scholarly journals Reduced Perinatal Leptin Availability May Contribute to Adverse Metabolic Programming in a Rat Model of Uteroplacental Insufficiency

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1813-1825 ◽  
Author(s):  
Eva Nüsken ◽  
Maria Wohlfarth ◽  
Gregor Lippach ◽  
Manfred Rauh ◽  
Holm Schneider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Leptin Receptor ◽  
Later Life ◽  
Maternal Blood ◽  
Metabolic Programming ◽  
Leptin Resistance ◽  
Sham Operation ◽  
Pregnant Rats ◽  
Hypoxic Conditions ◽  
Uterine Vessel

Abstract Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.

scholarly journals Suppression of Leptin Receptor Messenger Ribonucleic Acid and Leptin Responsiveness in the Ventromedial Nucleus of the Hypothalamus during Pregnancy in the Rat

Endocrinology ◽  
2005 ◽  
Vol 146 (9) ◽  
pp. 3868-3874 ◽  
Author(s):  
S. R. Ladyman ◽  
D. R. Grattan
Keyword(s):  
Choroid Plexus ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Ventromedial Nucleus ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Messenger Ribonucleic Acid ◽  
Leptin Receptors ◽  
Receptor Isoforms

Abstract Pregnancy in the rat is a state of leptin resistance associated with impaired leptin signal transduction in the hypothalamus. The aim of this study was to determine whether this leptin-resistant state is mediated by a change in the level of leptin receptors in the hypothalamus. Real-time RT-PCR was used to determine levels of mRNA for the various leptin receptor isoforms in a number of microdissected hypothalamic nuclei and the choroid plexus. To investigate the functional activation of the leptin receptor, immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (pSTAT3) was examined in the arcuate nucleus and the ventromedial nucleus of the hypothalamus (VMH) of fasted diestrous and d-14 pregnant rats after an intracerebroventricular (i.c.v.) injection of either leptin (4 μg) or vehicle. A significant reduction of Ob-Rb mRNA levels was observed in the VMH during pregnancy compared with the nonpregnant controls. Furthermore, in pregnant rats the number of cells positive for leptin-induced pSTAT3 in the VMH was greatly reduced during pregnancy compared with nonpregnant rats. There were no differences in the level of Ob-Rb mRNA or in the number of leptin-induced pSTAT3-positive cells in the arcuate nucleus of nonpregnant and pregnant rats. These data implicate the VMH as a key hypothalamic site involved in pregnancy-induced leptin resistance. There were also reduced levels of mRNA for Ob-Ra, a proposed leptin transporter molecule, in the choroid plexus on d 7 and 21 of pregnancy. Hence, diminished transport of leptin into the brain may also contribute to pregnancy-induced leptin resistance.

scholarly journals Protection Against High-Fat Diet-Induced Obesity in Helz2-Deficient Male Mice Due to Enhanced Expression of Hepatic Leptin Receptor

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3459-3472 ◽  
Author(s):  
Satoshi Yoshino ◽  
Tetsurou Satoh ◽  
Masanobu Yamada ◽  
Koshi Hashimoto ◽  
Takuya Tomaru ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
High Fat Diet ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
High Fat ◽  
Leptin Sensitivity ◽  
Amp Activated Protein Kinase ◽  
Central Leptin Resistance ◽  
Deficient Mice

Abstract Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.

scholarly journals Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

2021 ◽  
Author(s):  
Jaedeok Kwon ◽  
Maria Suessmilch ◽  
Alison McColl ◽  
Jonathan Cavanagh ◽  
Brian J. Morris
Keyword(s):  
Disease Risk ◽  
Later Life ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Poly I:C ◽  
Psychiatric Disease ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Pregnant Mice ◽  
Virus Exposure

AbstractExposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) RNA viral or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure specifically with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with the current SARS-CoV-2 pandemic. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

scholarly journals Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaedeok Kwon ◽  
Maria Suessmilch ◽  
Alison McColl ◽  
Jonathan Cavanagh ◽  
Brian J. Morris
Keyword(s):  
Disease Risk ◽  
Later Life ◽  
Maternal Blood ◽  
Maternal Plasma ◽  
Poly I:C ◽  
Psychiatric Disease ◽  
Mrna Levels ◽  
Pregnant Rats ◽  
Pregnant Mice ◽  
Virus Exposure

AbstractExposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) virus or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with recent events. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate Toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4 h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

scholarly journals Maternal protein restriction in mice causes adverse metabolic and hypothalamic effects in the F1 and F2 generations

2011 ◽  
Vol 106 (9) ◽  
pp. 1364-1373 ◽  
Author(s):  
Nayara Peixoto-Silva ◽  
Eliete Dalla Corte Frantz ◽  
Carlos Alberto Mandarim-de-Lacerda ◽  
Alessandra Pinheiro-Mulder
Keyword(s):  
Leptin Receptor ◽  
Protein Restriction ◽  
Metabolic Programming ◽  
Male Offspring ◽  
Leptin Resistance ◽  
Altered Expression ◽  
Leptin Sensitivity ◽  
Maternal Protein Restriction ◽  
Group 5 ◽  
F2 Generation

Maternal protein restriction causes metabolic alterations associated with hypothalamic dysfunction. Because the consequences of metabolic programming can be passed transgenerationally, the present study aimed to assess whether maternal protein restriction alters the expression of hypothalamic neuropeptides in offspring and to evaluate hormonal and metabolic changes in male offspring from the F1 and F2 generations. Female Swiss mice (F0) were mated and fed either a normal-protein (NP group; 19 % protein) or a low-protein (LP group; 5 % protein) diet throughout gestation of the F1 generation (NP1 and LP1). At 3 months of age, F1 females were mated to produce the F2 generation (NP2 and LP2). Animals from all groups were evaluated at 16 weeks of age. LP1 offspring had significantly lower weights and shorter lengths than NP1 offspring at birth, but they underwent a phase of rapid catch-up growth. Conversely, the LP2 offspring were not significantly different from the NP2 offspring in either weight or length. At 16 weeks, no differences were found in body mass among any of the groups, although LP1 and LP2 offspring showed hypercholesterolaemia, hypertriacylglycerolaemia, hyperglycaemia, glucose intolerance, insulin resistance, increased levels of insulin, leptin and resistin, decreased endogenous leptin sensitivity, increased adiposity with elevated leptin levels and leptin resistance characterised by altered expression of neuropeptide Y and pro-opiomelanocortin without any changes in the leptin receptor Ob-Rb. We conclude that severe maternal protein restriction promotes metabolic programming in F1 and F2 male offspring due to a dysregulation of the adipoinsular axis and a state of hypothalamic leptin resistance.

scholarly journals Leptin Deficiency and Diet-Induced Obesity Reduce Hypothalamic Kisspeptin Expression in Mice

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1541-1550 ◽  
Author(s):  
Janette H. Quennell ◽  
Christopher S. Howell ◽  
Juan Roa ◽  
Rachael A. Augustine ◽  
David R. Grattan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Third Ventricle ◽  
Cell Number ◽  
Leptin Resistance ◽  
Diverse Range ◽  
Cell Numbers ◽  
Diet Induced Obesity ◽  
Leptin Deficiency

Abstract The hormone leptin modulates a diverse range of biological functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect.

scholarly journals Roux-en-Y Gastric Bypass and Caloric Restriction but Not Gut Hormone-Based Treatments Profoundly Impact the Hypothalamic Transcriptome in Obese Rats

Nutrients ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 116
Author(s):  
Ulrich Dischinger ◽  
Tobias Heckel ◽  
Thorsten Bischler ◽  
Julia Hasinger ◽  
Malina Königsrainer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Bypass ◽  
Body Weight ◽  
Signaling Pathways ◽  
Leptin Receptor ◽  
Receptor Expression ◽  
Striking Difference ◽  
Sham Operation ◽  
Weight Changes ◽  
Gut Hormone

Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

scholarly journals A Genome-Wide Integrative Association Study of DNA Methylation and Gene Expression Data and Later Life Cognitive Functioning in Monozygotic Twins

2020 ◽  
Vol 14 ◽  
Author(s):  
Mette Soerensen ◽  
Dominika Marzena Hozakowska-Roszkowska ◽  
Marianne Nygaard ◽  
Martin J. Larsen ◽  
Veit Schwämmle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cognitive Functioning ◽  
Association Study ◽  
Gene Expression Data ◽  
Monozygotic Twins ◽  
Later Life ◽  
Expression Data ◽  
Genome Wide ◽  
A Genome

scholarly journals Gene Expression Profiling on Global cDNA Arrays Gives Hints Concerning Potential Signal Transduction Pathways Involved in Cardiac Fibrosis of Renal Failure

2003 ◽  
Vol 4 (6) ◽  
pp. 571-583 ◽  
Author(s):  
Kerstin Amann ◽  
Heidrun Ridinger ◽  
Christiane Rutenberg ◽  
Eberhard Ritz ◽  
Gerhard Mall ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Failure ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cardiac Remodelling ◽  
Cardiomyocyte Hypertrophy ◽  
Specific Gene ◽  
Interstitial Tissue ◽  
Sham Operation ◽  
Cdna Arrays

Cardiac remodelling with interstitial fibrosis in renal failure, which so far is only poorly understood on the molecular level, was investigated in the rat model by a global gene expression profiling analysis. Sprague–Dawley rats were subjected to subtotal nephrectomy (SNX) or sham operation (sham) and followed for 2 and 12 weeks, respectively. Heart-specific gene expression profiling, with RZPD Rat Unigene-1 cDNA arrays containing about 27 000 gene and EST sequences revealed substantial changes in gene expression in SNX compared to sham animals. Motor protein genes, growth and differentiation markers, and extracellular matrix genes were upregulated in SNX rats. Obviously, not only genes involved in cardiomyocyte hypertrophy, but also genes involved in the expansion of non-vascular interstitial tissue are activated very early in animals with renal failure. Together with earlier findings in the SNX model, the present data suggest the hypothesis that the local renin–angiotensin system (RAS) may be activated by at least two pathways: (a) via second messengers and Gproteins (short-term signalling); and (b) via motor proteins, actins and integrins (longterm signalling). The study documents that complex hybridization analysis yields reproducible and promising results of patterns of gene activation pointing to signalling pathways involved in cardiac remodelling in renal failure. The complete array data are available via http://www.rzpd.de/cgi-bin/services/exp/viewExpressionData.pl.cgi

Influence of photoperiod and gonadal status on food intake, adiposity, and gene expression of hypothalamic appetite regulators in a seasonal mammal

2007 ◽  
Vol 292 (1) ◽  
pp. R242-R252 ◽  
Author(s):  
Chantacha Anukulkitch ◽  
Alexandra Rao ◽  
Frank R. Dunshea ◽  
Dominique Blache ◽  
Gerald A. Lincoln ◽  
...  
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Reproductive Axis ◽  
Pomc Gene ◽  
Gonadal Status ◽  
Long Photoperiod ◽  
Refractory Phase

We studied the effects of photoperiod on metabolic profiles, adiposity, and gene expression of hypothalamic appetite-regulating peptides in gonad-intact and castrated Soay rams. Groups of five to six animals were studied 6, 18, or 30 wk after switching from long photoperiod (LP: 16 h of light) to short photoperiod (SP: 8 h of light). Reproductive and metabolic indexes were measured in blood plasma. Expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor (ObRb) in the arcuate nucleus was measured using in situ hybridization. Testosterone levels of intact animals were low under LP, increased to a peak at 16 wk under SP, and then declined. Voluntary food intake (VFI) was high under LP in both intact and castrated animals, decreased to a nadir at 12–16 wk under SP, and then recovered, but only in intact rams as the reproductive axis became photorefractory to SP. NPY gene expression varied positively and POMC expression varied negatively with the cycle in VFI, with differences between intact and castrate rams in the refractory phase. ObRb expression decreased under SP, unrelated to changes in VFI. Visceral fat weight also varied between the intact and castrated animals across the cycle. We conclude that 1) photoperiodic changes in VFI reflect changes in NPY and POMC gene expression, 2) changes in ObRb gene expression are not necessarily determinants of changes in VFI, 3) gonadal status affects the pattern of VFI that changes with photoperiod, and 4) in the absence of gonadal factors, animals can eat less but gain adiposity.

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