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KL Gatford, IJ Clarke, MJ De Blasio, IC McMillen, S Robinson J, and JA Owens

Poor prenatal growth is associated with limited evidence of GH deficiency in adult humans, which may contribute to their increased risk of cardiovascular and metabolic disease. We therefore examined the effects of placental restriction of fetal growth (PR) on size at birth, neonatal fractional growth rate (FGR) and the circulating GH profile in adolescent and young adult sheep of both sexes. Moderate or severe PR decreased birth size and increased neonatal FGR of weight, crown-rump length and abdominal circumference. In adolescent males, mean and baseline GH concentrations correlated negatively and independently with birth weight and FGR of weight, and mean GH concentrations correlated negatively with current weight. In young adult males, mean GH concentrations correlated negatively and independently with birth shoulder height and FGR of shoulder height whilst, in young adult females, these correlations were positive. This suggests that restricted fetal growth and reduced neonatal growth rate in sheep are followed by elevated circulating GH in adolescent and adult males, but GH deficiency or increased GH clearance in adult females.

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Wang Xiao, Fei Beibei, Shen Guangsi, Jiang Yu, Zhang Wen, Huang Xi, and Xu Youjia

Postmenopausal osteoporosis is a metabolic disease associated with estrogen deficiency. The results of numerous studies have revealed the positive correlation between iron accumulation and postmenopausal osteoporotic status. Although the results of previous studies have indicated that estrogen or iron alone have an effect on bone metabolism, their combined effects are not well defined. Using an in vivo mouse model, we found that bone mass was minimally affected by an excess of iron in the presence of estrogen. Once the source of estrogen was removed (ovariectomy), iron accumulation significantly decreased bone mass. These effects were accompanied by fluctuations in the level of oxidative stress. To determine whether these effects were related to bone formation or bone resorption, primary osteoblasts (OBs), RAW264.7 cells, and bone-marrow-derived macrophages were used for i n vitro experiments. We found that iron accumulation did inhibit the activity of OBs. However, estrogen had little effect on this inhibition. In contrast, iron promoted osteoclast differentiation through the production of reactive oxygen species. Estrogen, a powerful reactive oxygen scavenger, suppressed this effect in osteoclasts. Our data provided direct evidence that iron affected the bone mass only in the absence of estrogen. The inhibitory effect of estrogen on iron-induced osteopenia was particularly relevant to bone resorption rather than bone formation.

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Alice S Green, Paul J Rozance, and Sean W Limesand

Low birth weight is an important risk factor for impaired glucose tolerance and diabetes later in life. One hypothesis is that fetal β-cells inherit a persistent defect as a developmental response to fetal malnutrition, a primary cause of intrauterine growth restriction (IUGR). Our understanding of fetal programing events in the human endocrine pancreas is limited, but several animal models of IUGR extend our knowledge of developmental programing in β-cells. Pathological outcomes such as β-cell dysfunction, impaired glucose tolerance, and diabetes are often observed in adult offspring from these animal models, similar to the associations of low birth weight and metabolic diseases in humans. However, the identified mechanisms underlying β-cell dysfunction across models and species are varied, likely resulting from the different methodologies used to induce experimental IUGR, as well as from intraspecies differences in pancreas development. In this review, we first present the evidence for human β-cell dysfunction being associated with low birth weight or IUGR. We then evaluate relevant animal models of IUGR, focusing on the strengths of each, in order to define critical periods and types of nutrient deficiencies that can lead to impaired β-cell function. These findings frame our current knowledge of β-cell developmental programing and highlight future research directions to clarify the mechanisms of β-cell dysfunction for human IUGR.

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Paula J Brunton, Katie M Sullivan, David Kerrigan, John A Russell, Jonathan R Seckl, and Amanda J Drake

Glucocorticoid overexposure during pregnancy programmes offspring physiology and predisposes to later disease. However, any impact of ethologically relevant maternal stress is less clear, yet of physiological importance. Here, we investigated in rats the short- and long-term effects in adult offspring of repeated social stress (exposure to an aggressive lactating female) during late pregnancy on glucose regulation following stress, glucose–insulin homoeostasis and peripheral expression of genes important in regulating glucose and lipid metabolism and glucocorticoid action. Prenatal stress (PNS) was associated with reduced birth weight in female, but not male, offspring. The increase in blood glucose with restraint was exaggerated in adult PNS males compared with controls, but not in females. Oral glucose tolerance testing showed no effects on plasma glucose or insulin concentrations in either sex at 3 months; however, at 6 months, PNS females were hyperinsulinaemic following an oral glucose load. In PNS males, plasma triglyceride concentrations were increased, with reduced hepatic mRNA expression of 5α-reductase and peroxisome proliferator-activated receptor α (Ppar α (Ppara)) and a strong trend towards reduced peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1 α (Ppargc1a)) and Ppar γ (Pparg) expression, whereas only Pgc1 α mRNA was affected in PNS females. Conversely, in subcutaneous fat, PNS reduced mRNA expression of 11β-hydroxysteroid dehydrogenase type 1 (11 β hsd1), phosphoenolpyruvate carboxykinase (Pepck (Pck1)), adipose triglyceride lipase (Atgl) and diglyceride acyltransferase 2 (Dgat2) in females, but only Pepck mRNA expression was reduced in PNS males. Thus, prenatal social stress differentially programmes glucose homoeostasis and peripheral metabolism in male and female offspring. These long-term alterations in physiology may increase susceptibility to metabolic disease.

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Xi Tao, Yaxin Xu, Joseph Adu-Amankwaah, Zheng Gong, Yuxuan Wang, Fei Huang, and Hong Sun

Cardiac lipid accumulation and inflammation have been linked to stress. There is mounting evidence that estrogen reduces lipid deposition and has anti-inflammatory properties; however, the exact mechanism is unknown. Recent studies showed that NLRP3 inflammasome is a key trigger of cardiac inflammation, and it is also involved in the progression of metabolic diseases. This study investigated the crucial role of the NLRP3 inflammasome in lipid accumulation during stress and the regulatory mechanism of estrogen in this process. Stress models were established by isoproterenol treatments in mice and H9c2 cells. With 5 mM isoproterenol, NLRP3 inflammasome activation was observed earlier at 0.5 h than that of lipid accumulation at 1 h in H9c2 cells. At 1 h after stress, the isoproterenol concentration required for NLRP3 inflammasome activation was lower compared to the concentration required for lipid deposition in mice myocardia and H9c2 cells; the former required 210 mg/kg or 10 μM for activation while the latter required 280 mg/kg or 5 mM. Knocking out or inhibiting NLRP3 inflammasome reduced myocardial lipid accumulation caused by stress in the mice myocardia and H9c2 cells. Estrogen downregulated NLRP3 inflammasome and reduced lipid accumulation in cardiomyocytes during stress. Finally, the anti-inflammatory and lipid-lowering effect of estrogen disappeared in β2ARKO mice and H9c2 cells pre-treated with ICI118,551. In conclusion, the upregulation of NLRP3 inflammasome induced by stress led to myocardial lipid accumulation, and β2AR downregulated NLRP3 inflammasome thereby reducing lipid accumulation which was dependent on the estrogenic environment.

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Elena Zambrano, Tonantzin Sosa-Larios, Lizbeth Calzada, Carlos A Ibáñez, Carmen A Mendoza-Rodríguez, Angélica Morales, and Sumiko Morimoto

Maternal obesity (MO) is a deleterious condition that enhances susceptibility of adult offspring to metabolic diseases such as type 2 diabetes. The objective is to study the effect of MO on in vitro insulin secretion and pancreatic cellular population in offspring. We hypothesize that a harmful antenatal metabolic environment due to MO diminishes the basal glucose-responsive secretory function of pancreatic beta cells in offspring. Mothers were fed a control (C) or high-fat diet from weaning through pregnancy (120 days) and lactation. At postnatal days (PNDs) 36 and 110, pups were killed, peripheral blood was collected and pancreatic islets were isolated. Basal insulin secretion was measured in vitro in islets for 60 min. It was found that blood insulin, glucose and homeostasis model assessment (HOMA) index were unaffected by maternal diet and age in females. However, male MO offspring at PND 110 showed hyperinsulinemia and insulin resistance compared with C. Body weight was not modified by MO, but fat content was higher in MO pups compared with C pups. Triglycerides and leptin concentrations were higher in MO than in C offspring in all groups except in females at PND 36. Pancreatic islet cytoarchitecture was unaffected by MO. At PND 36, islets of male and female C and MO offspring responded similarly to glucose, but at PND 110, male and female MO offspring islets showed a 50% decrease in insulin secretion. It was concluded that MO impairs basal insulin secretion of offspring with a greater impact on males than females, and this effect mainly manifests in adulthood.

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J S Mayes, J P McCann, T C Ownbey, and G H Watson


Differing risk factors between men and women for a number of vascular and metabolic diseases have been linked to regional obesity. The differences in the distribution of adipose tissues between men (abdominal or upper-body obesity) and women (gluteal/femoral or lower body obesity) suggest a role for sex steroids in the regional distribution of fat. Previous work from this laboratory has shown the presence of oestrogen receptor (ER) in gluteal, perirenal and omental adipose tissues of ewes with similar physical characteristics to the ER in uterine tissue. The concentration profile for adipose ER was gluteal> perirenal>omental. In this report, we determined the physiological significance of adipose ERs by showing an up-regulation of the progesterone receptor (PR) in adipose tissues after oestrogen treatment in a fashion similar to that seen in a major responsive tissue such as uterus. Using PR antibodies (PR-6 and C-262), Western blot analysis of PR from oestrogen-treated sheep indicated that PR was induced in uterus>>>gluteal adipose>perirenal adipose consistent with the concentration of ER contained in these tissues. PR could not be detected by Western blotting in omental adipose tissue from oestrogen-treated animals or in gluteal, perirenal and omental adipose tissues from untreated animals. Sucrose gradient profiles of progestin (R-5020) binding from uterus and gluteal adipose tissues of oestrogen-treated ewes showed specific binding in both the 5S and 9S regions of the gradient, while perirenal and omental adipose tissue had only the 5S peak. The amount of specific binding was increased with oestrogen treatment in all the tissues. When gluteal adipose tissue cytosol was preincubated with PR antibody (C-262) to prevent binding of ligand and subjected to sucrose gradient analysis, both the 5S and 9S regions were diminished, suggesting that both peaks contained PR. Dilution of uterine cytosol resulted in an increase in the ratio of the 5S to the 9S peak, indicating that the 9S PR complex dissociates at low concentrations; this may be the reason why only the 5S peak was observed in perirenal and omental adipose tissues. These data offer further support for a direct role of sex steroids in regional adipose accretion and metabolism.

Journal of Endocrinology (1996) 148, 19–25

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Shaodong Guo

systemic metabolic homeostasis and how dysregulation of this system has been causally linked to a wide range of metabolic diseases ( Cao 2014 ). Obesity induces the production of inflammatory cytokines and the infiltration of immune cells into adipose

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Michael J Waters

expect beta-oxidation enhancing drugs to target individual fat depots or myogenesis-enhancing drugs to target muscles, for example, allowing the individual to sculpt body shape and minimize risk of type 2 diabetes. Metabolic diseases such as the current

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Umberto Simeoni, Clive Osmond, Ricardo Garay, Christophe Buffat, Farid Boubred, Christophe Chagnaud, Elisabeth Jouve, Christine Audebert, Jean-Michel Antoine, and Kent Thornburg

that low weight at the age of 1 year was associated with an increased risk for metabolic disease ( Barker et al. 1993 ) and left ventricular hypertrophy in adulthood ( Vijayakumar et al. 1995 ). The process by which early life stressors impart risk