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Laval Hospital Research Center and Merck-Frosst/IRSC Obesity Research Chair, 2725 chemin Sainte-Foy, Québec, Canada G1V 4G5
(Requests for offprints should be addressed to D Richard; Email: denis.richard{at}crhl.ulaval.ca)
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Abstract |
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Introduction |
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The central effects of CRF are mediated through two distinct high-affinity membrane receptors, which are referred to as CRF types 1 (CRF1R; Perrin et al. 1993) and 2 (CRF2R; Lovenberg et al. 1995) receptors. The CRF1R is widely distributed throughout the brain and the anterior and intermediate lobes of the pituitary. Within the PVN, CRF1R mRNA is barely detectable under basal conditions, but can be readily induced by stressful stimuli (Rivest et al. 1995). The CRF1R has been suggested to mediate the corticotropic effects of CRF and assure basal and stress-induced HPA axis activity (Desouza et al. 1991). The expression of the CRF2R is restricted to the particular limbic regions and the ventromedial hypothalamic nucleus (VMH). The VMH is thought to mediate the anorectic effects of CRF through the CRF2R (Vaughan et al. 1995), and lesions of VMH increase food intake and lead to obesity (Egawa et al. 1993, Dube et al. 1999). The expression of the CRF2R in the VMH is significantly lower in genetically obese rats than in lean rats (Richard et al. 1996, Timofeeva & Richard 1997). There is evidence that the central effects of leptin may be mediated at least partially through the VMH, where the leptin receptors are expressed (Elmquist et al. 1998a,b, Nishiyama et al. 1999).
The adipocyte-derived hormone leptin circulates in the blood in proportion to body adiposity (Zhang et al. 1994, Campfield et al. 1995) and has a marked potential in reducing energy deposition by decreasing food intake and increasing energy expenditure (Halaas et al. 1995, Pelleymounter et al. 1995, Levin et al. 1996, Huang et al. 1998). Leptin may affect the HPA axis at different levels. Plasma leptin is inversely correlated with diurnal variations in glucocorticoid levels (Korbonits et al. 1997, Licinio et al. 1997). Leptin administration inhibits adrenal glucocorticoid synthesis and release (Bornstein et al. 1997, Kruse et al. 1998), and may reduce the ACTH stress-induced secretion (Trottier et al. 1998, Oates et al. 2000, Wilson et al. 2005). The effects of leptin on the synthesis and secretion of CRF from the PVN remain largely controversial. In vitro studies have demonstrated a stimulatory (Costa et al. 1997, Raber et al. 1997) as well as an inhibitory (Heiman et al. 1997) effect of leptin on CRF release. Acute administration of leptin may induce the expression of c-fos (Van Dijk et al. 1996, Elmquist et al. 1997, 1998a, Badoer & Ryan 1999, Elias et al. 2000) and increases the CRF mRNA levels (Nishiyama et al. 1999) in the PVN. However, chronic administration of leptin reduces ACTH and glucocorticoids secretion and inhibits stress-induced Fos expression in the PVN neurons (Huang et al. 1998, Oates et al. 2000).
The present study was designed to investigate the long-term effects of chronically elevated central leptin levels on the expression of the primary CRF transcript and CRF types 1 and 2 receptors in the brain of rats stressed by treadmill running. The results of this study suggest that daily leptin infusion inhibits stress-induced activation of PVN CRFergic neurons by blunting de novo CRF synthesis as well as the induction of CRF1R. In addition, the present results confirm the ability of centrally infused leptin to increase the expression of VMH CRF2R, which could potentially enhance the anorectic effects of CRF.
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Materials and Methods |
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Thirty-two adult male Wistar rats were purchased from the Canadian Breeding Laboratories (St Constant, Quebec, Canada). All rats were cared for and handled according to the Canadian Guide for the Care and Use of Laboratory Animals and the present protocol was approved by our institutional animal care committee. The rats were individually housed in wire-bottom cages that were suspended above absorbent paper, and a stock diet was available ad libitum (Charles River Rodent Animal Diet, distributed by Ralston Products, Woodstock, Ontario, Canada). They were subjected to a 12 h light:12 h darkness cycle (light on 0645 h) and kept under an ambient temperature of 23 ± 1 °C.
On the tenth day after arrival, all rats were subjected to brain surgery to implant a guide cannula into the third ventricle. Rats were first anesthetized intraperitoneally with 1.5 ml mixture containing 20 mg/ml ketamine and 2.5 mg/ml xylazine and placed in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA, USA). Then, a 22 gauge guide cannula was aimed at the third ventricle using the following stereotaxic coordinates: 2.3 mm posterior to bregma at the midline and 8.4 mm ventral to the brain surface (Paxinos & Watson 1997). The guide cannula was secured with screws and dental cement (Dentsply International, York, PA, USA) and was directly connected to the Alzet osmotic minipump (Model 2001; ALZA Pharmaceuticals, Palo Alto, CA, USA; 1.0 µl/h), which contained PBS (pH 7.4) or recombinant murine leptin (2 µg/day per rat; high purity, endotoxin level < 0.1 ng/µg; US Biological, Swampscott, MA, USA). PBS or leptin was continuously infused into the third ventricle for 5 days. Thereafter, the rats were killed either (i) at rest (PBS-resting; leptin-resting), (ii) immediately following a treadmill running session lasting 60 min (PBS-running; leptin-running), or (iii) at rest following a recovery period of 120 min after 60-min running (PBS-post-running; leptin-post-running). The running session took place between 0730 and 0910 h. During running, the speed of the motor-driven treadmill was raised from 10 to 25 m/min by increase of 5 m/min every 15 min. The rats were forced to run continuously for 60 min. Each experimental group included five to six rats.
Body weight, food intake, and tissue weight
Measurements of body weight and food intake were performed every morning between 0700 and 0800 h. Rats weighed between 270 and 290 g at the time of surgery. Epididymal white adipose tissue (eWAT) was quickly dissected out during intracardial perfusion with saline.
Plasma determinations
An intracardial blood sample was taken from anesthetized rats immediately before the intracardial perfusion. Serum corticosterone was determined by a competitive protein-binding assay (sensitivity 0.058 nmol/l; inter-assay coefficient of variation 9.0%) using plasma from a dexamethasone-treated female rhesus monkey as the source of transcortin (Murphy 1967).
Brain preparation
Rats were anesthetized with 1.5 ml mixture containing 20 mg/ml ketamine and 2.5 mg/ml xylazine. Without delay, they were intracardially perfused with 50 ml ice-cold isotonic saline followed by 500 ml paraformaldehyde (4%) solution. Brains were removed and kept in paraformaldehyde for an additional period of 7 days. They were then transferred overnight to a solution containing paraformaldehyde and sucrose (10%) and sliced using a sliding microtome (Histoslide 2000, Reichert-Jung, Heidelberger, Germany). Brain sections were taken from the olfactory bulb to the brain stem. Thirty micrometer thick sections of brains were collected and stored at –30 °C in a cold cryoprotecting solution containing sodium phosphate buffer (50 mM), ethylene glycol (30%), and glycerol (20%).
In situ hybridization histochemistry
In situ hybridization histochemistry was used to localize CRF heteronuclear (hn) RNA, CRF1R mRNA, and CRF2R mRNA on the brain sections taken from the entire brain. The protocol used was largely adapted from the technique described by Simmons et al.(1989). Briefly, one out of every five brain sections were mounted onto poly-L-lysine coated slides. The sections were then successively fixed in paraformaldehyde (4%), digested with proteinase K (10 µg/ml in 100 mM Tris–HCl containing 50 mM EDTA (pH 8.0)), acetylated with acetic anhydride (0.25% in 0.1 M triethanolamine (pH 8.0)), and dehydrated through graded concentrations (50, 70, 95, and 100%) of alcohol. Thereafter, 90 µl hybridization mixture, which contains an antisense 35S-labeled cRNA probe (107 c.p.m./ml), were spotted on each slide. The slides were sealed with the coverslips and incubated overnight at 58 °C in a slide warmer. The next day, the coverslips were removed and the slides were rinsed four times with SSC (0.6 M NaCl, 60 mM trisodium citrate buffer (pH 7.0)), digested with RNAse A (20 µg/ml in 10 mM Tris–500 mM NaCl containing 1 mM EDTA), washed in descending concentrations of SSC (2x, 10 min; 1x, 5 min; 0.5x, 5 min; 0.1x, 30 min at 60 °C) and dehydrated through graded concentrations of alcohol. Slides were exposed to an X-ray film (Kodak). Once removed from the autoradiography cassettes, the slides were defatted in xylene, dipped in NTB2 nuclear emulsion (Eastman Kodak), and exposed from 7 to 21 days, before being developed in D 19 developer and fixed in rapid fixer (Kodak). Finally, tissues were rinsed in distilled water and counterstained with thionin (0.25%).
Antisense 35S-labeled cRNA probes
The hn CRF cRNA probe was generated from 530 bp fragment of the CRF intron 1 (Dr S Watson, University of Michigan, Ann Arbor, MI, USA) subcloned into pGem-3 plasmid (Stratagene, La Jolla, CA, USA), and linearized with HindIII and EcoRI (Pharmacia Biotech, Inc.) for antisense and sense probes respectively. The CRF1R cRNA was generated from a 1.3 kb PstI fragment of the rat CRF1R cDNA (Dr W Vale, Peptide Biology Laboratory, The Salk Institute, La Jolla, CA, USA) subcloned into pBluescript-SKII plasmid (Stratagene), and linearized with BamHI and EcoRI (Pharmacia Biotech, Inc.) for antisense and sense probes respectively. The rat CRF2R cRNA probe was prepared from a 275 bp fragment of the 5'-region cDNA of the CRF2
receptor (Dr T W Lovenberg, Neurocrine Biosciences, Inc., San Diego, CA, USA) subcloned into a pBluescript SK+ vector (Stratagene), and linearized with EcoRI and RamHI for antisense and sense probes respectively. The radioactive riboprobes were synthesized, extracted, and precipitated as described elsewhere (Timofeeva et al. 2003, 2005). The specificity of each probe was confirmed by the absence of positive signal in sections hybridized with sense probe.
Quantitative analysis of the hybridization signals
The hybridization signals revealed on NTB2 dipped nuclear emulsion slides were analyzed and quantified under a light microscope (Olympus, BX50) equipped with a black and white video camera (Sony, XC-77) coupled to a Macintosh computer (Power PC 7100/66) using Image software (version 1.55 non-FPU; Wayne Rasband, NIH, Bethesda, MD, USA). The optical density (OD) of the hybridization signal was measured under dark field illumination. Brain sections were matched for rostrocaudal levels as closely as possible according to the atlas of the rat brain (Paxinos & Watson 1997). The OD for each specific region was corrected for the average background signal, which was determined by sampling an unlabeled area outside the areas of interest. When no hybridization signal was visible under dark field illumination, the brain structures of interest were outlined under bright field illumination and then subjected to densitometric analysis under dark field illumination. Saturation of the hybridization signal was avoided by the creation of the calibration density profile plot for the strongest hybridization signals sampled for each region in every series. The luminosity of the system was then corrected, so that for the strongest hybridization signals, the reading OD did not exceed the half of the pixel value maximum, and this luminosity was conserved throughout the analysis of the entire series. The mean of OD for individual animals was used to determine the mean ± S.E.M. for each group.
Statistical analysis
A 2x3 ANOVA was used to examine the main and interaction effects of infusion (I; PBS, leptin) and activity (A; resting, running, and post-running) on the various dependent variables measured in this study. In the cases of significant IxA interactions, a posteriori comparisons were performed using the Bonferroni–Dunn multiple comparison procedure.
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Results |
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Figure 1
and Table 1 demonstrate the effects of an intracerebroventricular infusion of leptin on body weight, food intake, and weight of eWAT. Infusion of leptin led to a substantial decrease in food intake and body weight. The effect of leptin on food intake and body weight was already significant on the first or the second day of infusion. Cumulative food intake measured upon five consecutive days of infusion was two times higher in PBS-treated rats than in leptin-infused animals (Table 1). The weight of the eWAT was also affected by leptin. Five days of leptin infusion produced a twofold reduction in eWAT weight compared with PBS-treated animals (Table 1). Acute treadmill running did not noticeably affect body weight or eWAT weight.
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Table 1
presents the plasma levels of glucose, insulin, and corticosterone in PBS- and leptin-infused rats in resting, running, or post-running conditions. Plasma glucose and insulin levels were significantly lower in leptin-treated rats compared with PBS controls. Plasma corticosterone levels were not apparently different between resting leptin- and PBS-treated rats and noticeably increased in running rats in both the PBS- and leptin-infused animals. It is noteworthy that the increase in plasma corticosterone levels induced by running was apparently blunted by leptin infusion; increases in corticosterone response to running were 22.9 vs 14.5 times above basal levels in PBS and leptin rats respectively.
Expression of the CRF hnRNA in the PVN
The effects of leptin treatment and running stress on the expression of the CRF gene were evaluated by measuring the expression of CRF hnRNA using an intronic probe complementary to the intron 1 of the rat CRF gene. Intronic probe allows the rapid detection of the primary transcript of CRF (Rivest et al. 1995, Lacroix et al. 1996). The expression of CRF hnRNA increased during treadmill running in PBS, but not in leptin-treated rats (Figs 2 and 3). The levels of hnCRF transcript in PBS-treated rats returned to the basal values 2 h after running (Figs 2 and 3).
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The CRF1R transcript was barely detectable in resting rats in both the PVN and SON. However, CRF1R mRNA was significantly induced in these structures in PBS-treated rats after treadmill running. The increase in the CRF1R mRNA expression in both the PVN and SON in PBS-infused animals was not observed immediately after running, but during the post-running period, as shown on the histogram illustrating the ODs of the hybridization signal of the CRF1R mRNA in both structures (Fig. 4), and on the photomicrographs taken at the level of the PVN (Fig. 5) and SON (Fig. 6). The chronic leptin infusion significantly blunted the induction of expression of the CRF1R mRNA during the post-running period in the PVN and SON (Figs 4–6). In both structures, the increase in CRF1R mRNA expression after running was significantly low in leptin-infused rats compared with PBS-treated animals.
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The levels of expression of the CRF2R mRNA in the VMH were significantly higher in leptin-infused rats compared with the PBS-treated animals. The analysis of the ODs of the hybridization signal of CRF2R mRNA is shown in Fig. 7. The photomicrographs in Fig. 8 depict the positive signal for CRF2R transcript in the VMH of resting rats infused with PBS or leptin. Resting, running, and post-running leptin-infused rats demonstrated higher levels of CRF2R mRNA than PBS-treated animals, but within the leptin- or PBS-treated groups, the expression of CRF2R mRNA did not change during or after a session of treadmill running (Fig. 7).
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Discussion |
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Although, daily intracerebroventricular leptin infusion did not affect plasma levels of corticosterone in resting animals, it considerably blunted running-induced hypercorticosteronemia. This finding is consonant with previous results that demonstrated the ability of leptin to reduce the HPA axis activity in response to stress through actions exerted on the various components of the pituitary–adrenal system. Leptin has been reported to inhibit both the synthesis and release of adrenal glucocorticoids (Bornstein et al. 1997, Kruse et al. 1998), and reduce the magnitude and duration of stress-induced ACTH secretion (Trottier et al. 1998, Oates et al. 2000). In addition, it has been demonstrated that leptin may prevent the response of the pituitary–adrenal axis to insulin administration in rat (Giovambattista et al. 2000) and attenuate the elevation in plasma cortisol and ACTH following an unpredictable stress in rhesus monkeys (Wilson et al. 2005).
The present results also suggest that leptin may reduce the hypothalamic drive exerted by the hypophysiotropic CRF neurons on the HPA axis. Leptin infusion suppressed the expression of CRF in the PVN neurons during stress. In fact, while treadmill-induced expression of CRF hnRNA was readily detected in the parvocellular PVN of PBS control rats, it was barely apparent in rats chronically infused with leptin. The use of the intronic probe allows for the detection of the CRF primary transcript, whose brain constitutive expression is low but rapidly increases in the PVN in response to stressful conditions (Rivest et al. 1995, Lacroix et al. 1996). Whether the leptin effect on stress-induced activation of the CRF gene is due to a direct leptin action on the PVN neurons or involves the inhibition of larger assemblies of stress-related circuits has yet to be untangled. Leptin might directly affect the CRF-producing parvocellular PVN neurons as these cells moderately express the leptin receptor (Elmquist et al. 1998b). Leptin could increase the inhibitory tone on the hypo-thalamic neurons (Jo et al. 2005).
The PVN induction of CRF hnRNA after treadmill running was accompanied by the induction of the CRF1R gene, which was not only seen in the PVN but also in the SON. Several lines of evidence emerging from studies using CRF1R transgenic/knockout mice, CRF1R antisense oligonucleotide, and CRF1R agonists/antagonists have suggested that CRF1R mediates the endocrine, autonomic, and behavioral effects of CRF during stress (for review, see Behan et al. 1996, Takahashi 2001, Bale & Vale 2004). In resting conditions, the CRF1R transcript is barely detectable in the PVN, but it is readily induced by stress (Rivest et al. 1995). The induction of CRF1R in the PVN has indeed been shown in several stress paradigms (Desouza et al. 1991, Rivest et al. 1995, Timofeeva & Richard 1997, Timofeeva et al. 2003, Wang et al. 2004) and has to be seen as a valid marker of stress. The present study reports for the first time that leptin may blunt the stress-induced expression of CRF1R in both the PVN and SON. The mechanism underlying this action remains to be delineated. The observation that the PVN expression of CRF1R followed that of CRF hnRNA nonetheless suggests that the reduced expression of CRF1R following leptin might be a consequence of a leptin-induced reduction in the CRF tone, all the more since CRF has been reported to trigger the expression of its own type 1 receptor (Mansi et al. 1996). The CRF1R seemingly favors further activation of CRF PVN neurons via an ultrashort positive feedback loop (Imaki et al. 2001). It is noteworthy that the repressing effect of leptin on CRF1R mRNA was also seen in the SON, which is not recognized to markedly express CRF (Kawata et al. 1983, Merchenthaler 1984). Furthermore, the possibility for a direct effect of leptin on SON CRF1R expression is weak due to the reported absence of the leptin receptors in this hypothalamic structure (Elmquist et al. 1998b).
In addition to binding to the CRF1R, CRF also binds to the CRF2R, which could be involved in the anorectic effects of CRF (Vaughan et al. 1995, Richard et al. 2000, 2002). The present study demonstrates an increased expression of CRF2R mRNA in the VMH after leptin infusion into the brain. The levels of the CRF2R transcript were independent of the running activity, but were about two times higher in leptin-infused rats compared with PBS-treated animals. These data are in agreement with the reported increase in the VMH CRF2R expression after systemic administration of leptin (Nishiyama et al. 1999) and the positive correlation between the levels of VMH CRF2R expression and plasma leptin concentrations (Makino et al. 1998). We have observed a decrease in the expression of CRF2R in the VMH of food-deprived rats and in rats with uncontrolled diabetes, which exhibit decreases in plasma leptin levels (Timofeeva & Richard 1997, Huang et al. 2006). Leptin signaling deficiency due to the lack of leptin as in ob/ob mice, or to the dysfunctional leptin receptor as in fa/fa Zucker rats, also leads to a decrease in CRF2R expression in the VMH (Richard et al. 1996, Timofeeva & Richard 1997). Leptin may directly affect the VMH neurons, which express the leptin receptor and exhibit leptin-induced Fos expression (Elmquist et al. 1997, 1998b, Elias et al. 2000). Through the expression of CRF2R in the VMH, leptin may potentiate the anorectic effects of CRF.
In conclusion, the results of the present study provide evidence for the inhibitory effect of continuous central leptin infusion on the treadmill running-induced activation of the CRF hypophysiotropic system. Chronic leptin infusion prevented stress-induced de novo synthesis of CRF, and significantly decreased the induction of expression of CRF1R in the PVN. In addition, leptin infusion increased the expression of the CRF2R mRNA in the VMH. These results provide evidence that chronic increase in central leptin signaling may blunt the HPA axis response to stress and increase the anorectic effects of CRF.
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Acknowledgements |
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Received 6 April 2006
Received in final form 6 July 2006
Accepted 11 July 2006
Made available online as an Accepted Preprint 2 August 2006
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significantly different from the resting rats within the same infusion, P < 0.05.
