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Département de Physiologie, Faculté de Médecine, Université Laval, Québec G1K 7P4, Canada
Address all correspondence and requests for reprints to: Denis Richard, Département de Physiologie, Faculté de Médecine, Université Laval, Québec G1K 7P4, Canada. E-mail: denis.richard{at}phs.ulaval.ca
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Introduction |
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The observation that leptin can reduce the activity of the pituitary-adrenal axis suggests that leptin can also inhibit the hypothalamic drive to the pituitary. So far, there has however been no demonstration that leptin could reduce the activity of hypophysiotropic neurosystems such as the CRF system. The hypophysiotropic function of CRF, which is insured by CRF-containing neurons located in the medial parvocellular division of the PVN, is likely not the sole action of CRF that could be modulated by leptin. Just like leptin, CRF exerts anorectic and thermogenic actions (14, 15), raising the possibility that leptin could modulate the effects of CRF on food intake and energy expenditure.
In this study, the effect of leptin on the expression of CRF mRNA in the PVN and on the activity of the PVN CRF neurons were studied in fed and food-deprived lean and obese (ob/ob) mice. The ob/ob mice were used to verify whether there could be a relationship between the hypothalamic-pituitary-adrenal (HPA) axis overactivity and the leptin deficiency that characterizes these mutants. The food deprivation paradigm was used to study the effect of leptin under intense activation of the CRF neurosystem. Indeed, food deprivation has been demonstrated to strongly stimulate the CRF system in genetically obese rats (16), and there has been indication that fasting can also be a potent activator of the HPA axis in ob/ob mice (17).
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Methods |
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Lean and obese mice were divided into leptin- and PBS-treated subgroups that were killed in fed or in fasted state. The eight groups thus formed were identified as follows: lean/PBS/ad libitum, lean/leptin/ad libitum, obese/PBS/ad libitum, obese/leptin/ad libitum, lean/PBS/food-deprived, lean/leptin/food-deprived, obese/PBS/food-deprived, and obese/leptin/food-deprived. Each group was comprised of five mice. Leptin and PBS were infused during 7 days using Alzet osmotic minipumps Model 1007D, which deliver their content at a flow rate of 0.5 µl/h for 7 days (ALZA Corp., Palo Alto, CA). The daily dose of leptin delivered was 100 µg/kg. The pumps were sc implanted under fluoxetane anesthesia. Recombinant murine leptin (r-MuLeptin) was kindly provided by Dr. Frank Collins (Amgen, Thousand Oaks, CA). The food-deprived groups had their food removed 24 h before euthanasia.
Body weight, food intake, and tissue weight
Measurements of body weight and food intake were performed every
day during the study. Epididymal white adipose tissue (EWAT) and
interscapular brown adipose tissue (IBAT) were quickly dissected out
during the first phase (the saline perfusion) of the intracardial
perfusion that took place at the end of the treatments (see below).
Brain preparation
Mice were anesthetized with 0.3–0.5 ml of a mixture containing
40 mg/ml ketamine and 2.0 mg/ml xylazine. Without delay, they were
intracardially perfused with 20 ml ice-cold isotonic saline followed by
100 ml paraformaldehyde (4%) solution. The brains were removed at the
end of perfusion and kept in paraformaldehyde for an additional period
of 3–4 days. They were then transferred to a solution containing
paraformaldehyde and sucrose (10%) before being cut 12 h later
using a sliding microtome (Histoslide 2000, Reichert-Jung, Heidelberg,
Germany). Brain sections were taken from the olfactory bulb to the
brain stem. Sections (25 µm thick) were collected and stored at -30
C in a cold cryoprotecting solution containing sodium phosphate buffer
(50 mM), ethylene glycol (30%), and glycerol (20%). Brain
perfusion and removal of tissues were carried out between 0800 and
1100 h.
In situ hybridization histochemistry
In situ hybridization histochemistry was used to
localize CRF and NPY mRNAs on tissue sections taken from the entire
brain. The protocol used was largely adapted from the technique
described by Simmons et al. (18). Briefly, one out of every
five brain sections were mounted onto poly-L-lysine coated
slides and allowed to desiccate overnight under vacuum. The sections
were then successively fixed for 20 min in paraformaldehyde (4%),
digested for 30 min at 37 C 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
trietholamine, pH 8.0), and dehydrated through graded concentrations
(50, 70, 95, and 100%) of alcohol. After vacuum drying for at least
2 h, 90 µl of the hybridization mixture, which contained an
antisense 35S-labeled complementary RNA (cRNA) probe
(107 cpm/ml), were spotted on each slide. The slides were
sealed under a coverslip and incubated overnight at 60 C in a slide
warmer. The next day, the coverslips were removed and the slides rinsed
four times with 4x SCC (0.6 M NaCl, 60 mM
trisodium citrate buffer, pH 7.0), digested for 30 min at 37 C 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; and 0.1x, 30 min at 60
C), and dehydrated through graded concentrations of alcohol. After a
2-h period of vacuum drying, the slides were exposed on an x-ray film
(Eastman Kodak, Rochester, NY) for periods varying between 24–48 h,
depending on the nature of the probes used. Once removed from the
autoradiography cassettes, the slides were defatted in xylene and
dipped in NTB2 nuclear emulsion (Kodak). Again depending on the probe
used, the slides were exposed from 7–14 days before being developed in
D19 developer (Kodak) for 3.5 min at 14–15 C and fixed in rapid fixer
(Kodak) for 5 min. Finally, tissues were rinsed in running distilled
water for 1–2 h, counterstained with thionin (0.25%), dehydrated
through graded concentrations of alcohol, cleared in xylene, and
coverslipped with DPX.
Antisense 35S-labeled cRNA probes
The CRH cRNA probe was generated from the 1.2-kb
EcoRI fragment of a rat CRH cDNA (Dr. K. Mayo, Northwestern
University, Evanston, IL) subcloned into a pGEM4 vector (Stratagene, La
Jolla, CA) and linearized with HindIII and EcoRI
(Pharmacia Biotech Canada, Baie d’Urfé (Qc), Canada) for
antisense and sense probes, respectively. The NPY antisense cRNA probe
was generated from a 287-bp XbaI-SalI fragment of
a rat NPY cDNA (Dr. D. S. Larhammer, Uppsala University, Sweden)
subcloned into a pGEM2 plasmid (Stratagene) that was linearized with
EcoRI and HindIII (Pharmacia Biotech Canada) for
antisense and sense probes, respectively. The radioactive antisense
riboprobes were synthesized by incubation of 250 ng of the linearized
plasmids in 6 mM MgCl2, 36 mM Tris
(pH 7.5), 2 mM spermidine, 10 mM
dithiothreitol, 0.2 mM of ATP/GTP/cytidine triphosphate and
[
-35S]uridine triphosphate, 40 U RNase inhibitor
(Promega, Madison, WI), and 20 U of either SP6 (CRF) or T7 (NPY) RNA
polymerase. Unincorporated nucleotides were removed using the ammonium
acetate method; 100 µl DNase solution (1 µl DNase, 5 µl 5 mg/ml
transfer RNA, and 94 µl 10 mM Tris containing 10
mM MgCl2) was added, and 10 min later an
extraction was accomplished using a phenol-chloroform solution. The
cRNA was precipitated for 20 min on dry ice with 80 ml 5 M
ammonium acetate and 500 µl ethanol (100%). The pellet was washed
with 500 µl ethanol, dried, and resuspended in 100 µl 10
mM Tris/1 mM EDTA (pH 8.0). A concentration of
107 cpm was mixed into 1 ml of the hybridization solution,
which consisted of 500 µl formamide, 60 µl 5 M NaCl, 10
µl 1 M Tris (pH 8.0), 2 µl 0.5 M EDTA (pH
8.0), 20 µl 50x Denhart’s solution, 200 µl 50% dextran sulfate,
50 µl 10 mg/ml transfer RNA, and 10 µl 1 M
dithiothreitol. This solution was mixed and heated for 5 min at 65 C
before being spotted on slides. Radioactive sense (control) cRNA copies
were also prepared to verify the specificity of each probe.
Hybridization with these probes did not reveal any positive signal in
the brain of rats.
Combination of immunocytochemistry with in situ hybridization
Immunocytochemical detection of Fos, the protein encoded by the
oncogene c-fos, was combined with detection of CRF mRNA to
determine whether CRF cells were activated during food deprivation.
Brain sections were first processed for immunocytochemical detection of
Fos using a conventional avidin-biotin-immunoperoxidase method.
Briefly, brain slices were washed in sterile 50 mM
potassium PBS (KPBS) that was treated with diethylprocarbonate water.
They were then incubated for 70 h at 4 C with a Fos antibody
(rabbit polyclonal IgG; Oncogene Science, Uniondale, NY). The Fos
antibody was used at a 1:50,000 dilution in KPBS (50 mM)
with heparin (0.25%), Triton X-100 (0.4%), and BSA (2%). Following
incubation at 4 C with the first antibody, the brain slices were rinsed
in sterile KPBS and incubated with a mixture of KPBS, Triton X-100,
heparin, and biotinylated goat antirabbit IgG (1:1500 dilution; Vector
Labs., CA) for 60 min. Sections were then rinsed with KPBS and
incubated at room temperature for 60 min with an
avidin-biotin-peroxidase complex (Vectastain ABC Elite Kit; Vector
Labs., Burlingame, CA), followed by a second incubation with a mixture
of KPBS, Triton X-100, heparin, and biotinylated goat antirabbit IgG
with the ABC Elite solution. After several rinses in sterile KPBS, the
brain slices were allowed to react in a mixture containing sterile
KPBS, the chromagen 3,3'-diaminobenzidine tetrahydrochloride (DAB,
0.05%), and 1% hydrogen peroxide. Thereafter, tissues were rinsed in
sterile KPBS, mounted onto poly-L-lysine-coated slides,
desiccated overnight under vacuum, fixed in paraformaldehyde (4%) for
30 min, and digested for 30 min at 37 C with proteinase K (10 mg/ml in
100 mM Tris HCl, pH 8.0, and 50 mM EDTA).
Prehybridization, hybridization, and posthybridization steps were
performed as described above except for the dehydration step, which was
shortened to avoid decolorization of Fos-immunoreactive (Fos-ir) cells.
After vacuum drying for 2 h, sections were exposed on x-ray film,
defatted in xylene, and dipped in the NTB2 nuclear emulsion. Slides
were exposed for 7 days, developed in D19 developer for 3.5 min at 15
C, and fixed in rapid fixer for 5 min. Thereafter, tissues were rinsed
in running distilled water for 1–2 h, rapidly dehydrated through
graded concentrations of alcohol, cleared in xylene, and coverslipped
with DPX.
Quantitative analyses of the hybridization signals
The hybridization signals revealed on NTB2-dipped nuclear
emulsion slides were analyzed and quantified under a light microscope
(Olympus, BX50, New Hyde Park, NY) equipped with a black and white
video camera (model XC-77, Sony, Japan) coupled to a MacIntosh computer
(Power PC 7100/66, Apple Computer, Cupertino, CA) using Image software
(version 1.55 non-FPU; Wayne Rasband, NIH, Bethesda, MD). The optical
density (OD) of the hybridization signal was measured under darkfield
illumination. Brain sections from the different groups of mice were
matched for rostrocaudal levels as closely as possible using an atlas
of the mouse brain (19). The OD for each specific region was corrected
for the average background signal, which was determined by sampling
unlabeled areas outside of the areas of interest. Brain sections of
five mice were analyzed for semiquantification of OD.
Plasma determinations
An intracardial blood sample was taken in anesthetized mice
immediately before the beginning of the intracardial perfusion with
paraformaldehyde. Plasma corticosterone was determined by a competitive
protein-binding assay (sensitivity, 0.058 nmol/L; interassay
coefficient of variation, 9.0%) using plasma from a
dexamethasone-treated female Rhesus monkey as the source of transcortin
(20).
Statistical analyses
A 2 x 2 x 2 ANOVA was used to examine the main and
interaction effects of infusion [PBS, Leptin], nutrition [fed,
food-deprived], and phenotype [lean (+/?), obese (ob/ob)]
on the various dependent variables measured in this study. Whenever
relevant, a posteriori comparisons were performed using the
Bonferoni/Dunn multiple-comparison-procedure.
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Results |
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illustrate the effects of leptin on body weight, weight of fat tissues,
and food intake of fed and starved lean and obese mice. The body weight
and food intake measurements were performed every day between 0800 and
0900 h. As seen in Fig. 1A, leptin led to a quickly occurring
decrease of body weight gain in ob/ob mice. After 7 days of
treatment, the body weight (final body weight, Fig. 1B) of the obese
mice treated with leptin was significantly lower than that of the
ob/ob mutants infused with PBS. There was no significant
effect of leptin on the body weight of lean mice. The line graph (Fig. 1A) also emphasizes the body weight drop following food deprivation on
the last day of treatment. The effect of food deprivation translates
into a significant reduction of the final body weight (Fig. 1B). The
interaction effect of infusion and phenotype, which was clearly
significant on final body weight, was also manifest on IBAT weight
(Fig. 1B). In fact, leptin led to a reduction in IBAT weight that was
much stronger in obese than in lean mice. It was evident from the
visual examination of IBAT that the changes in tissue weights following
treatments were largely accounted for by changes in tissue triglyceride
contents. There was no interaction effect of infusion and phenotype on
EWAT weight, and the effect of leptin on the weight of this tissue was
seen in both lean and obese mice. The effect of leptin on the total
amount of food ingested by each of the various groups of mice included
in this study is also illustrated on Fig. 1 (food intake, Fig. 1B).
Leptin exerted a stronger effect on food intake in ob/ob
mice than in lean animals.
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illustrates the effect of
leptin on plasma levels of corticosterone in fed and food-deprived lean
and obese mice. Leptin was shown to lower corticosterone levels in
obese mutants, whereas it had no effect in lean animals. These effects
appeared more evident in food-deprived than in fed mice; leptin seemed
capable of preventing the rise in corticosterone levels induced by food
deprivation.
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and 4 illustrate the effect of leptin on the
PVN levels of CRF mRNA. As is apparent from the photomicrographs of
Fig. 3 and the bar graph in Fig. 4, leptin completely prevented the
overexpression of CRF mRNA in the PVN of fasted ob/ob mice.
This effect of leptin was consistent with its ability to hinder the
stimulation of CRF PVN neurons that was also induced by food
deprivation in obese mice; leptin prevented the increase in the number
of cells colocalizing Fos and CRF mRNA in the PVN of fasted
ob/ob mice (Fig. 5A). Figure 5, B and C illustrate coronal brain sections of the PVN obtained from
food-deprived ob/ob mice perfused with either PBS (Fig. 5B)
or leptin (Fig. 5C). These sections were treated to detect Fos
immunoreactivity (ir) (gray nuclei) and CRF mRNA (silver grains within
cytoplasm). In the PVN, Fos was only significantly expressed in
food-deprived ob/ob mice treated with PBS.
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and 7 illustrate the effect of leptin on the
ARC levels of NPY mRNA. Leptin was found to prevent the enhanced NPY
mRNA expression induced by obesity. As seen in Fig. 6, food deprivation
raised the levels of NPY mRNA in lean mice but had no effect in obese
animals. In lean mice, leptin did not prevent the overexpression of NPY
in the ARC that was induced by food deprivation.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The prevention of the activation of the CRF hypophysiotropic neurons following food deprivation in ob/ob mice could represent an important mechanism whereby leptin exerts its effect in the regulation of energy balance. Leptin-deficient (33) and leptin-unresponsive (34) obese animals are characterized by a hyperactivity of the HPA axis, which is likely involved in the development of obesity. Indeed, the removal of glucocorticoids by adrenalectomy represents the most effective procedure to block the development of obesity in laboratory animals (35, 36, 37, 38, 39, 40, 41). The HPA axis hyperactivity of obese animals is exacerbated by food deprivation, which can be classified in obese rats as a neurogenic stress (42, 43) leading to a prompt and strong activation of the hypophysiotropic PVN CRF neurons (16). By preventing the stress-like response induced by food deprivation, leptin demonstrates its capacity to modulate the HPA axis in obese animals. Assuming that the exaggerated response of the PVN CRF system is a key feature in the development of obesity, the effect of leptin in preventing this response can be seen as a mechanism to prevent or reverse the development of obesity. Our results demonstrate the ability of leptin to partially reduce plasma levels of corticosterone in obese mice. This effect appeared more striking following food deprivation, a finding consistent with the effects food deprivation is exerting on the PVN CRF system of obese mice.
In lean mice, leptin did not prevent the increase in corticosterone levels following 24 h of fasting. This finding is different from but not totally inconsistent with the results of Ahima et al. (13), who demonstrated the efficiency of leptin to partially block the elevation of plasma corticosterone induced by a fasting period of 48 h in lean mice. Given the lack of apparent effect of leptin on the endocrine CRF system of fasted lean mice, it can be argued that a fasting period of 24 h is not sufficiently long in lean animals to elevate corticosterone levels via a central neuroendocrine mechanism; food deprivation can reduce the plasma clearance of corticosterone (44). The presence of a central mechanism could be a prerequisite for leptin to manifest an action on the levels of corticosterone. It is not certain whether 48 h of food deprivation lead to a central neuroendocrine stimulation of the pituitary-adrenal axis in lean mice, but such a possibility is plausible considering the considerable energy deficit that causes a nutritional deprivation of 48 h in a mammal as small as a mouse. In obese mice, in which leptin could reduce the levels of corticosterone, 24 h of fasting undoubtedly led to an important stimulation of the hypophysiotropic CRF system.
In light of the anorectic and thermogenic properties of CRF (14, 15), one would not a priori be inclined to predict an attenuation of the central CRF tone following a treatment with an antiobesity protein such as leptin. However, the ability of leptin to reduce the activity of the neuroendocrine CRF neurons must not be seen as necessarily contradictory to the acknowledged anorectic and thermogenic attributes of CRF. The regulation of energy balance is only one among the numerous actions of the CRF system and this action is, in addition, possibly not insured by the CRF neurons of the parvocellular division of the PVN, whose main role is the control of the HPA axis activity. Other workers have recently provided evidence that leptin can stimulate the expression of the CRF gene (45). This enhanced expression was observed in the PVN of food-deprived lean rats. Because fasting reduces expression of CRF in lean animals (46), in contrast to what it does in obese animals, it is not clear whether the action of leptin in food-deprived rats is to increase or maintain within normal values the PVN levels of CRF mRNA.
The NPY-containing neurons of the ARC are known to project to the PVN, where they could modulate the activity of the hypophysiotropic CRF neurons (47, 48). NPY has been shown to considerably elevate plasma levels of corticosterone in rats, and this has also been reported to occur independently of the NPY effect on food intake (49). Under the experimental conditions of this study, we examined the expression of NPY in the ARC neurons in an attempt to establish a connection between the NPY and CRF systems. The results obtained do not provide ineluctable evidence for a role of the ARC NPY in the effect of leptin in blunting the rise in activity of the PVN CRF system induced by fasting in ob/ob mice. In fact, the measured variations of NPY mRNA levels did not exactly match those of CRF mRNA levels. However, our results demonstrate the efficacy of leptin to prevent the overexpression of NPY mRNA in the ARC of ob/ob mice and, therefore, does not preclude the possibility that a reduced stimulation of the ARC NPY could contribute to the effects of leptin in preventing the effects of fasting on the CRF system in ob/ob. It is worthy of emphasis that leptin did not prevent the elevation of NPY expression induced by 24 h of fasting in lean animals. This finding partly contrasts with that of Cusin et al. (50), who showed that leptin could prevent the increase in ARC NPY levels induced by food deprivation in lean rats.
In conclusion, the present results emphasize the ability of leptin to modulate the activity of hypophysiotropic CRF system in response to food deprivation. Leptin prevented both the induction of CRF synthesis in the PVN and activation of the PVN CRF neurons in food-deprived ob/ob mice and hindered the elevation of ARC NPY synthesis inherent to obesity in mice. The present results also provide good evidence that leptin can alter plasma levels of corticosterone. In obese mice, leptin blunted the obesity-associated increase in plasma levels of corticosterone. Finally, leptin was found to reduce body weight gain and fat deposition. These effects were seen to be particularly striking in obese mutants, in which leptin also caused an important reduction in food intake. Altogether the present results suggest a role for leptin in the excessive response of the hypophysiotropic CRF system of the ob/ob mouse.
Received May 29, 1997.
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G. Trottier, K. G. Koski, T. Brun, D. J. Toufexis, D. Richard, and C.-D. Walker Increased Fat Intake during Lactation Modifies Hypothalamic-Pituitary-Adrenal Responsiveness in Developing Rat Pups: A Possible Role for Leptin Endocrinology, September 1, 1998; 139(9): 3704 - 3711. [Abstract] [Full Text] [PDF]
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K. Arvaniti, Y. Deshaies, and D. Richard Effect of leptin on energy balance does not require the presence of intact adrenals Am J Physiol Regulatory Integrative Comp Physiol, July 1, 1998; 275(1): R105 - R111. [Abstract] [Full Text] [PDF]
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