Increased uncoupling protein-2 mRNA abundance and glucocorticoid action in adipose tissue in the sheep fetus during late gestation is dependent on plasma cortisol and triiodothyronine

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), 11β-hydroxysteroid dehydrogenase (11βHSD) 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 ∼147 days)- or late (110–147 days) gestation. GR and 11βHSD1 mRNA increased with fat mass and were all maximal within the 6-mo observation period. 11βHSD2 mRNA abundance demonstrated a converse decline, whereas UCP2 peaked at 30 days. GR and 11βHSD1 mRNA abundance were strongly correlated with total and relative perirenal adipose tissue weight, and UCP2 was strongly correlated with GR and 11βHSD1 mRNA. Early- to midgestational NR increased GR, 11βHSD1, and UCP2 mRNA, but decreased 11βHSD2 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.

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PC53 THE EFFECT OF NUTRITIONAL DEPRIVATION IN MID AND LATE GESTATION ON UNCOUPLING PROTEIN-2 MRNA ABUNDANCE IN THE OVINE NEONATAL AND ADOLESCENT LUNG

Journal of Pediatric Gastroenterology and Nutrition ◽

10.1097/00005176-200406001-01369 ◽

2004 ◽

Vol 39 (Supplement 1) ◽

pp. S532

Author(s):

G. M. Gnanalingham ◽

A. Mostyn ◽

G. S. Gopalakrishnan ◽

J. Dandrea ◽

M. E. Symonds ◽

...

Keyword(s):

Uncoupling Protein ◽

Mrna Abundance ◽

Late Gestation ◽

Uncoupling Protein 2 ◽

Nutritional Deprivation

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Nutritional manipulation between early to mid-gestation: effects on uncoupling protein-2, glucocorticoid sensitivity, IGF-I receptor and cell proliferation but not apoptosis in the ovine placenta

Reproduction ◽

10.1530/rep-06-0369 ◽

2007 ◽

Vol 134 (4) ◽

pp. 615-623 ◽

Cited By ~ 19

Author(s):

M G Gnanalingham ◽

P Williams ◽

V Wilson ◽

J Bispham ◽

M A Hyatt ◽

...

Keyword(s):

Cell Proliferation ◽

Uncoupling Protein ◽

Mitochondrial Protein ◽

Mrna Abundance ◽

Uncoupling Protein 2 ◽

Type I ◽

Voltage Dependent Anion Channel ◽

Glucocorticoid Sensitivity ◽

Ucp2 Mrna ◽

Glucocorticoid Action

In sheep, modest maternal nutrient restriction (NR) over the period of rapid placental growth restricts placentome growth and results in offspring in which glucocorticoid action is enhanced. Therefore, this study investigated the placental effects of early to mid-gestational NR on glucocorticoid receptor (GR), 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2), uncoupling protein-2 (UCP2), and IGF type-I receptor (IGF-IR) mRNA abundance together with cell proliferation and apoptosis as determined histologically, and the mitochondrial proteins voltage-dependent anion channel and cytochrome c that are involved in apoptosis. Placenta was sampled at 80 and 140 days gestation (dGA; term ~147 dGA). NR was imposed between 28 and 80 days gestation when control and nutrient-restricted groups consumed 150 or 60% respectively of their total metabolizable energy requirements. All mothers were then fed to requirements up to term. Total fetal placentome weights were decreased by NR at 80 dGA but were heavier at 140 dGA following 60 days of nutritional rehabilitation. GR and UCP2 mRNA abundance increased whilst 11βHSD2 mRNA decreased with gestational age. NR persistently up-regulated GR and UCP2 mRNA abundance. 11βHSD2 mRNA was reduced by NR at 80 dGA but increased near to term. IGF-IRmRNA abundance was only decreased at 80 dGA. Placental apoptosis and mitochondrial protein abundance were unaffected by NR, whereas cell proliferation was markedly reduced. In conclusion, placental UCP2 and local glucocorticoid action are affected by the gestational nutritional status and may result in the offspring showing enhanced glucocorticoid sensitivity, thereby predisposing them to disease in later life.

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Differential effects of leptin administration on the abundance of UCP2 and glucocorticoid action during neonatal development

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00228.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. E1093-E1100 ◽

Cited By ~ 5

Author(s):

M. G. Gnanalingham ◽

A. Mostyn ◽

R. Webb ◽

D. H. Keisler ◽

N. Raver ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Chronic Administration ◽

Mrna Abundance ◽

Protein Abundance ◽

Tissue Sampling ◽

Nonesterified Fatty Acids ◽

Differential Effects ◽

Brown Adipose ◽

Glucocorticoid Action

In the neonate, adipose tissue and the lung both undergo a rapid transition after birth, which results in dramatic changes in uncoupling protein abundance and glucocorticoid action. Leptin potentially mediates some of these adaptations and is known to promote the loss of uncoupling protein (UCP)1, but its effects on other mitochondrial proteins or glucocorticoid action are not known. We therefore determined the effects of acute and chronic administration of ovine recombinant leptin on brown adipose tissue (BAT) and/or lung in neonatal sheep. For the acute study, eight pairs of 1-day-old lambs received, sequentially, 10, 100, and 100 μg of leptin or vehicle before tissue sampling 4 h from the start of the study, whereas in the chronic study, nine pairs of 1-day-old lambs received 100 μg of leptin or vehicle daily for 6 days before tissue sampling on day 7. Acute leptin decreased the abundance of UCP2, glucocorticoid receptor, and 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 mRNA and increased 11β-HSD type 2 mRNA abundance in BAT, a pattern that was reversed with chronic leptin administration, which also diminished lung UCP2 protein abundance. In BAT, UCP2 mRNA abundance was positively correlated to plasma leptin and nonesterified fatty acids and negatively correlated to mean colonic temperature in the leptin group at 7 days. In conclusion, leptin administration to the neonatal lambs causes differential effects on UCP2 abundance in BAT and lung. These effects may be important in the development of these tissues, thereby optimizing lung function and fat growth.

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Regulation of Uncoupling Protein-2 and -3 by Growth Hormone in Skeletal Muscle and Adipose Tissue in Growth Hormone-Deficient Adults1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.11.6109 ◽

1999 ◽

Vol 84 (11) ◽

pp. 4073-4078 ◽

Cited By ~ 1

Author(s):

Steen B. Pedersen ◽

Kurt Kristensen ◽

Sanne Fisker ◽

Jens Otto Lunde Jørgensen ◽

Jens Sandahl Christiansen ◽

...

Keyword(s):

Skeletal Muscle ◽

Growth Hormone ◽

Adipose Tissue ◽

Uncoupling Protein ◽

Uncoupling Protein 2

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The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014868 ◽

2020 ◽

Vol 295 (51) ◽

pp. 17535-17548

Author(s):

Xanthe A. M. H. van Dierendonck ◽

Tiphaine Sancerni ◽

Marie-Clotilde Alves-Guerra ◽

Rinke Stienstra

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Macrophage Activation ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Obesity And Diabetes ◽

Adipose Tissue Macrophages

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

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Effects of thyroid hormones on pulmonary and renal angiotensin-converting enzyme concentrations in fetal sheep near term

Journal of Endocrinology ◽

10.1677/joe.0.1730143 ◽

2002 ◽

Vol 173 (1) ◽

pp. 143-150 ◽

Cited By ~ 13

Author(s):

AJ Forhead ◽

AL Fowden

Keyword(s):

Angiotensin Converting Enzyme ◽

Thyroid Hormones ◽

Plasma Cortisol ◽

Experimental Manipulation ◽

Late Gestation ◽

Converting Enzyme ◽

Fetal Sheep ◽

Near Term ◽

Sheep Fetus

In the sheep fetus, pulmonary and renal concentrations of angiotensin-converting enzyme (ACE) increase towards term in parallel with the prepartum surges in plasma cortisol and tri-iodothyronine (T(3)). The ontogenic change in pulmonary ACE has been shown to be induced, at least in part, by cortisol but the role of the thyroid hormones is unknown. Therefore, this study investigated the effects of thyroid hormones on tissue ACE concentration in fetal sheep during late gestation. Pulmonary and renal ACE concentrations were measured in sheep fetuses after experimental manipulation of thyroid hormone status by fetal thyroidectomy and exogenous hormone infusion. In intact fetuses, pulmonary and renal ACE concentrations increased between 127-132 and 142-145 days of gestation (term 145 +/- 2 days), coincident with the prepartum rises in plasma cortisol and T(3). The ontogenic increment in pulmonary ACE concentration was abolished when the prepartum surge in T(3), but not cortisol, was prevented by fetal thyroidectomy. At 143-145 days, ACE concentration in the lungs and kidneys of the thyroidectomised fetuses were both lower than those in the intact fetuses. In intact fetuses at 127-132 days, pulmonary ACE was upregulated by intravenous infusions of either cortisol (2-3 mg/kg per day) or T(3) (8-12 microg/kg per day) for 5 days. Renal ACE was unaffected by cortisol or T(3) infusion. Therefore, thyroid hormones have an important role in the developmental control of pulmonary and renal ACE concentration in the sheep fetus towards term. In addition, the prepartum rise in plasma T(3) appears to mediate, in part, the maturational effect of cortisol on pulmonary ACE concentration.

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Fetal and neonatal adipose maturation: a primary site of cytokine and cytokine-receptor action

Biochemical Society Transactions ◽

10.1042/bst0290080 ◽

2001 ◽

Vol 29 (2) ◽

pp. 80-85 ◽

Cited By ~ 18

Author(s):

T. Stephenson ◽

H. Budge ◽

A. Mostyn ◽

S. Pearce ◽

R. Webb ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Maternal Nutrition ◽

Short Form ◽

Uncoupling Protein ◽

Prolactin Receptor ◽

Late Gestation ◽

Metabolic Adaptation ◽

Postnatal Life ◽

Brown Adipose

During late gestation, the maturation of fetal adipose tissue is geared towards the synthesis of high levels of uncoupling protein 1 (UCP1), which is unique to brown adipose tissue. At birth, rapid activation of UCP1 ensures a large increase in heat production. These adaptations are nutritionally sensitive, and may be mediated in part by rapid changes in prolactin and leptin secretion after birth. Restriction of maternal nutrition reduces adipose tissue deposition, with no effect on UCP1. Increased maternal food intake results in increases in levels of UCP1 and the short form of the prolactin receptor, but in a decrease in adipose tissue content per kg of fetus. The ontogeny of the long and short forms of the prolactin receptor follows that of UCP1, to peak at birth. Then, during postnatal life, UCP1 disappears in parallel with the loss of prolactin receptors. Treatment of neonatal lambs with prolactin increases body temperature and the thermogenic potential of brown adipose tissue. In contrast, acute leptin treatment results in maintenance of colonic temperature, but chronic leptin treatment accelerates UCP1 loss. Increasing our understanding of the interaction between prolactin and leptin during perinatal development may enable the establishment of strategies aimed at maximizing adipose tissue development in order to promote metabolic adaptation to the extra-uterine environment.

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Ontogeny and Effects of Hypothalamic Pituitary Disconnection on Formation of Inositol Trisphosphate in Fetal Sheep Pituitary Cells

Endocrinology ◽

10.1210/en.2006-1185 ◽

2007 ◽

Vol 148 (3) ◽

pp. 1440-1444 ◽

Cited By ~ 3

Author(s):

Luke C. Carey ◽

Stephen B. Tatter ◽

James C. Rose

Keyword(s):

Gestational Age ◽

Plasma Cortisol ◽

Inositol Trisphosphate ◽

Second Messenger ◽

Late Gestation ◽

Pituitary Cells ◽

Fetal Sheep ◽

The Impact ◽

Pituitary Adrenal Axis ◽

Sheep Fetus

In late gestation fetal sheep, the pituitary becomes increasingly responsive to stimulation by arginine vasopressin (AVP). This change appears to be one important factor mediating the plasma cortisol surge, a critical developmental event. It is not known precisely why pituitary corticotropes become more responsive at this time. In this study we examined the possibility that changes in second messenger generation [inositol trisphosphate (IP3)] are responsible. Two studies were undertaken. The first was an ontogeny study, where pituitaries were isolated from 100-, 120-, and 140-d gestational age (dGA) fetal sheep. Cells were cultured, stimulated with AVP, and the formation of IP3 assessed. The amount of IP3 generated increased with gestational age (percent increases from unstimulated controls were 4.6, 11.5, and 21.5 for 100, 120, and 140 dGA, respectively), with significant differences between the 140-dGA group and both earlier groups apparent. The second study examined the impact of 120-dGA hypothalamo-pituitary disconnection (HPD), which prevents corticotrope maturation, on responsiveness of pituitary cells isolated from 140-dGA fetuses. Cells were stimulated with AVP, and the formation of IP3 and secretion of ACTH were assessed. Significantly less IP3 was formed, and ACTH secreted in cells from HPD compared with control fetuses (IP3 and ACTH levels were 50% and 35% lower, respectively). Results from the HPD study demonstrate that the ontogenic changes in IP3 after AVP require an intact hypothalamic-pituitary-adrenal axis. These findings suggest that heightened second messenger generation may be a key reason for increased ACTH secretory responsiveness to AVP in the late gestation sheep fetus.

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Timing of nutrient restriction and programming of fetal adipose tissue development

Proceedings of The Nutrition Society ◽

10.1079/pns2004366 ◽

2004 ◽

Vol 63 (3) ◽

pp. 397-403 ◽

Cited By ~ 80

Author(s):

Michael E. Symonds ◽

Sarah Pearce ◽

Jayson Bispham ◽

David S. Gardner ◽

Terence Stephenson

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Tissue Growth ◽

Fat Deposition ◽

Late Gestation ◽

Nutrient Restriction ◽

Adult Obesity ◽

Uncoupling Protein 1 ◽

Voltage Dependent Anion Channel ◽

Brown Adipose

It is apparent from epidemiological studies that the timing of maternal nutrient restriction has a major influence on outcome in terms of predisposing the resulting offspring to adult obesity. The present review will consider the extent to which maternal age, parity and nutritional restriction at defined stages of gestation can have important effects on fat deposition and endocrine sensitivity of adipose tissue in the offspring. For example, in 1-year-old sheep the offspring of juvenile mothers have substantially reduced fat deposition compared with those born to adult mothers. Offspring of primiparous adult mothers, however, show increased adiposity compared with those born to multiparous mothers. These offspring of multiparous ewes show retained abundance of the brown adipose tissue-specific uncoupling protein 1 at 1 month of age. A stimulated rate of metabolism in brown fat of these offspring may act to reduce adipose tissue deposition in later life. In terms of defined windows of development that can programme adipose tissue growth, maternal nutrient restriction targetted over the period of maximal placental growth results in increased adiposity at term in conjunction with enhanced abundance of mRNA for the insulin-like growth factor-I and -II receptors. In contrast, nutrient restriction in late gestation, coincident with the period of maximal fetal growth, has no major effect on adiposity but results in greater abundance of specific mitochondrial proteins, i.e. voltage-dependent anion channel and/or uncoupling protein 2. These adaptations may increase the predisposal of these offspring to adult obesity. Increasing maternal nutrition in late gestation, however, can result in proportionately less fetal adipose tissue deposition in conjunction with enhanced abundance of uncoupling protein 1.

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