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Localization of Leptin Receptor (Ob-R) Messenger Ribonucleic Acid in the Rodent Hindbrain¹

Molecular Neuroendocrinology Unit (J.G.M., K.M.M.) and Molecular Physiology Group (N.H.), Rowett Research Institute, Bucksburn, Aberdeen, Scotland AB21 9SB

Address all correspondence and requests for reprints to: Dr. J. G. Mercer, Molecular Neuroendocrinology Unit, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen, Scotland AB21 9SB. E-mail: jgm{at}rri.sari.ac.uk

	Abstract

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The behavioral and neuroendocrine effects of the adipose tissue-derived circulating protein, leptin, appear to be mediated by the hypothalamus. We have investigated whether the leptin receptor gene is expressed in hindbrain regions known to be involved in the processing of satiety and energetic signals of peripheral origin. In the mouse, gene expression was detected in the nucleus of the solitary tract, lateral parabrachial nucleus, and medullary reticular nucleus and diffusely elsewhere by in situ hybridization. Receptor messenger RNA in these neuronal areas consisted largely, if not exclusively, of the long splice variant, Ob-Rb. Presumed short receptor splice variants were abundantly expressed in the leptomeninges and the choroid plexus of the fourth ventricle. Similar levels of leptin receptor gene expression were present in the hindbrain of lean and obese (ob/ob) mice. The leptin receptor gene was expressed comparatively weakly in the nucleus of the solitary tract of the rat and was not detectable in the lateral parabrachial nucleus. However, by contrast with the mouse, a high level of receptor gene expression was observed in the cerebellum of the rat. A number of rodent hindbrain sites expressing the leptin receptor gene are activated by circulating leptin and may form a monitoring/signaling pathway to complement more direct hypothalamic interactions.

	Introduction

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LEPTIN, the protein product of the ob gene (1), is secreted primarily by adipocytes and has complimentary effects on food intake and energy expenditure that reduce the body weight of obese, ob/ob, mice (2, 3, 4). The leptin receptor was cloned from choroid plexus (5), exists in a number of splice variants (6, 7), and mediates the interaction of leptin with hypothalamic neuroendocrine systems (8, 9, 10, 11). We demonstrated previously that leptin receptor messenger RNA (mRNA) is present in a number of hypothalamic areas in the mouse (12); these include the arcuate, ventromedial, paraventricular, dorsomedial, and ventral premammillary nuclei and the lateral hypothalamic area. A similar distribution of receptor gene expression has recently been reported in the rat hypothalamus (11). Leptin receptor gene expression is also present in other areas of the rodent forebrain (11, 12), suggesting a widespread regulatory role for leptin in the central nervous system (CNS), although recent data suggest that the precise hybridization pattern observed may be probe specific (13). The product of the immediate early gene, c-fos, has been used to examine the CNS circuitry activated by leptin (14, 15, 16), and hindbrain structures have been implicated in leptin signaling pathways.

Discrete regions of the rodent hindbrain are known to have a chemosensory function or to be involved in the relaying of satiety and other visceral signals from the periphery. Using probes that hybridize to either the common extracellular domain of the leptin receptor gene (Ob-R) or the long intracellular domain specific to the Ob-Rb splice variant, we now report the localization of leptin receptor gene expression in the mouse and rat hindbrain. We also compare leptin receptor mRNA levels in key hindbrain structures of lean and obese (ob/ob) mice.

	Materials and Methods

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Animals
Lean (+/?) and obese (ob/ob) Aston mice and Hooded Lister rats were drawn from colonies maintained at the Rowett Research Institute. Food (Biosure; Special Diets Services, Witham, Essex, UK) and water were available ad libitum. All animals were killed by cervical dislocation in the middle of the light phase.

Probe synthesis
Receptor-specific PCR primers were used to generate probes for 1) the common extracellular domain of the leptin receptor sequence, Ob-R, which recognizes all of the known splice variants (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re, and muB219); and 2) the long form of the receptor, Ob-Rb. Species-specific Ob-R probes (473 bp) were cloned from both mouse and rat brain, respectively. The mouse-specific Ob-R primers were 5'-CAGATTCGATATGGCTTAATGGG-3' (+1704 to +1726) and 5'-GTTAAAATTCACAAGGGAAGCG-3' (+2177 to +2156; GenBank U42467). The rat-specific Ob-R primers were 5'-CAGATTCGATATGGCTTAAATGG-3' (+1704 to +1726) and 5'-GTTAAAATTCACAAGGGAGGCA-3' (+2177 to +2156; GenBank U52966). The long form specific mouse Ob-Rb probe (533 bp) was generated using the primers 5'-GTGTGAGCATCTCTCCTGGAG-3' (+2829 to +2849) and 5'-ACCACACCAGACCCTGAAAG-3' (+3362 to +3343; GenBank U49107). In each case, a single PCR product was observed by gel electrophoresis, purified using Wizard PCR preps (Promega, Madison, WI), and cloned directly into pGEM-T (Promega). The sequence and orientation of the inserts were confirmed by automated sequencing. Plasmids were linearized with SacI or ApaI for transcription with T7 or SP6 RNA polymerase to generate antisense and sense riboprobes.

In situ hybridization
Leptin receptor gene expression in the hindbrain was examined in 10- or 20-µm coronal sections by in situ hybridization, using antisense and sense riboprobes to the common extracellular domain of the leptin receptor (Ob-R), and the long form of the receptor, Ob-Rb, as described in detail previously (12). Briefly, after fixation in 4% paraformaldehyde and acetylation, hybridization was performed using ³⁵S-labeled complementary RNA probes at concentrations of 1.5–2.5 x 10⁷ cpm/ml. Where specified, unlabeled riboprobes were synthesized by substituting 1 µl 10 mM UTP for [³⁵S]UTP in the transcription reaction. After hybridization, slides were treated with ribonuclease A (RNase A), washed at high stringency in 0.1 x SSC (standard saline citrate) at 60 C, and dehydrated. Higher wash temperatures were employed where indicated. Slides were apposed to Hyperfilm ß-max (Amersham, Arlington Heights, IL) for film autoradiography. For microscopic examination, slides were coated in autoradiographic emulsion (LM-1, Amersham), exposed for 3–20 weeks, and counterstained with toluidine blue. Where appropriate, autoradiographic images were quantified using the BioImage system (Millipore Corp., Bedford, MA) as described previously (9). Brain areas were identified by reference to toluidine blue-stained sections and atlases of the rat and mouse brains (17, 18).

Statistics
Data are presented as the mean ± SE and were analyzed by t tests. Differences were considered statistically significant if P < 0.05.

	Results

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Mouse
Leptin receptor mRNA was detected in a number of murine brain stem sites, using either Ob-R or Ob-Rb probes cloned from the mouse brain (Fig. 1). In caudal sections, receptor gene expression was readily apparent in the nucleus of the solitary tract (NTS; Figs. 1, a–c, and 2); hybridization was apparent in the medial and ventrolateral subnuclei. Elsewhere within coronal sections of this hindbrain region, receptor gene expression was apparent, ventral and lateral to the NTS, in individual neurons or local neuronal aggregations that were distributed in an arc spanning the dorsal medullary reticular nucleus, intermediate reticular nucleus, and ventral medullary reticular nucleus (Fig. 1, a–c, and Fig. 2); hybridization was particularly striking with the Ob-Rb probe. Leptin receptor mRNA was not detected in the area postrema or hypoglossal nucleus. The Ob-R antisense probe produced a higher background signal over murine brain stem sections than did the Ob-Rb probe; this background signal was not markedly reduced by a higher stringency posthybridization wash (0.1 x SSC at 75 C). The Ob-R probe, but not the long form-specific Ob-Rb probe, hybridized strongly to the leptomeninges (LEP) surrounding the cerebellum and medulla and to the choroid plexus (CP) of the fourth ventricle (CP4V) and its lateral recess (CPLR4V; Fig. 1d). Autoradiographic signals emanating from the cerebellar lobules of the mouse appeared to be nonspecific (Fig. 1). Further forward in the hindbrain, both Ob-R and Ob-Rb antisense probes hybridized to the pontine lateral parabrachial nucleus (LPB; Figs. 1e and 2) and the central grey, whereas the Ob-R probe hybridized to the LEP. No differences were observed between lean and obese (ob/ob) mice in the levels of receptor gene expression in the NTS and LPB with either Ob-R or Ob-Rb probes (Fig. 3).

View larger version (104K): [in this window] [in a new window]   Figure 1. Autoradiographic localization of leptin receptor mRNA in coronal sections of mouse hindbrain. Adjacent sections were hybridized with antisense (A/S) or sense (S) probes to the Ob-Rb splice variant and the common extracellular domain of the leptin receptor (Ob-R). AP, Area postrema; ‘12’, hypoglossal nucleus; MdV, ventral medullary reticular nucleus; MdD, dorsal medullary reticular nucleus; IRt, intermediate reticular nucleus; CG, central grey. a–c, Equivalent to Bregma -14.08 to -13.68 mm (17); d, equivalent to Bregma -7.08 mm (18); e, equivalent to Bregma -5.02 mm (18). Images were derived from 10-µm (a–d) or 20-µm (e) sections exposed to autoradiographic film for 6 and 2 weeks, respectively.

View larger version (66K): [in this window] [in a new window]   Figure 2. Photomicrographs of 20-µm murine hindbrain sections on which in situ hybridization was performed using antisense (a–c) or sense (d) probes specific to the intracellular domain (Ob-Rb) of the leptin receptor gene. MdV, Ventral medullary reticular nucleus. a, Gene expression in the NTS (equivalent to Fig. 1a); b, gene expression in the MdV (equivalent to Fig. 1a); c, gene expression in the LPB (equivalent to Fig. 1e); d, NTS section adjacent to panel a hybridized with the Ob-Rb sense probe. Magnification, x160.

View larger version (19K): [in this window] [in a new window]   Figure 3. Leptin receptor gene expression in the NTS and LPB of lean and obese (ob/ob) mice. Leptin receptor mRNA was measured with probes to the common leptin receptor sequence, Ob-R, and the Ob-Rb splice variant. Data from obese mice are expressed as a percentage of the lean control values. Groups contained four (LPB) or six (NTS) animals.

View larger version (88K): [in this window] [in a new window]   Figure 4. Autoradiographic localization of leptin receptor mRNA in coronal sections of rat hindbrain. Rat Ob-R and mouse Ob-Rb probes were hybridized to sections from different animals. Images were derived from 20-µm sections exposed to autoradiographic film for 8 weeks. a, Bregma -13.68 mm; b, Bregma -12.3 mm.

View larger version (121K): [in this window] [in a new window]   Figure 5. Photomicrographs of 20-µm rat hindbrain sections on which in situ hybridization for the leptin receptor gene was performed using antisense (a–c) or sense (d) probes to the common extracellular sequence of the rat gene (Ob-R) or the intracellular domain of the mouse gene (Ob-Rb). CB, Cerebellum. a, Gene expression in the NTS; b, gene expression in the CP4V; c, gene expression in the CB; d, NTS sections adjacent to panel a hybridized with the respective sense probes. Magnification, x160.

	Discussion

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Although the hypothalamus is a critical center in the regulation of food intake and energy homeostasis, and is certainly elevated in the neuroendocrine hierarchy of feeding, other levels of the nervous system are also involved. For example, several hindbrain sites are responsive to peptide injection, and onward signaling to the forebrain may not be required for the effects of peripheral peptides on feeding behavior (19). In particular, the NTS and relays to the LPB form an important connection between peripheral nutrient sensors and the CNS. The localization of leptin receptor mRNA in the NTS, LPB, and reticular nuclei of the mouse hindbrain is consistent with visceral sensory involvement (20). The NTS, an entry point for sensory information of widespread origin, has several classes of projection. These include projections to the medullary reticular formation, regions of which are involved in coordinating autonomic reflexes, and ascending projections taking in most of the remainder of the central autonomic system. A number of forebrain regions, including several in the hypothalamus, receive information of visceral origin either directly from the NTS or by relay via the LPB (20).

As in rodent hypothalamus, neuronal sites of leptin receptor gene expression appear to contain mainly, if not exclusively, the Ob-Rb putative signaling variant, whereas the majority of receptor mRNA in the blood-brain barrier tissues of the LEP and CP corresponds to short splice variants (11, 12, 13). Unexpectedly, the Ob-Rb antisense probes consistently gave a stronger signal in the mouse brain stem than an equivalent concentration of the Ob-R probe hybridized to adjacent sections. This contrasted with our previous finding in the hypothalamus, where both signals were comparable (12). However, tissue background was higher in murine sections probed with the Ob-R probe, and it is possible that the respective probes may have different hybridization efficiencies in different CNS tissues. Alternatively, it is possible that the Ob-Rb probe may cross-hybridize. The 533-bp Ob-Rb fragment does not have high homology to EMBL database sequences, other than the leptin receptors of different mammalian origins, but the possibility of hybridization to an as yet unidentified member of the receptor family cannot be ruled out.

The very low level of leptin receptor mRNA in the rat NTS compared with that in the mouse and the apparent absence of gene expression in the LPB and other medullary sites appear to reflect a species difference in expression levels. Signal amplification through application of in situ reverse transcription-PCR could be employed to assess whether the receptor gene is expressed in other rat hindbrain regions at an abundance that is below the level of detection afforded by the present methodology. However, the functional significance of such low levels of expression is open to question. In contrast to the low levels of receptor gene expression in the rat medulla, a dense and specific hybridization signal was observed over the rat cerebellum after incubation with either Ob-R or Ob-Rb probes. This further species difference between rats and mice was confirmed by RNase treatment and competition studies. Significantly, preliminary Northern analysis of total RNA isolated from rat cerebellum using the rat Ob-R complementary DNA probe corroborated the in situ hybridization data, with the presence of a band similar in size to published Ob-Ra/Ob-Rb isoforms (5, 13). In addition, a second band, of approximately 2 kilobases was observed (our unpublished observations). As with the other hindbrain hybridization sites, and indeed with receptor gene expression elsewhere in the brain, it will be important to establish whether a functional protein is present in the rat cerebellum.

The NTS and LPB are likely to form part of a signaling pathway conveying information on circulating leptin concentrations. This contention is supported by studies of the neural circuitry activated by leptin. When delivered to the cerebroventricular system (15), leptin caused an accumulation of c-Fos-like immunoreactivity (c-FLI) in the forebrain of the rat (paraventricular hypothalamic, dorsomedial hypothalamic, and central amygdala), but not in the hindbrain. It is not clear whether leptin administered intracerebroventricularly can access the hindbrain via the cerebral aqueduct (15). By contrast, rats in which leptin was administered systemically, a route more closely mimicking that by which endogenous leptin accesses the CNS, expressed c-FLI in the NTS and LPB of the brain stem as well as in both the above hypothalamic nuclei and, additionally, the ventromedial hypothalamic and ventral premammillary hypothalamic nuclei (16). The NTS and LPB thus contain functional receptor protein, suggested by receptor gene expression to be the Ob-Rb splice variant; are part of a specific neural pathway that is activated by leptin; or present a combination of these two putative signaling systems. A number of metabolic and endocrine stimuli are known to activate (c-FLI) the NTS-LPB axis via a vagal mechanism (19, 20).

Further description of the roles of NTS and LPB in leptin signaling must await anatomical definition of receptor fields and sites of c-FLI, although given the comparatively low level of expression of receptor mRNA in rat hindbrain compared with those in the mouse and in hypothalamic tissues, demonstration of receptor protein in this site may be difficult. [¹²⁵I]Leptin uptake into the brain after systemic injection has only been examined in the forebrain (21). The ability of circulating leptin to access brain stem sites is thus uncertain, although the proximity to the NTS of the area postrema, a circumventricular organ, should allow access to circulating humoral agents (22). The induction of c-FLI may be a secondary response related to the processing of afferent signals or to other physiological responses to an increased plasma leptin concentration (16). However, if the functional receptor protein is present in the rodent hindbrain, leptin may have a direct receptor-mediated action to either initiate or modulate afferent signals. This putative hindbrain signaling pathway may complement more direct hypothalamic interactions. That the regulation of leptin receptor gene expression by circulating plasma leptin appears to be restricted to the hypothalamus (9, 13) hints at the hierarchy of the relationship between these putative signaling routes; the absence of functional leptin in the obese (ob/ob) mouse did not affect Ob-R or Ob-Rb mRNA levels in the NTS and LPB.

	Footnotes

 
¹ This work was supported by the Scottish Office Department for Agriculture, Environment, and Fisheries.

Received July 29, 1997.

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