanced postnatal accretion of lean tissue and altered metabolic function. This may indicate altered fetal programming secondary to therapeutic manipulation of the intrauterine environment.