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1.
Endocrinology ; 157(8): 3242-52, 2016 08.
Article in English | MEDLINE | ID: mdl-27254004

ABSTRACT

Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα(-/-)). Female POMC-ERα(-/-) and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 µg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα(-/-) mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.


Subject(s)
Bone Density/drug effects , Cortical Bone/drug effects , Estrogen Receptor alpha/genetics , Estrogens/pharmacology , Hypothalamus/drug effects , Neurons/drug effects , Pro-Opiomelanocortin/metabolism , Animals , Arcuate Nucleus of Hypothalamus/drug effects , Arcuate Nucleus of Hypothalamus/metabolism , Cortical Bone/metabolism , Female , Hypothalamus/metabolism , Mice , Mice, Knockout , Neurons/metabolism , Pro-Opiomelanocortin/genetics
2.
J Neuroendocrinol ; 25(6): 580-9, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23414303

ABSTRACT

Interleukin (IL)-1 and IL-6 are immune modulating cytokines that also affect metabolic function because both IL-1 receptor I deficient (IL-1RI⁻/⁻) and IL-6 deficient (IL-6⁻/⁻) mice develop late-onset obesity and leptin resistance. Both IL-1 and IL-6 appear to target the central nervous system (CNS) to increase energy expenditure. The hypothalamic arcuate nucleus (ARC) is a major relay between the periphery and CNS in body fat regulation (e.g. by being a target of leptin). The present study aimed to investigate the possible mechanisms responsible for the effects exerted by endogenous IL-1 and IL-6 on body fat at the level of the ARC, as well as possible interactions between IL-1 and IL-6. Therefore, we measured the gene expression of neuropeptides of the ARC involved in energy balance in IL-1RI⁻/⁻ and IL-6⁻/⁻ mice. We also investigated the interactions between expression of IL-1 and IL-6 in these mice, and mapped IL-6 receptor α (IL-6Rα) in the ARC. The expression of the obesity promoting peptide neuropeptide Y (NPY), found in the ARC, was increased in IL-1RI⁻/⁻ mice. The expression of NPY and agouti-related peptide (AgRP), known to be co-expressed with NPY in ARC neurones, was increased in cold exposed IL-6⁻/⁻ mice. IL-6Rα immunoreactivity was densely localised in the ARC, especially in the medial part, and was partly found in NPY positive cell bodies and also α-melanocyte-stimulating hormone positive cell bodies. The expression of hypothalamic IL-6 was decreased in IL-1RI⁻/⁻ mice, whereas IL-1ß expression was increased in IL-6⁻/⁻ mice. The results of the present study indicate that depletion of the activity of the fat suppressing cytokines IL-1 and IL-6 in knockout mice can increase the expression of the obesity promoting neuropeptide NPY in the ARC. Depletion of IL-1 activity suppresses IL-6 expression, and IL-6Rα-like immunoreactivity is present in neurones in the medial ARC, including neurones containing NPY. Therefore, IL-6, IL-1 and NPY/AgRP could interact at the level of the hypothalamic ARC in the regulation of body fat.


Subject(s)
Adipose Tissue/physiology , Arcuate Nucleus of Hypothalamus/physiology , Body Composition , Interleukin-1/physiology , Interleukin-6/physiology , Animals , Base Sequence , DNA Primers , Hypothalamus/metabolism , Hypothalamus/physiology , Interleukin-1/genetics , Interleukin-1/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuropeptide Y/metabolism , Real-Time Polymerase Chain Reaction , Receptors, Interleukin-1/genetics , Receptors, Interleukin-1/metabolism , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/metabolism
3.
Neuroscience ; 180: 201-11, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21303683

ABSTRACT

The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 µg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin-treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro-anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects.


Subject(s)
Behavior, Animal/physiology , Brain/physiology , Emotions/physiology , Gene Expression/physiology , Ghrelin/metabolism , Animals , Behavior, Animal/drug effects , Brain/drug effects , Electrophysiology , Emotions/drug effects , Gene Expression/drug effects , Ghrelin/administration & dosage , Injections, Intraventricular , Male , Maze Learning/physiology , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction
4.
Neuroscience ; 171(4): 1180-6, 2010 Dec 29.
Article in English | MEDLINE | ID: mdl-20933579

ABSTRACT

Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food.


Subject(s)
Eating/drug effects , Ghrelin/pharmacology , Receptors, Nicotinic/physiology , Signal Transduction/physiology , Ventral Tegmental Area/drug effects , Analysis of Variance , Animals , Choline O-Acetyltransferase/metabolism , Conditioning, Operant/drug effects , Drug Administration Routes , Drug Interactions , Eating/physiology , Fasting/physiology , Food Preferences/drug effects , Food Preferences/physiology , Hexamethonium/pharmacology , Male , Mecamylamine/pharmacology , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Nicotinic Antagonists/pharmacology , Nucleus Accumbens/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Ghrelin/deficiency , Receptors, Nicotinic/drug effects , Signal Transduction/drug effects , Ventral Tegmental Area/cytology
5.
J Neuroendocrinol ; 21(9): 777-85, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19703102

ABSTRACT

In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.


Subject(s)
Central Nervous System/drug effects , Ghrelin/pharmacology , Hormone Antagonists/pharmacology , Obesity/chemically induced , Receptors, Ghrelin/antagonists & inhibitors , Animals , Body Composition/drug effects , Body Weight/drug effects , Central Nervous System/metabolism , Central Nervous System/physiology , Eating/drug effects , Gene Expression/drug effects , Ghrelin/administration & dosage , Ghrelin/adverse effects , Ghrelin/antagonists & inhibitors , Hormones/blood , Hypothalamus/drug effects , Hypothalamus/metabolism , Injections, Intraventricular , Male , Obesity/blood , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects
6.
Am J Physiol Endocrinol Metab ; 292(5): E1418-25, 2007 May.
Article in English | MEDLINE | ID: mdl-17244725

ABSTRACT

To study the role of the growth hormone receptor (GHR) in the development of cardiovascular structure and function, female GHR gene-disrupted or knockout (KO) and wild-type (WT) mice at age 18 wk were used. GHR KO mice had lower plasma renin levels (12 +/- 2 vs. 20 +/- 4 mGU/ml, P < 0.05) and increased aortic endothelial NO synthase (eNOS) expression (146%, P < 0.05) accompanied by a 25% reduction in systolic blood pressure (BP, 110 +/- 4 vs. 147 +/- 3 mmHg, P < 0.001) compared with WT mice. Aldosterone levels were unchanged, whereas the plasma potassium concentration was elevated by 14% (P < 0.05) in GHR KO. Relative left ventricular weight was 14% lower in GHR KO mice (P < 0.05), and cardiac dimensions as analyzed by echocardiography were similarly reduced. Myograph studies revealed a reduced maximum contractile response in the aorta to norepinephrine (NE) and K(+) (P < 0.05), and aorta media thickness was decreased in GHR KO (P < 0.05). However, contractile force was normal in mesenteric arteries, whereas sensitivity to NE was increased (P < 0.05). Maximal acetylcholine-mediated dilatation was similar in WT and GHR KO mice, whereas the aorta of GHR KO mice showed an increased sensitivity to acetylcholine (P < 0.05). In conclusion, loss of GHR leads to low BP and decreased levels of renin in plasma as well as increase in aortic eNOS expression. Furthermore, GHR deficiency causes functional and morphological changes in both heart and vasculature that are beyond the observed alterations in body size. These data suggest an important role for an intact GH/IGF-I axis in the maintenance of a normal cardiovascular system.


Subject(s)
Blood Pressure/physiology , Cardiovascular System/metabolism , Nitric Oxide Synthase Type II/biosynthesis , Receptors, Somatotropin/deficiency , Renin/blood , Aldosterone/blood , Animals , Aorta, Thoracic/enzymology , Aorta, Thoracic/metabolism , Cardiovascular Physiological Phenomena , Echocardiography, Doppler , Electrocardiography , Female , Heart/anatomy & histology , Mice , Mice, Inbred BALB C , Mice, Knockout , Muscle Contraction/physiology , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type III , Organ Size , Potassium/blood , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction
7.
Gut ; 54(7): 907-13, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15849166

ABSTRACT

BACKGROUND AND AIMS: The gastric hormone ghrelin has been reported to stimulate food intake, increase weight gain, and cause obesity but its precise physiological role remains unclear. We investigated the long term effects of gastrectomy evoked ghrelin deficiency and of daily ghrelin injections on daily food intake, body weight, fat mass, lean body mass, and bone mass in mice. METHODS: Ghrelin was given by subcutaneous injections (12 nmol/mouse once daily) for eight weeks to young female mice subjected to gastrectomy or sham operation one week previously. RESULTS: Gastrectomy reduced plasma concentrations of total ghrelin (octanoylated and des-octanoylated) and active (octanoylated) ghrelin by approximately 80%. Immediately after injection of ghrelin, the plasma concentration was supraphysiological and was still elevated 16 hours later. Daily food intake was not affected by either gastrectomy or ghrelin treatment. The effect of ghrelin on meal initiation was not studied. At the end point of the study, mean body weight was 15% lower in gastrectomised mice than in sham operated mice (p<0.001); daily ghrelin injections for eight weeks partially prevented this weight loss. In sham operated mice, ghrelin had no effect on body weight. The weight of fat was reduced in gastrectomised mice (-30%; p<0.01). This effect was reversed by ghrelin, enhancing the weight of fat in sham operated mice also (+20%; p<0.05). Gastrectomy reduced lean body mass (-10%; p<0.01) and bone mass (-20%; p<0.001) compared with sham operated mice. Ghrelin replacement prevented the gastrectomy induced decrease in lean body mass but did not affect bone. In sham operated mice, ghrelin affected neither of these two parameters. CONCLUSIONS: Ghrelin replacement partially reversed the gastrectomy induced reduction in body weight, lean body mass, and body fat but not in bone mass. In sham operated mice, ghrelin only increased fat mass. Our results suggest that ghrelin is mainly concerned with the control of fat metabolism and that ghrelin replacement therapy may alleviate the weight loss associated with gastrectomy.


Subject(s)
Adipose Tissue/drug effects , Gastrectomy , Peptide Hormones/pharmacology , Weight Gain/drug effects , Adipose Tissue/pathology , Animals , Body Composition/drug effects , Bone Density/drug effects , Eating/drug effects , Female , Femur/pathology , Ghrelin , Mice , Peptide Hormones/blood , Peptide Hormones/deficiency , Postoperative Period
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