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Joslin Diabetes Center and Harvard Medical School (E.G.K., N.A.T., J.W.M., E.M.-F.), Boston, Massachusetts 02215; and Eli Lilly & Co. Research Laboratories (L.S.), Indianapolis, Indiana 46285
Address all correspondence and requests for reprints to: Eleftheria Maratos-Flier, M.D., Joslin Diabetes Center, Room 620, One Joslin Place, Boston, Massachusetts 02215. E-mail: terry.maratos-flier{at}joslin.harvard edu.
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Abstract |
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i. This receptor was initially cloned in rat and
human and designated SLC-1 because of its homology to the somatostatin
receptor. In rat brain, it is expressed in a pattern that mirrors the
previously described pattern of projections of MCH-immunoreactive
fibers. In the present study we cloned the mouse MCH receptor (MCH-R) ortholog by a rapid amplification of 5'- and 3'-cDNA ends approach and have found it to be 98% homologous with the rat sequence. We have characterized MCH-R messenger RNA distribution in the mouse brain by in situ hybridization and have shown MCH-R to be expressed in diverse brain areas implicated in the regulation of feeding, body adiposity, and sensory integration of smell and gustatory inputs, including the hypothalamus [paraventricular nucleus (magnocellular part) and dorsomedial, ventromedial, and arcuate nucleus], areas of the olfactory pathway, and the nucleus of the solitary tract.
We also studied MCH-R regulation and found that MCH-R expression is increased 7-fold by 48-h fasting or genetic leptin deficiency (ob/ob mice) and is completely blunted by leptin administration. In contrast, MCH-R messenger RNA expression remains unaltered in genetic MCH deficiency. Our findings suggest that MCH-R constitutes a central target of leptin action in the mammalian brain.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MCH is one of several hypothalamic neuropeptides, including neuropeptide Y (NPY), agouti-related peptide, and MSH, known to regulate energy homeostasis, which are also known to be regulated positively or negatively by leptin (9, 10). Leptin administration to fasting mice blunts the fasting-induced rise of hypothalamic MCH and NPY mRNA (11). Leptin administration to leptin-deficient ob/ob mice also leads to a significant decrease in NPY expression in the hypothalamus (12). We have observed similar effects of leptin on MCH expression (Tritos, N., and E. Maratos-Flier, unpublished observations). In contrast, leptin stimulates POMC expression (13). The potential ability of leptin to regulate expression of receptors for these peptides has not been examined.
MCH acts through a specific G protein-coupled receptor (MCH-R) that was initially identified as SLC-1 through its homology to somatostatin receptors (14). The sequences of the human and rat receptor have been reported. MCH-R was found by Northern blot analysis to be expressed in brain, skeletal muscle, eye, and tongue. MCH-R activation is specific for MCH and leads to a decrease in cAMP levels and a calcium influx (14, 15, 16, 17).
In the present study we cloned the mouse ortholog of MCH-R complementary DNA (cDNA), and we performed in situ hybridization histochemistry to characterize the distribution of MCH-R in the murine brain. We subsequently examined changes in MCH-R expression at different metabolic stages (fasting and genetic leptin deficiency) with or without leptin administration as well as in MCH deficiency. We found that MCH-R is expressed in areas of the brain that have been implicated in the integration of feeding behavior, such as the cerebral cortex. We have also shown that leptin acts as a negative regulator of MCH-R expression in the brain, whereas MCH per se has no obvious effect on MCH-R expression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quantitative RT-PCR
Animals were killed by CO2. Their organs
were rapidly removed and immediately frozen in liquid
N2, followed by long-term (<1 month) storage at
(-80 C). RNA was extracted from frozen mouse tissues (-80 C) using
the Ultraspec RNA isolation system (Biotecx, Houston, TX) according to
manufacturer’s instructions. One hundred nanograms of RNA were used in
multiplex one-step RT, followed by 40 cycles of PCR amplification (95
C, 15 sec; 60 C, 1 min) in a 50-µl reaction mixture (TaqMan One-Step
RT-PCR mix, PE Biosystems) containing 900 nM of each MCH-R
mouse-specific forward primer (5'-gccacctcctcgcacaa-3') and reverse
primer (5'-cttcaccacggcaaaaatgac-3') and 250 nM MCH-R
mouse-specific fluorescent-labeled probe
(5'FAM-ctacatcaacatcatcatgccttcagtgtttggta-3'TAMRA) and
glyceraldehyde-6-phosphate dehydrogenase (GAPDH)-specific primers and
VIC-labeled probe (TaqMan Rodent GAPDH control reagents, PE
Biosystems, Foster City, CA). Real-time amplification data were
collected by an ABI Prism 7700 Sequence Detection System (PE
Biosystems).
The design of optimal SLC-1 primers pair and probe was facilitated by the Primer Express Software (PE Biosystems). To exclude genomic DNA amplification, the sequence of the MCH-R forward primer was designed to span an intron splice site. Furthermore, all PCR amplification reactions were performed in the presence and the absence of reverse transcriptase. Samples were run in quadruplicate. The simultaneous amplification in the same reaction tube of a housekeeping gene (GAPDH) was used to control for RNA input and integrity as well as efficiency of the amplification reaction.
Animals
Adult (20–24 wk) male (25–30 g) C57BL/6J mice and obese
ob/ob mice (45–55 g) were maintained at a 12-h light, 12-h
dark cycle and constant temperature (22 C), and were allowed chow food
(Purina mouse chow) and water ad libitum. In experiments
involving fasting, C57BL/6J mice were either fasted for 48 h or
kept on chow diet. Fasted mice were treated with either leptin (1
µg/g, ip, twice daily) or saline. Control mice received saline
injections as well. In experiments involving ob/ob mice, fed
ob/ob animals were treated with either leptin (1 µg/g, ip,
twice daily) or saline for 48 h and control C57BL/6J mice were
treated with saline. The generation of the MCH knockout (MCH-KO) mice
has been described previously (8), and the animals have
now been backcrossed to the C57BL/6J background for six generations.
The study protocol was approved by the animal use review committee at
the Joslin Diabetes Center.
In situ hybridization histochemistry
Animals were killed 2 h into the onset of the light cycle.
Mice were anesthetized with sodium pentobarbital (90 mg/kg, ip) and
perfused transcardially with 20 ml saline and 50 ml 10% neutral
buffered formalin (Accustain, Sigma, St. Louis, MO).
Brains were removed, postfixed in 10% formalin for 4 h, and
cryoprotected in 20% sucrose in PBS for at least 24 h. The brain
tissue was subsequently frozen in dry-ice, and coronal sections (30
µm thick) were obtained using a sliding microtome (AO Instrument Co,
Buffalo, NY). In situ hybridization histochemistry was
performed as previously described. Briefly, brain slices were mounted
on glass slides, postfixed, acetylated, ethanol dehydrated, and stored
at -20 C until hybridization. Antisense riboprobes were synthesized
using a commercially available in vitro transcription kit
(Promega Corp., Madison, WI). Sections were hybridized
with the appropriate riboprobe in hybridization buffer in an air oven
(57 C) for 18 h as described previously. Tissue sections were
subsequently ribonuclease A-treated, washed, ethanol-dehydrated,
air-dried, and exposed to Biomax MR film (Eastman Kodak Co., Rochester, NY) for 5–7 days. Slides were subsequently
dipped in NTB-2 emulsion (Kodak), exposed at 4 C for 4
weeks, developed, counterstained with thionin, dehydrated in graded
ethanol series, and coverslipped.
The absorbance of the autoradiographic images was measured by using a computing densitometer (Molecular Dynamics, Inc.) and the ImageQuant software (Molecular Dynamics, Inc.). The intensity of the hybridization signal in specific brain regions was also estimated by counting silver granules in microscopic images with the use of a BX60 microscope (Olympus Corp., Japan) and commercially available image analysis software (ImagePro).
Statistical comparisons of differences between animal groups were performed by ANOVA (StatView 4.5, Abacus Concepts, Berkeley, CA), and P < 0.05 after the Bonferroni correction for multiple comparisons were considered significant. Densitometry data were plotted as percent relative density units, with the absorbance in the control group set arbitrarily at 100%.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. At the
nucleotide level, the mouse MCH-R cDNA has 92% and 88% homology to
the rat and human MCH-R cDNA sequences, respectively. At the amino acid
level, the mouse MCH-R has 98% and 96% homology to the rat and human
MCH-R, respectively. The genomic organization of the mouse SLC-1 gene
seems to parallel that of rat and human (14, 17), with one
intron of approximately 1.2 kb in length spanning the entire coding
region (data not shown). In addition, sequence information derived from
two different 5'-extended clones indicates that those clones represent
two different mRNA species that are alternatively spliced, thus
implying the presence of an intron in the 5'-untranslated region of the
gene (data not shown).
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). Specific
hybridization signal is present in cortical areas (orbital, piriform,
frontal associative, primary motor, prelimbic, primary somatosensory,
posterior parietal associative, retrosplenial, auditory, and visual).
In addition, specific hybridization signal was detected in the
olfactory nerve layer, olfactory bulb, anterior olfactory nucleus
(lateral and external), mitral cell layer (accessory olfactory bulb),
olfactory tubercle, nucleus accumbens, and the striatum (caudate
nucleus and putamen). Hybridization signal was also present in the
hippocampus. In the hypothalamus, hybridization signal was detected in
the paraventricular (magnocellular part), dorsomedial, ventromedial,
and arcuate nucleus. In the brainstem, hybridization signal was present
in the superior colliculus (superficial gray, intermediate gray,
intermediate white), inferior colliculus (external cortex, central
nucleus), locus coeruleus, and nucleus of the solitary tract. The
specificity of the hybridization signal was verified by demonstrating
complete absence of hybridization signal to a sense MCH-R RNA probe. By
in situ hybridization analysis MCH-R mRNA was also found to
be present in the epithelium of the mouse tongue and kidney, whereas
sections from heart, liver, and spleen were found to be negative by the
same technique (Fig. 2B). Quantitative RT-PCR analysis of various mouse
tissues revealed the highest level of MCH-R expression in brain (Fig. 2C).
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; fasted
vs. fed animals, P < 0.05), whereas the
pattern of MCH-R expression remained unchanged, as indicated by
microscopic examination of the dipped slides (data not shown). When
similarly fasted animals were treated with leptin, the fasting-induced
up-regulation of MCH-R mRNA was abolished. Leptin-treated fasted
animals had lower levels of expression than fed animals. Consistent
with the hypothesis of leptin-mediated down-regulation of MCH-R
expression, brains from leptin-deficient ob/ob mice
exhibited a marked global increase in MCH-R expression (Fig. 4A). Quantitation of signal from several
animals revealed that ob/ob mice expressed 3-fold higher
levels of MCH-R mRNA compared with control animals (Fig. 4B, ob/ob vs. controls; P < 0.05).
Leptin treatment of ob/ob mice resulted in a significant
blunting of MCH-R expression in total mouse brain. Evaluation of the
arcuate nucleus by visualization of silver granules on dipped slides
revealed a striking difference in the staining intensity in the arcuate
hypothalamic nucleus of ob/ob mice compared with controls
(Fig. 4C). More specifically, ob/ob mice showed a 5-fold
increase in MCH-R expression in the arcuate nucleus (Fig. 4C;
ob/ob vs. controls, P < 0.0010).
Our quantitative RT-PCR analysis of MCH-R expression using total brain
RNA from various experimental groups, as described above, confirmed the
results obtained by in situ hybridization histochemistry
analysis, demonstrating a 2.6-fold increase in MCH-R mRNA expression in
ob/ob mice compared with controls (Fig. 5A; P < 0.05).
Furthermore, ob/ob animals responded to leptin treatment by
a significant reduction in MCH-R expression (P <
0.01). Fasting in ob/ob mice resulted in a moderate (40%)
decrease in MCH-R mRNA expression that was borderline statistically
significant (Fig. 5B; P = 0.048). Using the same
experimental approach, we compared MCH-R mRNA levels among MCH-KO
animals and their control littermates, and we found these levels to be
no different (Fig. 5C; P = 0.37). Similar results were
obtained by in situ hybridization analysis of MCH-R
expression in total brain of MCH-KO and control animals (n =
5/group; data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the mouse, MCH-R was expressed predominantly in the brain, as is also the case for the rat and human transcripts (14, 15, 19, 20). We as well as other investigators detected SLC-1 mRNA expression in tissues other than brain, such as kidney, testis, white adipose tissue (21), skeletal muscle, and tongue. These observations raise the possibility of a peripheral action for MCH. The presence of MCH-R transcripts and protein in rat white adipose tissue (21) is in support of this hypothesis. Furthermore, in the same system a functional role for MCH in increasing leptin expression and secretion has been demonstrated. Alternatively, those low level (compared with brain) MCH-R transcripts may be of no physiological significance.
Our in situ hybridization analysis in mouse brain slices confirmed that the distribution of the MCH-R mRNA in mouse brain parallels that in the rat brain, involving areas participating in the integration of sensory inputs and the regulation of food intake (20). The MCH-R mRNA brain expression well parallels the previously known distribution of MCH-immunoreactive neuronal fibers (22). The presence of MCH-R transcripts in neurons of the olfactory pathway suggests a role for MCH in olfactory gating and integration mechanisms. Similarly, the detection of MCH-R expression in the nucleus of the solitary tract suggests a role for MCH in gating of gustatory information relayed through this nucleus. We are extending previous observations in rat brain by demonstrating the presence of MCH-R transcripts in the arcuate hypothalamic nucleus, suggesting that MCH may modulate the function of arcuate hypothalamic neurons involved in appetite regulation and energy homeostasis. We are currently working on identifying the arcuate hypothalamic neurons expressing MCH-R.
The negative regulation of MCH-R mRNA by leptin in brain was somewhat
unexpected. It has been previously established that orexigenic
neuropeptides, such as MCH and NPY, are up-regulated by leptin
deficiency and in conditions of low energy stores (2, 3).
Based on these findings, one might expect MCH-R to be down-regulated
under conditions of increased expression of its ligand, as is the case
for MSH and MC4-R (23). However, this scenario seems
not to be true for MCH and its receptor. Surprisingly, MCH-R is
up-regulated in two diverse metabolic stages, one of genetic obesity
and one of food deprivation, that both have as a common denominator low
or absent systemic leptin levels (11, 24). Furthermore,
exogenous leptin administration results in lowering MCH-R expression
levels in conditions where those seem to be elevated, as in fasting and
in ob/ob mice. Finally, in ob/ob mice that are
leptin deficient, MCH-R mRNA levels fail to raise with fasting, as is
true for control animals, indicating that the majority of MCH-R mRNA
regulation in brain is attributed to leptin effects. Thus, MCH-R
appears to be independent of its ligand in sensing the organism’s
metabolic needs as these are communicated by leptin.
Alternatively, one might hypothesize that MCH-R expression is positively regulated by its ligand, as both paradigms analyzed above (fasting and leptin deficiency) are accompanied by increased MCH levels (2), that can also be down-regulated by leptin treatment (Tritos, N. A., and E. Maratos-Flier, unpublished observations). The analysis of the MCH-KO animals revealed that this is not the case either, as the absence of the endogenous ligand had little or no effect on MCH-R brain expression.
Based on these data, it is not yet clearly established that the effects of leptin on MCH-R regulation are direct. Systemic corticosterone levels are increased in both fasted C57BL/6J and fed ob/ob mice and are blunted in response to leptin treatment (11). To exclude the possibility that changes in corticosterone levels have influenced MCH-R mRNA levels in our study, we have examined MCH-R mRNA levels in C57BL/6J mice after dexamethasone treatment, and we have found them to be unchanged (data not shown). The demonstration of colocalization of MCH-R with leptin receptors in various brain areas would further support a direct action of leptin on MCH-R regulation.
In conclusion, in the present study we have cloned the mouse MCH-R, analyzed its brain distribution, and identified it as a central target of leptin’s action. In contrast to appetite-regulating hypothalamic peptides, the precise physiological role of their receptors has just started to emerge.
Received August 23, 2000.
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