Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring

2009 ◽  
Vol 296 (3) ◽  
pp. E462-E472 ◽  
Author(s):  
Christophe Breton ◽  
Marie-Amélie Lukaszewski ◽  
Pierre-Yves Risold ◽  
Mihaela Enache ◽  
Johann Guillemot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Regulatory System ◽  
Male Rat ◽  
Dark Phase ◽  
Mrna Levels ◽  
Nutritional Regulation ◽  
Energy Status ◽  
Maternal Undernutrition ◽  
Immunoreactive Fiber

Epidemiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% food-restricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of β-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm.

scholarly journals The lack of specificity of neuropeptide Y (NPY) antisense oligodeoxynucleotides administered intracerebroventricularly in inhibiting food intake and NPY gene expression in the rat hypothalamus

1998 ◽  
Vol 157 (1) ◽  
pp. 169-175 ◽  
Author(s):  
S Dryden ◽  
L Pickavance ◽  
D Tidd ◽  
G Williams
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Third Ventricle ◽  
Antisense Oligodeoxynucleotides ◽  
Mrna Levels ◽  
Inhibit Gene Expression ◽  
Negative Findings ◽  
Antisense Odns

To evaluate the role of neuropeptide Y (NPY), a potent appetite stimulant, in controlling food intake and body weight, we investigated the use of antisense oligodeoxynucleotides (ODNs) to inhibit NPY gene expression in the hypothalamus. We compared the hypothalamic distribution of fluorescein-labelled ODNs administered intracerebroventricularly, and effects on food intake and NPY gene expression, of three different structural modifications of an antisense ODN sequence against NPY. Rats had either the antisense or missense ODNs (24 micrograms/day) or saline infused into the third ventricle by osmotic minipumps for 7 days. The unmodified phosphodiester ODN was not detectable in the hypothalamus after 7 days and had no effects on food intake. The phosphorothioate ODN was widely distributed throughout the hypothalamus but had nonselective effects, with similar changes in food intake and NPY mRNA levels in the antisense and missense groups, and was severely toxic. The propyl-protected ODN appeared to penetrate the hypothalamus well but had no antisense-selective effects on NPY mRNA levels or food intake. Antisense ODNs are increasingly used to inhibit gene expression in vitro and in intact animals. These negative findings underline the need for rigorous evaluation of any effects of antisense ODNs administered into the central nervous system, and raise doubts about the validity of this approach in physiological or pharmacological studies.

Maternal undernutrition programs the apelinergic system of adipose tissue in adult male rat offspring

2017 ◽  
Vol 8 (1) ◽  
pp. 3-7 ◽  
Author(s):  
S. Lecoutre ◽  
L. Marousez ◽  
A. Drougard ◽  
C. Knauf ◽  
C. Guinez ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adult Male ◽  
Messenger Rna ◽  
Leptin Receptor ◽  
Female Rats ◽  
Male Rat ◽  
Mrna Levels ◽  
Maternal Undernutrition ◽  
Rat Offspring ◽  
Adult Male Rat

Based on the Developmental Origin of Health and Disease concept, maternal undernutrition has been shown to sensitize adult offspring to metabolic pathologies such as obesity. Using a model of maternal 70% food restriction in pregnant female rats throughout gestation (called FR30), we previously reported that obesity-prone adult male rat offspring displayed hyperleptinemia with modifications in leptin and leptin receptor messenger RNA (mRNA) levels in white adipose tissue (WAT). Apelin is a member of the adipokine family that regulates various aspects of energy metabolism and WAT functionality. We investigated whether apelin and its receptor APJ could be a target of maternal undernutrition. Adult male rat offspring from FR30 dams showed increased plasma apelin levels and apelin gene expression in WAT. Post-weaning high-fat diet led to marked increase in APJ mRNA and protein levels in offspring’s WAT. We demonstrate that maternal undernutrition and post-weaning diet have long-term consequences on the apelinergic system of adult male rat offspring.

scholarly journals Diurnal Corticosterone Presence and Phase Modulate Clock Gene Expression in the Male Rat Prefrontal Cortex

Endocrinology ◽  
2016 ◽  
Vol 157 (4) ◽  
pp. 1522-1534 ◽  
Author(s):  
Elizabeth R. Woodruff ◽  
Lauren E. Chun ◽  
Laura R. Hinds ◽  
Robert L. Spencer
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Clock Gene ◽  
Expression Patterns ◽  
Time Of Day ◽  
Male Rat ◽  
Mrna Levels ◽  
Diurnal Pattern ◽  
Peripheral Tissues ◽  
Clock Gene Expression

Abstract Mood disorders are associated with dysregulation of prefrontal cortex (PFC) function, circadian rhythms, and diurnal glucocorticoid (corticosterone [CORT]) circulation. Entrainment of clock gene expression in some peripheral tissues depends on CORT. In this study, we characterized over the course of the day the mRNA expression pattern of the core clock genes Per1, Per2, and Bmal1 in the male rat PFC and suprachiasmatic nucleus (SCN) under different diurnal CORT conditions. In experiment 1, rats were left adrenal-intact (sham) or were adrenalectomized (ADX) followed by 10 daily antiphasic (opposite time of day of the endogenous CORT peak) ip injections of either vehicle or 2.5 mg/kg CORT. In experiment 2, all rats received ADX surgery followed by 13 daily injections of vehicle or CORT either antiphasic or in-phase with the endogenous CORT peak. In sham rats clock gene mRNA levels displayed a diurnal pattern of expression in the PFC and the SCN, but the phase differed between the 2 structures. ADX substantially altered clock gene expression patterns in the PFC. This alteration was normalized by in-phase CORT treatment, whereas antiphasic CORT treatment appears to have eliminated a diurnal pattern (Per1 and Bmal1) or dampened/inverted its phase (Per2). There was very little effect of CORT condition on clock gene expression in the SCN. These experiments suggest that an important component of glucocorticoid circadian physiology entails CORT regulation of the molecular clock in the PFC. Consequently, they also point to a possible mechanism that contributes to PFC disrupted function in disorders associated with abnormal CORT circulation.

scholarly journals Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism

2007 ◽  
Vol 293 (1) ◽  
pp. E165-E171 ◽  
Author(s):  
Christopher D. Morrison ◽  
Xiaochun Xi ◽  
Christy L. White ◽  
Jianping Ye ◽  
Roy J. Martin
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Food Intake ◽  
Mtor Signaling ◽  
Acid Mixture ◽  
Mrna Levels ◽  
Amino Acid Availability ◽  
The Brain ◽  
Amino Acid Concentrations

Metabolic fuels act on hypothalamic neurons to regulate feeding behavior and energy homeostasis, but the signaling mechanisms mediating these effects are not fully clear. Rats placed on a low-protein diet (10% of calories) exhibited increased food intake ( P < 0.05) and hypothalamic Agouti-related protein ( Agrp) gene expression ( P = 0.002). Direct intracerebroventricular injection of either an amino acid mixture (RPMI 1640) or leucine alone (1 μg) suppressed 24-h food intake ( P < 0.05), indicating that increasing amino acid concentrations within the brain is sufficient to suppress food intake. To define a cellular mechanism for these direct effects, GT1–7 hypothalamic cells were exposed to low amino acids for 16 h. Decreasing amino acid availability increased Agrp mRNA levels in GT1–7 cells ( P < 0.01), and this effect was attenuated by replacement of the amino acid leucine ( P < 0.05). Acute exposure to elevated amino acid concentrations increased ribosomal protein S6 kinase phosphorylation via a rapamycin-sensitive mechanism, suggesting that amino acids directly stimulated mammalian target of rapamycin (mTOR) signaling. To test whether mTOR signaling contributes to amino acid inhibition of Agrp gene expression, GT1–7 cells cultured in either low or high amino acids for 16 h and were also treated with rapamcyin (50 nM). Rapamycin treatment increased Agrp mRNA levels in cells exposed to high amino acids ( P = 0.01). Taken together, these observations indicate that amino acids can act within the brain to inhibit food intake and that a direct, mTOR-dependent inhibition of Agrp gene expression may contribute to this effect.

scholarly journals Maternal Perinatal Undernutrition Drastically Reduces Postnatal Leptin Surge and Affects the Development of Arcuate Nucleus Proopiomelanocortin Neurons in Neonatal Male Rat Pups

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 470-475 ◽  
Author(s):  
Fabien Delahaye ◽  
Christophe Breton ◽  
Pierre-Yves Risold ◽  
Mihaela Enache ◽  
Isabelle Dutriez-Casteloot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasma Levels ◽  
Metabolic Disorders ◽  
Arcuate Nucleus ◽  
Nerve Fibers ◽  
Male Rats ◽  
Male Rat ◽  
Maternal Undernutrition ◽  
Rat Pups ◽  
Plasma Leptin

A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 ± 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 ± 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive β-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation.

scholarly journals Marginal zinc deficiency in rats decreases leptin expression independently of food intake and corticotrophin-releasing hormone in relation to food intake

2007 ◽  
Vol 98 (3) ◽  
pp. 485-489 ◽  
Author(s):  
In-Sook Kwun ◽  
Young-Eun Cho ◽  
Ria-Ann R. Lomeda ◽  
Soon-Tae Kwon ◽  
Yangha Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Rate ◽  
Food Intake ◽  
Mononuclear Cells ◽  
Zn Deficiency ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Releasing Hormone ◽  
Sprague Dawley Rats ◽  
Marginal Zinc Deficiency

Zn deficiency reduces food intake and growth rate in rodents. To determine the relationship between Zn deficiency and the regulation of food intake, we evaluated leptin gene expression in epididymal white adipose tissue (eWAT), and hypothalamic corticotropin-releasing hormone (hCRH) and hypothalamic neuropeptide Y (hNPY) of rats Zn-deficient only to show reduced food intake and growth rate but not food intake cycling. Growing male Sprague-Dawley rats (240 g) were randomly assigned to one of four dietary groups: Zn-adequate (ZA; 30 mg/kg diet), Zn-deficient (ZD; 3 mg/kg diet), pair-fed with ZD (PF; 30 mg/kg diet) and Zn-sufficient (ZS; 50 mg/kg diet) (n 8), and were fed for 3 weeks. Food intake and body weight were measured, as were blood mononuclear cells and pancreas Zn levels. eWAT leptin, hCRH and hNPY mRNA levels were determined. Food intake was decreased by about 10 % in ZD and PF rats compared to ZA and ZS rats. Growth and eWAT leptin mRNA levels were unaffected in PF rats but were significantly (P < 0·05) decreased in ZD rats. However, hNPY showed a tendency to increase, and hCRH significantly (P < 0·05) decreased, in both ZD and PF rats. These results suggest that while leptin gene expression may be directly affected by Zn, hNPY and hCRH are likely responding to reduced food intake caused by Zn deficiency.

scholarly journals Photoperiod effects on gene expression for hypothalamic appetite-regulating peptides and food intake in the ram

2003 ◽  
Vol 284 (1) ◽  
pp. R101-R115 ◽  
Author(s):  
Iain J. Clarke ◽  
Alexandra Rao ◽  
Yves Chilliard ◽  
Carole Delavaud ◽  
Gerald A. Lincoln
Keyword(s):  
Gene Expression ◽  
Energy Balance ◽  
Food Intake ◽  
Leptin Receptor ◽  
Negative Energy ◽  
Positive Energy ◽  
Mrna Levels ◽  
Expression Of Genes ◽  
Positive Energy Balance ◽  
Plasma Leptin

Relationship between voluntary food intake (VFI) and gene expression for appetite-regulating peptides was examined in the brains of Soay rams under contrasting photoperiods. Two groups ( n = 8) were subjected to alternating block long-day (LD) and short-day photoperiods (SD) over a period of 42 wk to entrain long-term cycles in VFI. Five animals from each group were killed 18 wk into LD or SD, and the brains were collected for in situ hybridization studies. VFI was fourfold higher under LD compared with SD. Body weight, abdominal fat, or plasma leptin levels were similar under LD and SD. LD animals were in positive energy balance and sexually inactive, and SD animals were in negative energy balance and sexually active. Neuropeptide Y (NPY) mRNA levels were higher in the arcuate nucleus (ARC) under LD, and pro-opiomelanocortin expression was lower under LD. Leptin receptor (Ob-Rb) was higher in the ARC under LD. We conclude that photoperiod-induced increase in VFI correlates with expression of NPY, but not with expression of genes for other putative orexigenic peptides. Ob-Rb gene expression is regulated by photoperiod.

beta 3-Adrenergic-mediated suppression of leptin gene expression in rats

1997 ◽  
Vol 272 (6) ◽  
pp. E1031-E1036 ◽  
Author(s):  
H. Li ◽  
M. Matheny ◽  
P. J. Scarpace
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Food Intake ◽  
Uncoupling Protein ◽  
Mrna Levels ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose ◽  
Cgp 12177 ◽  
Rat Strain

To investigate the role of beta 3-adrenergic receptors in the suppression of leptin gene expression, we fasted F-344 rats to decrease leptin mRNA levels, refed the rats to stimulate leptin mRNA production, and examined the ability of the beta 3-adrenergic agonist CGP-12177 to prevent the rise in leptin mRNA levels. In the initial 2 h after CGP-12177 (0.75 mg/kg), there were significant reductions in both food consumption and leptin mRNA levels in epididymal, perirenal, and interscapular white adipose tissue. We were unable to detect leptin mRNA in interscapular brown adipose tissue (IBAT), whereas there was a significant increase in uncoupling protein mRNA levels in IBAT after CGP-12177. The suppression of leptin mRNA and food intake by CGP-12177 was confirmed in a second experiment using another rat strain, the F-344 x BN. Furthermore, refeeding after a period of fasting increased leptin mRNA, which was prevented by CGP-12177. These data indicate a role for beta 3-adrenergic-mediated regulation of leptin gene expression in nonmutant rodents and are consistent with other reports suggesting that beta 3-adrenergic agonists suppress food intake.

Gonadotrophin-releasing hormone regulation of gonadotrophin subunit gene expression: studies in tri-iodothyronine-suppressed rats

1989 ◽  
Vol 122 (1) ◽  
pp. 117-125 ◽  
Author(s):  
D. J. Haisenleder ◽  
G. A. Ortolano ◽  
A. C. Dalkin ◽  
S. J. Paul ◽  
W. W. Chin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blot Hybridization ◽  
Male Rats ◽  
Male Rat ◽  
Mrna Levels ◽  
Dot Blot ◽  
Α Subunit ◽  
Releasing Hormone ◽  
Gonadotrophin Releasing Hormone ◽  
Prolactin Mrna

ABSTRACT We have previously shown that a pulsatile gonadotrophin-releasing hormone (GnRH) stimulus can increase steady-state levels of α and LH-β subunit mRNAs in the male rat pituitary. Since α subunit is produced in both thyrotroph and gonadotroph cells, the effect of GnRH specifically on gonadotroph α gene expression is uncertain. To address this tissue, adult male rats were given injections of tri-iodothyronine (T3; 20 μg/100 g body wt, i.p.) daily for 8 days (day 8 = day of death) in order to decrease thyrotroph α mRNA levels (+ T3 group). Saline injections (i.p.) were given to control animals (− T3 group). Three days before GnRH administration, the animals were castrated and testosterone implants inserted s.c., to inhibit endogenous GnRH secretion. GnRH pulses (25 ng/pulse; 30-min interval) were given to freely moving animals (saline pulses to controls) via an atrial cannula for 12, 24 or 48 h. Serum LH and FSH were measured before and 20 min after the last GnRH pulse. Pituitary RNA was extracted and α, LH-β, FSH-β and prolactin mRNA levels were determined by dot-blot hybridization using 32P-labelled cDNA probes. Castration and testosterone replacement reduced α and LH-β mRNA levels by 30 and 40% respectively, compared with levels in untreated intact males, but did not decrease FSH-β concentrations. T3 administration further decreased α mRNA to 30% of values seen in intact males, but LH-β mRNA levels were unchanged. FSH-β mRNA concentrations were decreased by 23% in T3-treated rats (P < 0·05 vs intact controls). In −T3 rats, 12 h of GnRH pulses increased FSH-β mRNA levels (twofold) vs saline-pulsed controls, but significant increases in α or LH-β mRNA levels were not seen until after 24 h of GnRH pulses. In the +T3 group, an increase in α mRNA was observed earlier, after 12 h of GnRH pulses. After 24 and 48 h of GnRH, the increments in α and LH-β were of similar magnitude in both the +T3 and − T3 groups (4–5 and 3–4 fold increases in α and LH-β respectively; P < 0·05 vs saline-pulsed controls). In contrast, the stimulatory effect of GnRH on FSH-β mRNA was lost in + T3 animals after 48 h of pulses. In order to examine whether this loss in FSH-β mRNA responsiveness to GnRH was related to an inhibitory interaction of T3 in the presence of testosterone, a second study was conducted in castrated animals. The results showed that α mRNA levels were decreased by 33% in +T3 compared with −T3 castrated animals (P < 0·05), but LH-β and FSH-β mRNAs were unaffected by T3 administration. In castrated animals given GnRH pulses, T3 inhibited subunit mRNA responses and this effect was most marked for FSH-β mRNA. In contrast, prolactin mRNA levels were significantly higher (P < 0·05) in all +T3 experimental groups compared with their −T3 controls. These data indicate that T3 can inhibit FSH-β mRNA responses to pulsatile GnRH and that this action occurs in the absence of testosterone. Journal of Endocrinology (1989) 122, 117–125

Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet

2011 ◽  
Vol 301 (3) ◽  
pp. E548-E559 ◽  
Author(s):  
Marie-Amélie Lukaszewski ◽  
Sylvain Mayeur ◽  
Isabelle Fajardy ◽  
Fabien Delahaye ◽  
Isabelle Dutriez-Casteloot ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
The Body ◽  
Male Rat ◽  
Adult Offspring ◽  
High Fat ◽  
Maternal Undernutrition ◽  
The Metabolic Syndrome ◽  
Leptin Sensitivity

Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11β-HSD1, 11β-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11β-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition.

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