Long-term hypoxia modulates expression of key genes regulating adipose function in the late-gestation ovine fetus

A major function of abdominal adipose in the newborn is nonshivering thermogenesis. Uncoupling protein (UCP) UCP1 and UCP2 play major roles in thermogenesis. The present study tested the hypothesis that long-term hypoxia (LTH) modulates expression of UCP1 and UCP2, and key genes regulating expression of these genes in the late-gestation ovine fetus. Ewes were maintained at high altitude (3,820 m) from 30 to 138 days gestation (dG); perirenal adipose tissue was collected from LTH and age-matched, normoxic control fetuses at 139–141 dG. Quantitative real-time PCR was used to analyze mRNA for UCP1, UCP2, 11β hydroxysteroid dehydrogenase type 1 (HSD11B1) and 2 (HSD11B2), glucocorticoid receptor (GR), β3 adrenergic receptor (β3AR), deiodinase type 1 (DIO1) and DIO2, peroxisome proliferator activated receptor (PPAR) α and γ and PPARγ coactivator 1 (PGC1α). Concentrations of mRNA for UCP1, HSD11B1, PPARγ, PGC1, DIO1, and DIO2 were significantly higher in perirenal adipose of LTH compared with control fetuses, while mRNA for HSD11B2, GR, or PPARα in perirenal adipose did not differ between control and LTH fetuses. The increased expression of UCP1 is likely an adaptive response to LTH, assuring adequate thermogenesis in the event of birth under oxygen-limiting conditions. Because both glucocorticoids and thyroid hormone regulate UCP1 expression, the increase in HSD11B1, DIO1, and DIO2 implicate increased adipose capacity for local synthesis of these hormones. PPARγ and its coactivator may provide an underlying mechanism via which LTH alters development of the fetal adipocyte. These findings have important implications regarding fetal/neonatal adipose tissue function in response to LTH.

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The effect of maternal arginine supplementation on the development of the thermogenic program in the ovine fetus

Animal Production Science ◽

10.1071/an14310 ◽

2014 ◽

Vol 54 (10) ◽

pp. 1843 ◽

Cited By ~ 7

Author(s):

S. McCoard ◽

N. Wards ◽

J. Koolaard ◽

M. Senna Salerno

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Cell Number ◽

Late Gestation ◽

Dna And Rna ◽

Brown Adipose ◽

Fat Stores ◽

Ovine Fetus ◽

Arginine Supplementation

Brown adipose tissue (BAT) is a specialised fat store that is metabolised by the newborn lamb to ensure effective adaptation to the cold challenge of the extra-uterine environment. Increasing BAT reserves therefore has the potential to increase neonatal thermogenesis and survival. It is established that arginine supplementation can increase fetal BAT stores but the biological mechanisms involved are unclear. The objective of this study was to test the hypothesis that increased fetal BAT stores resulting from maternal arginine supplementation is mediated by activation of the thermogenic program. Brown adipose tissue was collected from fetuses of ewes supplemented with arginine from 100 to 140 days of gestation. Increased peri-renal fat stores in fetuses from arginine-supplemented ewes was associated with an increase in uncoupling protein 1 (UCP-1) and PRD1-BF-1-RIZ1 homologous domain containing protein-16 expression, but not proliferator-activated receptor gamma or proliferator-activated receptor gamma-co-activator-1α in BAT. The activity of UCP-1 is regulated by hormones including cortisol and thyroid hormones. Cortisol level in fetuses from supplemented sheep was 68% greater than those from control ewes, indicating that cortisol may control upregulation of UCP-1 expression in the ovine neonate. The DNA and RNA concentration in BAT of both groups suggest that increased peri-renal fat stores is not associated with an increase in cell number or number of ribosomes, but rather an increase in the size of individual fat cells. Collectively, these results indicate that maternal arginine supplementation during mid to late gestation improved the thermoregulatory ability of lambs and this could potentially increase their survival in early life.

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Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

10.21203/rs.2.20297/v1 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Xiyu Feng ◽

Chao Deng ◽

Lu Liu ◽

Yanping Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Brown Adipose Tissue ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Olanzapine Treatment ◽

Brown Adipose

Abstract BackgroundPrescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant sedation, weight gain, and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.MethodsTo investigate the efficacy of interventions of statin aimed at reversing SGA-induced dyslipidemia, young Sprague Dawley (SD) rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O+S), or vehicle (control) for 5 weeks.ResultsOlanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O+S co-treatment significantly reversed body weight gain but had no significant effect on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O+S co-treatment significantly ameliorated these changes. A down-regulating of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) expression was observed in brown adipose tissue (BAT) in the olanzapine-only group, following a significant decrease in the ratio of phosphorylated PKA (p-PKA)/PKA. Interestingly, these protein changes could be reversed by co-treatment with O+B. Our results demonstrated simvastatin to be effective in ameliorating TC and TG elevated by olanzapine.ConclusionsModulation of BAT activity could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

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Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin

10.21203/rs.2.20297/v4 ◽

2020 ◽

Author(s):

Xuemei Liu ◽

Xiyu Feng ◽

Chao Deng ◽

Lu Liu ◽

Yanping Zeng ◽

...

Keyword(s):

Adipose Tissue ◽

Weight Gain ◽

Food Intake ◽

Brown Adipose Tissue ◽

Body Weight Gain ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Olanzapine Treatment ◽

Brown Adipose

Abstract Background Prescription of second-generation antipsychotic drugs (SGAs) to childhood/adolescent has exponentially increased in recent years, which was associated with the greater risk of significant weight gain and dyslipidemia. Statin is considered a potential preventive and treatment approach for reducing SGA-induced weight gain and dyslipidemia in schizophrenia patients. However, the effect of statin treatment in children and adolescents with SGA-induced dyslipidemia is not clearly demonstrated.Methods To investigate the efficacy of statin interventions for reversing SGA-induced dyslipidemia, young Sprague Dawley rats were treated orally with either olanzapine (1.0 mg/kg, t.i.d.), simvastatin (3.0 mg/kg, t.i.d.), olanzapine plus simvastatin (O+S), or vehicle (control) for 5 weeks. Results Olanzapine treatment increased weight gain, food intake and feeding efficiency compared to the control, while O+S co-treatment significantly reversed body weight gain but without significant effects on food intake. Moreover, olanzapine treatment induced a slight but significant reduction in body temperature, with a decrease in locomotor activity. Fasting plasma glucose, triglycerides (TG), and total cholesterol (TC) levels were markedly elevated in the olanzapine-only group, whereas O+S co-treatment significantly ameliorated these changes. Pronounced activation of lipogenic gene expression in the liver and down-regulated expression of uncoupling protein-1 (UCP1) and peroxisome-proliferator-activated receptor-γ co-activator-1α (PGC-1α) in brown adipose tissue (BAT) was observed in the olanzapine-only group. Interestingly, these protein changes could be reversed by co-treatment with O+B. Conclusions Simvastatin is effective in ameliorating TC and TG elevated by olanzapine. Modulation of BAT activity by statins could be a partial mechanism in reducing metabolic side effects caused by SGAs in child and adolescent patients.

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Peroxisome Proliferator-Activated Receptor α (PPARα) Potentiates, whereas PPARγ Attenuates, Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells

Endocrinology ◽

10.1210/en.2004-1430 ◽

2005 ◽

Vol 146 (8) ◽

pp. 3266-3276 ◽

Cited By ~ 71

Author(s):

Kim Ravnskjaer ◽

Michael Boergesen ◽

Blanca Rubi ◽

Jan K. Larsen ◽

Tina Nielsen ◽

...

Keyword(s):

Insulin Secretion ◽

Mitochondrial Membrane ◽

Uncoupling Protein ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Β Cells ◽

Pancreatic Β Cells ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Stimulated Insulin Secretion

Abstract Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic β-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of β-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARα and retinoid X receptor α (RXRα) in INS-1E β-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARα target genes and enhances FA uptake and β-oxidation. In contrast, ectopic expression of PPARγ/RXRα increases FA uptake and deposition as triacylglycerides. Although the expression of PPARα/RXRα leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARγ/RXRα attenuates GSIS, the expression of PPARα/RXRα potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes α and γ on lipid partitioning and insulin secretion when systematically compared in a β-cell context.

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Fetal endocrinology and development--manipulation and adaptation to long-term nutritional and environmental challenges

Reproduction ◽

10.1530/rep.0.1210853 ◽

2001 ◽

pp. 853-862 ◽

Cited By ~ 52

Author(s):

ME Symonds ◽

H Budge ◽

T Stephenson ◽

IC McMillen

Keyword(s):

Adipose Tissue ◽

Maternal Nutrition ◽

Uncoupling Protein ◽

Prolactin Receptor ◽

Endocrine System ◽

Adult Obesity ◽

Maternal Undernutrition ◽

Increased Risk ◽

Long Form

This article reviews the fetal endocrine system in sheep, a species that has a long gestation and primarily produces a singleton fetus. Attention is focused on information that is applicable to humans. The endocrinology of metabolic homeostasis in sheep fetuses is well adapted to respond to a range of metabolic challenges, including placental restriction and maternal undernutrition. A small placenta results in hypoxaemia, hypoglycaemia, reduced abundance of anabolic hormones, and fetal growth restriction. Fetuses with restricted growth are characterized by tissue-specific reductions in hormone receptor mRNA, for example mRNA for the long form of prolactin receptor is reduced in adipose tissue. In contrast, the adipose tissue of fetuses with accelerated growth, stimulated by increasing maternal nutrition in the second half of gestation, has more protein for the long form of the prolactin receptor and more uncoupling protein 1, by which large amounts of heat are generated at birth. Maternal undernutrition in early gestation, coinciding with the period of rapid placental growth, initially restricts placental growth, but when mothers are fed to requirements, a longer fetus results with a disproportionately large placenta. This nutritional manipulation replicates, in part, epidemiological findings from the Dutch famine of 1944-1945, for which the offspring are at increased risk of adult obesity.

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Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing

Cells ◽

10.3390/cells8080831 ◽

2019 ◽

Vol 8 (8) ◽

pp. 831 ◽

Cited By ~ 1

Author(s):

Virag Vas ◽

Tamás Háhner ◽

Gyöngyi Kudlik ◽

Dávid Ernszt ◽

Krisztián Kvell ◽

...

Keyword(s):

Adipose Tissue ◽

Uncoupling Protein ◽

Growth Factor Receptor ◽

Cellular Level ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Kinase Substrate ◽

Downstream Signaling ◽

Brown Adipose ◽

Morphological Differences

Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.

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Enhanced Fatty Acid Flux Triggered by Adiponectin Overexpression

Endocrinology ◽

10.1210/en.2011-1339 ◽

2012 ◽

Vol 153 (1) ◽

pp. 113-122 ◽

Cited By ~ 23

Author(s):

Shoba Shetty ◽

Maria A. Ramos-Roman ◽

You-Ree Cho ◽

Jonathan Brown ◽

Jorge Plutzky ◽

...

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Free Fatty Acid ◽

Uncoupling Protein ◽

Retinol Binding Protein ◽

Peroxisome Proliferator ◽

Tissue Mass ◽

Triglyceride Synthesis ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

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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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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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The Lou/C rat: a model of spontaneous food restriction associated with improved insulin sensitivity and decreased lipid storage in adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90592.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. E1120-E1132 ◽

Cited By ~ 23

Author(s):

Christelle Veyrat-Durebex ◽

Xavier Montet ◽

Manlio Vinciguerra ◽

Asllan Gjinovci ◽

Paolo Meda ◽

...

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Food Restriction ◽

Wistar Rats ◽

Uncoupling Protein ◽

Caloric Intake ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

The inbred Lou/C rat, originating from the Wistar strain, has been described as a model of resistance to diet-induced obesity, but little is known about its metabolism. Since this knowledge could provide some clues about the etiology of obesity/insulin resistance, this study aimed at characterizing glucose and lipid metabolism in Lou/C vs. Wistar rats. This was achieved by performing glucose and insulin tolerance tests, euglycemic hyperinsulinemic clamps, and characterization of intracellular insulin signaling in skeletal muscle. Substrate-induced insulin secretion was evaluated using perfused pancreas and isolated islets. Finally, body fat composition and the expression of various factors involved in lipid metabolism were determined. Body weight and caloric intake were lower in Lou/C than in Wistar rats, whereas food efficiency was similar. Improved glucose tolerance of Lou/C rats was not related to increased insulin output but was related to improved insulin sensitivity/responsiveness in the liver and in skeletal muscles. In the latter tissue, this was accompanied by improved insulin signaling, as suggested by higher activation of the insulin receptor and of the Akt/protein kinase B pathway. Fat deposition was markedly lower in Lou/C than in Wistar rats, especially in visceral adipose tissue. In the inguinal adipose depot, expression of uncoupling protein-1 was detected in Lou/C but not in Wistar rats, in keeping with a higher expression of peroxisome proliferator-activated receptor-γ coactivator-1 in these animals. The Lou/C rat is a valuable model of spontaneous food restriction with associated improved insulin sensitivity. Independently from its reduced caloric intake, it also exhibits a preferential channeling of nutrients toward utilization rather than storage.

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