Ontogeny and nutritional programming of uncoupling protein-2 and glucocorticoid receptor mRNA in the ovine lung
TL;DR: The findings suggest that the developmental ontogeny of U CP2 mRNA in the ovine lung is under local glucocorticoid hormone action and that maternal nutrient restriction has long‐term consequences for UCP2 and GR mRNA abundance in the lung irrespective of its timing.
Abstract: This study investigated the developmental and nutritional programming of uncoupling protein-2 (UCP2), glucocorticoid receptor (GR) and 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) mRNA in the sheep lung from the time of uterine attachment to 6 months of age. The effect of maternal nutrient restriction on lung development was determined in early to mid gestation (i.e. 28-80 days gestation, period of maximal placental growth, and embryonic and pseudoglandular stages of fetal lung development) and late gestation (i.e. 110-147 days gestation, period of maximal fetal growth, and canalicular and saccular stages of fetal lung development). Fetal lungs were sampled at 80 and 140 days (term approximately 148 days) gestation, and sheep lungs at 1, 7, 30 days and 6 months. GR and 11betaHSD1 mRNA were maximal at 140 days gestation, whereas UCP2 mRNA peaked at 1 day of age and then declined with postnatal age. Maternal nutrient restriction in both early-to-mid and late gestation had no effect on lung weight, but increased UCP2, GR and 11betaHSD1 mRNA abundance at every sampling age. These findings suggest that the developmental ontogeny of UCP2 mRNA in the ovine lung is under local glucocorticoid hormone action and that maternal nutrient restriction has long-term consequences for UCP2 and GR mRNA abundance in the lung irrespective of its timing.
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TL;DR: Recent advances in understanding the mechanism that underlies the early life origins of disease are discussed to place studies in a broader life-course context and suggest a possible means for reducing risk of induced noncommunicable disease.
Abstract: There is considerable evidence for induction of differential risk of noncommunicable diseases in humans by variation in the quality of the early life environment. Studies in animal models show that induction and stability of induced changes in the phenotype of the offspring involve altered epigenetic regulation by DNA methylation and covalent modifications of histones. These findings indicate that such epigenetic changes are highly gene specific and function at the level of individual CpG dinucleotides. Interventions using supplementation with folic acid or methyl donors during pregnancy, or folic acid after weaning, alter the phenotype and epigenotype induced by maternal dietary constraint during gestation. This suggests a possible means for reducing risk of induced noncommunicable disease, although the design and conduct of such interventions may require caution. The purpose of this review is to discuss recent advances in understanding the mechanism that underlies the early life origins of disease and t...
368 citations
TL;DR: The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.
Abstract: There is considerable evidence for the induction of different phenotypes by variations in the early life environment, including nutrition, which in man is associated with a graded risk of metabolic disease; fetal programming. It is likely that the induction of persistent changes to tissue structure and function by differences in the early life environment involves life-long alterations to the regulation of gene transcription. This view is supported by both studies of human subjects and animal models. The mechanism which underlies such changes to gene expression is now beginning to be understood. In the present review we discuss the role of changes in the epigenetic regulation of transcription, specifically DNA methylation and covalent modification of histones, in the induction of an altered phenotype by nutritional constraint in early life. The demonstration of altered epigenetic regulation of genes in phenotype induction suggests the possibility of interventions to modify long-term disease risk associated with unbalanced nutrition in early life.
336 citations
Cites background from "Ontogeny and nutritional programmin..."
...Altered expression of GR has also been reported in the lung, liver, adrenal gland and kidney of the offspring of sheep fed a restricted diet during pregnancy (Whorwood et al. 2001; Brennan et al. 2005; Gnanalingham et al. 2005)....
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TL;DR: UCP2 has an important role in the pathogenesis of type 2 diabetes by inhibiting insulin secretion in islet beta cells and is associated with increased risk of cardiovascular disease and atherosclerosis, which illustrates that therapeutic applications involving UCP2 likely will have to regulate expression and activity in a tissue-specific manner.
Abstract: The uncoupling proteins (UCPs) are attracting an increased interest as potential therapeutic targets in a number of important diseases. UCP2 is expressed in several tissues, but its physiological functions as well as potential therapeutic applications are still unclear. Unlike UCP1, UCP2 does not seem to be important to thermogenesis or weight control, but appears to have an important role in the regulation of production of reactive oxygen species, inhibition of inflammation, and inhibition of cell death. These are central features in, for example, neurodegenerative and cardiovascular disease, and experimental evidence suggests that an increased expression and activity of UCP2 in models of these diseases has a beneficial effect on disease progression, implicating a potential therapeutic role for UCP2. UCP2 has an important role in the pathogenesis of type 2 diabetes by inhibiting insulin secretion in islet beta cells. At the same time, type 2 diabetes is associated with increased risk of cardiovascular di...
169 citations
TL;DR: There is both significant scope and an urgent need for further research-informed refinement to the use of antenatal corticosteroid use in pregnancy.
Abstract: Background The use of antenatal steroid therapy is common in pregnancy. In early pregnancy, steroids may be used in women for the treatment of recurrent miscarriage or fetal abnormalities such as congenital adrenal hyperplasia. In mid-late pregnancy, the antenatal administration of corticosteroids to expectant mothers in anticipation of preterm birth is one of the most important advances in perinatal medicine; antenatal corticosteroids are now standard care for pregnancies at risk of premature delivery in high- and middle-income countries. The widespread uptake of this therapy is due to a compelling body of evidence demonstrating improved neonatal outcomes following antenatal corticosteroid exposure, stemming most notably from corticosteroid-driven maturation of fetal pulmonary function. As we approach the 50th anniversary of landmark work in this area by Liggins and Howie, it is apparent that much remains to be understood with regards to how we might best apply antenatal corticosteroid therapy to improve pregnancy outcomes at both early and mid to late gestation. Methods Drawing on advances in laboratory science, pre-clinical and clinical studies, we performed a narrative review of the scientific literature to provide a timely update on the benefits, risks and uncertainties regarding antenatal corticosteroid use in pregnancy. Three, well-established therapeutic uses of antenatal steroids, namely recurrent miscarriage, congenital adrenal hyperplasia and preterm birth, were selected to frame the review. Results Even the most well-established antenatal steroid therapies lack the comprehensive pharmacokinetic and dose-response data necessary to optimize dosing regimens. New insights into complex, tissue-specific corticosteroid signalling by genomic-dependent and independent mechanisms have not been used to inform corticosteroid treatment strategies. There is growing evidence that some fetal corticosteroid treatments are either ineffective, or may result in adverse outcomes, in addition to lasting epigenetic changes in a variety of homeostatic mechanisms. Nowhere is the need to better understand the intricacies of corticosteroid therapy better conveyed than in the findings of Althabe and colleagues who recently reported an increase in overall neonatal mortality and maternal morbidity in association with antenatal corticosteroid administration in low-resource settings. Conclusions New research to clarify the benefits and potential risks of antenatal corticosteroid therapy is urgently needed, especially with regard to corticosteroid use in low-resource environments. We conclude that there is both significant scope and an urgent need for further research-informed refinement to the use of antenatal corticosteroids in pregnancy.
149 citations
Cites background from "Ontogeny and nutritional programmin..."
...…steroid dosing. mRNA studies in sheep have suggested that GR expression in the fetal lung is higher at 140 days gestation than at 80 days gestation, although it was unclear from this study if differences in mRNA expression materially altered GR receptor density (Gnanalingham et al., 2005)....
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...In sheep, maternal nutrient restriction did not impact lung growth but did result in small increases (relative to animals maintained on normal diets) in lung GR mRNA expression at 80 and 140 days gestation in singleton lambs (Gnanalingham et al., 2005)....
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...higher at 140 days gestation than at 80 days gestation, although it was unclear from this study if differences in mRNA expression materially altered GR receptor density (Gnanalingham et al., 2005)....
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TL;DR: It is concluded that the continual rise in glucocorticoid action and fat mass after birth may underlie the development of later obesity.
Abstract: Increased glucocorticoid action and adipose tissue inflammation contribute to excess adiposity. These adaptations may be enhanced in offspring exposed to nutrient restriction (NR) in utero, thereby increasing their susceptibility to later obesity. We therefore determined the developmental ontogeny of glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenase (11betaHSD) types 1 and 2, and uncoupling protein (UCP)-2 mRNA in perirenal adipose tissue between late gestation and 6 mo after birth in the sheep, as well as the effect of maternal NR targeted between early to mid (28-80 days, term approximately 147 days)- or late (110-147 days) gestation. GR and 11betaHSD1 mRNA increased with fat mass and were all maximal within the 6-mo observation period. 11betaHSD2 mRNA abundance demonstrated a converse decline, whereas UCP2 peaked at 30 days. GR and 11betaHSD1 mRNA abundance were strongly correlated with total and relative perirenal adipose tissue weight, and UCP2 was strongly correlated with GR and 11betaHSD1 mRNA. Early- to midgestational NR increased GR, 11betaHSD1, and UCP2 mRNA, but decreased 11betaHSD2 mRNA abundance, an adaptation reversed with late-gestational NR. We conclude that the continual rise in glucocorticoid action and fat mass after birth may underlie the development of later obesity. The magnitude of this adaptation is partly dependent on maternal food intake through pregnancy.
123 citations
Cites background from "Ontogeny and nutritional programmin..."
...In addition, irrespective of the period of gestational NR, UCP2, GR, and 11 HSD1 mRNA were upregulated in the fetal and postnatal lung (25)....
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...In adipose tissue, UCP2 mRNA abundance peaked at 30 days, before declining up to 6 mo postnatal age, in contrast to the peak at 1 day of age in the lung (25)....
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...In particular, the developmental ontogeny of local glucocorticoid action contrasts with other tissues such as the lung, where GR and 11 HSD1 mRNA abundance both peak during late gestation before declining with postnatal age (25)....
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...increased glucocorticoid action and UCP2 mRNA abundance in the lung of the fetus and postnatal sheep (25)....
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...In the sheep lung, the peak abundance in GR and 11 HSD1 mRNA occurs close to term, whereas UCP2 mRNA peaks just after birth and is barely detectable after 1 mo of age (25)....
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References
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Journal Article•
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.
289,852 citations
"Ontogeny and nutritional programmin..." refers methods in this paper
...Mitochondria were prepared from 1 g frozen lung tissue as previously described (Symonds et al. 1992) and the protein content C© The Physiological Society 2005 of each preparation determined (Lowry et al. 1951)....
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TL;DR: It is demonstrated here that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet and a role for UCP2 in the limitation of ROS and macrophage-mediated immunity is indicated.
Abstract: The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1–3). As Ucp2 is widely expressed in mammalian tissues4,5, uncouples respiration6 and resides within a region of genetic linkage to obesity4, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages4,5,7, suggesting a role for Ucp2 in immunity or inflammatory responsiveness4. We investigated the response to infection with Toxoplasma gondii in Ucp2−/− mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2−/− mice (63% decrease, P<0.04). Macrophages from Ucp2 −/− mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
1,062 citations
"Ontogeny and nutritional programmin..." refers background in this paper
...2000) and macrophage-mediated immunity (Arsenijevic et al. 2000)....
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...…remains a subject of intense debate (Nedergaard & Cannon, 2003) and it has postulated roles in energy balance (Buemann et al. 2001), reactive oxygen species production (Negre-Salvayre et al. 1997), apoptosis (Voehringer et al. 2000) and macrophage-mediated immunity (Arsenijevic et al. 2000)....
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...1993), as an increased abundance of UCP2 has been shown to result in enhanced susceptibility to infection and death from toxoplasmosis in rodents (Arsenijevic et al. 2000)....
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...…the increased abundance with postnatal life may have deleterious consequences in terms of lung function (Symonds et al. 1993), as an increased abundance of UCP2 has been shown to result in enhanced susceptibility to infection and death from toxoplasmosis in rodents (Arsenijevic et al. 2000)....
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TL;DR: This review has summarized the multiple endogenous and exogenous factors that have been shown to be involved in this signaling cascade and, thus, to alter glucocorticoid sensitivity.
Abstract: I. Introduction STEROID hormones are essential constituents of the intercellular communication system that maintains homeostasis in higher organisms. Glucocorticoids, a major subclass of steroid hormones, modulate a large number of metabolic, cardiovascular, immune, and behavioral functions (for a review see Refs. 1 and 2). Glucocorticoids are produced by the adrenal cortex under the regulatory influence of ACTH. The latter is produced by corticotrophs of the anterior pituitary, in turn, under the regulatory influence of hypothalamic CRH and arginine vasopressin (AVP). The hypothalamic-pituitary-adrenal (HPA) axis is kept in balance by the negative feedback effects of cortisol on the secretion of ACTH, CRH, and usually, to a lesser extent, AVP. In the resting state, basal levels of CRH, AVP, ACTH, and cortisol are released in a pulsatile and circadian fashion. At these baseline levels, the main function of cortisol is to sustain normoglycemia and to prevent arterial hypotension. Whether and to what extent...
930 citations
"Ontogeny and nutritional programmin..." refers background in this paper
...11βHSD type 1 (11βHSD1) behaves predominantly as an 11-oxoreductase, catalysing the conversion of cortisone to bioactive cortisol and as an intracellular amplifier of glucocorticoid excess to GR (Bamberger et al. 1996; Stewart & Krozowski, 1999)....
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TL;DR: Lower birth weight was associated with worse adult lung function and death from chronic obstructive airways disease in adult life, and promoting lung growth in fetuses and infants and reducing the incidence of lower respiratory tract infection in infancy may reduce the incidence in the next generation.
Abstract: OBJECTIVE--To examine whether birth weight, infant weight, and childhood respiratory infection are associated with adult lung function and death from chronic obstructive airways disease. DESIGN--Follow up study of men born during 1911-30 whose birth weights, weights at 1 year, and childhood illnesses were recorded at the time by health visitors. SETTING--Hertfordshire, England. SUBJECTS--5718 men born in the county during 1911-30 and a subgroup of 825 men born in the county during 1920-30 and still living there. MAIN OUTCOME MEASURES--Death from chronic obstructive airways disease, mean forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), and respiratory symptoms. RESULTS--55 men died of chronic obstructive airways disease. Death rates fell with increasing birth weight and weight at 1 year. Mean FEV1 at age 59 to 70 years, adjusted for height and age, rose by 0.06 litre (95% confidence interval 0.02 to 0.09) with each pound (450 g) increase in birth weight, independently of smoking habit and social class. Bronchitis or pneumonia in infancy was associated with a 0.17 litre (0.02 to 0.32) reduction in adult FEV1 and with an increased odds ratio of wheezing and persistent sputum production in adult life independently of birth weight, smoking habit, and social class. Whooping cough in infancy was associated with a 0.22 litre (0.02 to 0.42) reduction in adult FEV1. CONCLUSIONS--Lower birth weight was associated with worse adult lung function. Intrauterine influences which retard fetal weight gain may irrecoverably constrain the growth of the airways. Bronchitis, pneumonia, or whooping cough in infancy further reduced adult lung function. They also retarded infant weight gain. Consistent with this, death from chronic obstructive airways disease in adult life was associated with lower birth weight and weight at 1 year. Promoting lung growth in fetuses and infants and reducing the incidence of lower respiratory tract infection in infancy may reduce the incidence of chronic obstructive airways disease in the next generation.
858 citations
"Ontogeny and nutritional programmin..." refers background in this paper
...Email: michael.symonds@nottingham.ac.uk Epidemiological studies of infants, children and adults indicate that prenatal compromises that restrict feto-placental growth and cause low birth weight increase the risk of respiratory deficiencies after birth (Barker et al. 1991)....
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TL;DR: A major goal will be to investigate the possible roles of UCP2 and UCP3 in response to oxidative stress, lipid peroxidation, inflammatory processes, fever and regulation of temperature in certain specific parts of the body.
Abstract: Animal and plant uncoupling protein (UCP) homologues form a subfamily of mitochondrial carriers that are evolutionarily related and possibly derived from a proton/anion transporter ancestor. The brown adipose tissue (BAT) UCP1 has a marked and strongly regulated uncoupling activity, essential to the maintenance of body temperature in small mammals. UCP homologues identified in plants are induced in a cold environment and may be involved in resistance to chilling. The biochemical activities and biological functions of the recently identified mammalian UCP2 and UCP3 are not well known. However, recent data support a role for these UCPs in State 4 respiration, respiration uncoupling and proton leaks in mitochondria. Moreover, genetic studies suggest that UCP2 and UCP3 play a part in energy expenditure in humans. The UCPs may also be involved in adaptation of cellular metabolism to an excessive supply of substrates in order to regulate the ATP level, the NAD(+)/NADH ratio and various metabolic pathways, and to contain superoxide production. A major goal will be the analysis of mice that either lack the UCP2 or UCP3 gene or overexpress these genes. Other aims will be to investigate the possible roles of UCP2 and UCP3 in response to oxidative stress, lipid peroxidation, inflammatory processes, fever and regulation of temperature in certain specific parts of the body.
801 citations
"Ontogeny and nutritional programmin..." refers background in this paper
...While UCP2 mRNA is expressed in a variety of tissues (Ricquier & Bouillaud, 2000), UCP2 protein expression is limited to the spleen, lungs, stomach and white adipose tissue, due to translational regulation of the UCP2 mRNA by an upstream open reading frame located in exon 2 of the UCP2 gene, which…...
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