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Biology of Reproduction 64, 1614-1618 (2001)
© 2001 Society for the Study of Reproduction, Inc.

Regular Article

Developmental Changes in the Long Form Leptin Receptor and Related Neuropeptide Gene Expression in the Pig Brain1

Ji Linc, C. Richard Barb2,d, Robert R. Kraelingd, and George B. Rampacekc

c Department of Animal and Dairy Science, University of Georgia, Athens, Georgia 30602 d USDA, Agricultural Research Service, Athens, Georgia 30605

ABSTRACT

The hypothalamus is the key site of central regulation of energy homeostasis, appetite, and reproduction. The long form leptin receptor (Ob-Rl) is localized within the hypothalamus along with several neuropeptides that are involved in regulation of the neuroendocrine axis. In the present study, developmental changes in gene expression of the Ob-Rl, preproorexin, proopiomelanocortin (POMC), corticotropin releasing factor (CRF), somatostatin, and GnRH in the hypothalamus was studied. Expression of Ob-Rl and neuropeptide mRNA was examined by semiquantitative reverse transcription-polymerase chain reaction in hypothalami collected from 106-day-old fetus (n = 3) and 7-day-old (n = 3), 3.5-mo-old (n = 3), and 6-mo-old (n = 2) gilts. In addition, leptin mRNA expression in the first three ages was examined in back fat. Leptin mRNA expression increased (P < 0.05) by 7 days postnatal, but Ob-Rl mRNA expression increased (P < 0.01) by 3.5 mo. Expression of preproorexin (P < 0.05), somatostatin, and GnRH (P < 0.01) mRNA peaked by 3.5 mo of age while POMC mRNA expression increased markedly (P < 0.01) by 6 mo of age. The CRF mRNA expression did not change across ages. These findings suggest a possible relationship among Ob-Rl and a number of hypothalamic and peripheral peptides in the development of the neuroendocrine axis. These peptides may serve as messengers that link mechanisms that regulate reproduction and energy balance.

developmental biology, hypothalamic hormones, hypothalamus, leptin, leptin receptor, neuropeptides

INTRODUCTION

The hypothalamus is the key site of central nervous system (CNS) regulation of energy homeostasis and reproduction. These effects are mediated by interactions between neurotransmitters such as norepinephrine, dopamine, and neuropeptides, including neuropeptide Y (NPY), GnRH, corticotropin releasing factor (CRF), orexin, somatostatin, proopiomelanocortin (POMC), and peripheral hormones that act at the hypothalamus (e.g., leptin or insulin). The recently discovered ob gene product, leptin, a 16-kDa protein produced mainly by adipocytes, plays an important role in regulating feed intake, energy balance, and reproduction. It is well documented that leptin's central action is largely due to mediating hypothalamic NPY gene expression [1, 2]. Neuropeptide Y is also an important central regulator of food intake, energy expenditure, and reproductive function. The long form leptin receptor (Ob-Rl) is coexpressed in NPY neurons in the arcuate nucleus of the hypothalamus [3]. Leptin treatment inhibited NPY synthesis in the hypothalamus and, thus, reduced feed intake and increased energy expenditure [3]. However, hypothalamic NPY is not the only CNS target for leptin because NPY knockout mice responded to leptin treatment [4]. The leptin receptor is colocalized with several other neuropeptides within the hypothalamus such as CRF, POMC, and orexin [5, 6] that are involved in CNS regulation of feed intake, energy balance, and reproduction. In the present study, we investigated developmental changes in Ob-Rl, preproorexin, POMC, CRF, somatostatin, and GnRH gene expression in the hypothalamus and leptin mRNA expression in back fat in the pig.

MATERIALS AND METHODS

Animals

All animal experiments were approved by the Animal Care and Use Committee of the University of Georgia and the USDA Richard Russell Agricultural Research Center. Crossbred 106-day-old female fetus (n = 3) and 7-day-old (n = 3), 3.5-mo-old (n = 3), and 6-mo-old (n = 2) prepuberal gilts were used. These ages are associated with developmental changes in LH secretory patterns [7–10]. Pigs were satiated prior to euthanizing by an i.v. injection of sodium thiopental, except for the 6-mo-old animals that were fasted 12 h prior to exsanguination at a local abattoir. After exsanguination, tissues were collected from all pigs. The cranial vault was opened and the hypothalamus excised within 5–8 min after making the following cuts: rostral to the optic chiasm, rostral to the mammillary bodies, lateral to the hypothalamic sulci, and ventral to the anterior commissure. Dorsal subcutaneous adipose tissue was collected from a 106-day-old female fetus, and 7-day-old and 3.5-mo-old animals as previously described [11]. All tissue samples were frozen in liquid nitrogen and maintained at -80°C until RNA isolation.

RNA Isolation and Purification

Total RNA was extracted using Trizol reagent (Gibco, Grand Island, NY) according to the manufacture's procedure. Isolated RNA was treated with RQ1 RNase-free DNase (Promega, Madison, WI) to eliminate possible genomic DNA contamination. In brief, 10 µg of the RNA sample plus 5 µl 10x reaction buffer (400 mM Tris-HCl [pH 7.9], 100 mM NaCl, 60 mM MgCl2, 100 mM CaCl2), 5 units DNase, 1 µl RNasin (Promega, 40 U/µl), and RNase-free water was added to a final volume of 50 µl and incubated at 37°C for 30 min, then an equal volume of phenol/chloroform (Amresco, Solon, OH) was added. The mixture was vortexed and centrifuged at 12 000 x g for 15 min, the aqueous phase carefully transferred to a new Eppendorf microcentrifuge tube, and 1 ml 100% ethanol added and centrifuged at 12 000 x g for 10 min. The pellet was washed in 100% ethanol and centrifuged again. The pellet was air dried and resuspended in 20 µl RNase-free water and quantified by spectrophotometer (model DU640; Beckman, Fullerton, CA) at 260 nm and 280 nm. Quality of RNA was checked by electrophoresis using a 1% denatured agarose gel and stained with ethidium bromide.

Semiquantitative Reverse Transcription-Polymerase Chain Reaction

Two micrograms of total RNA was denatured with 500 ng oligo(dT) and 25 ng random primer at 70°C for 10 min and chilled on ice. Then, 4 µl 5x buffer (250 mM Tris-HCl [pH 8.3], 375 mM KCl, 15 mM MgCl2), 2 µl 0.1 M dithiothreitol, 1 µl dNTP mixture (10 mM each), 1 µl Superscript II reverse transcriptase (Gibco), and 0.5 µl of RNasin (Promega) and RNase-free water were added to a final reaction volume of 20 µl. The tube was incubated at room temperature for 10 min and then transferred to 48°C for 50 min followed by additional 10 min at 70°C in a thermocycler (Gradient 40 robocycler; Stratagene, La Jolla, CA). After reverse transcription (RT), a 20-µl volume contained 2 µl of cDNA, 1 µl primer mixture (50 pmol each except 10 pmol each for 18s), 2 µl 10x buffer (500 mM KCl, 100 mM Tris-HCl [pH 9.0 at 25°C], 1% Triton X-100), 15 mM MgCl2, 1 µl dNTP mixture (10 mM each), and 2.5 units Taq DNA polymerase (Promega) was used for the polymerase chain reaction (PCR). The PCR was performed at 1 cycle of 94°C for 3 min, specific annealing temperature for 1 min, and 72°C for 1 min, followed by 28 cycles at 94°C for 30 sec, specific annealing temperature for 1 min, and 72°C for 1 min and for 10 min in the last cycle. Specific annealing temperature and primers for each gene are presented in Table 1. Yield of 18s and ObR-l PCR products from 20–32 cycles was measured to determine the linear amplification range (Fig. 1). Negative controls were total RNA without reverse transcriptase. The PCR product for each specific gene was confirmed by its size and enzyme digestion. The PCR products were electrophoresed on a 2% agarose gel followed by ethidium bromide staining (0.4 µg/ml) and analyzed with an image analysis system (Flurochem; Alpha Innotech Corporation, San Leandro, CA) and related software (Flurochem version 1.02).


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  		TABLE 1. Primer pairs for each selected gene, the annealing temperature, the length of PCR products, and the Genbank access number from which the primers were selected



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  		FIG. 1. Linear range of 18s rRNA and Ob-Rl mRNA PCR amplification. R2 = 0.993 and 0.970, respectively

Data Analysis

Data from the image analysis were expressed as a ratio of Ob-Rl or neuropeptide mRNA relative to 18s rRNA. Expression data were subjected to square root transformation and one-way ANOVA according to the general linear model procedure of the Statistical Analysis System [12]. Differences between ages were determined by least-square contrasts. Linear regression was performed on the 18S rRNA and Ob-Rl mRNA amplification. A P value equal to or less than 0.05 was considered significant.

RESULTS

Data from image analysis are presented in Table 2, and an RT-PCR analysis of mRNA from a representative animal for each age is presented in Figure 2. Expression of Ob-Rl was greater (P < 0.05) at 3.5 mo and 6 mo of age than at the two earlier ages. Leptin mRNA expression in back fat was lower (P < 0.01) in 106-day-old fetuses than in 7-day-old and 3.5-mo-old gilts, whereas leptin mRNA was lower (P < 0.01) in 3.5-mo-old gilts than in 7-day-old gilts. Preproorexin mRNA expression was similar among 106-day-old fetuses and 7-day-old and 6-mo-old gilts but was greater (P < 0.05) in 3.5-mo-old gilts than in the other three age groups. The CRF mRNA expression was similar across ages. Somatostatin mRNA expression and GnRH mRNA expression was similar for 106-day-old fetuses, and 7-day-old and 6-mo-old gilts, whereas expression of mRNA for these neuropeptides was greater (P < 0.02) in 3.5-mo-old gilts compared to the other groups. The POMC mRNA expression was greater (P < 0.01) in 6-mo-old gilts compared to other groups.


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  		TABLE 2. Hypothalamic expression of OB-Rl, preproorexin, CRF, somatostatin (SS), GnRH and POMC mRNA, and adipose tissue expression of leptin (LS mean ± SEM) for 106-day-old fetus (n = 3) and 7-day-old (n = 3), 3.5-mo-old (n = 3), and 6-mo-old (n = 2) gilts.a



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  		FIG. 2. The RT-PCR analysis of 18s rRNA, Ob-Rl, GnRH, POMC, somatostatin, preproorexin, CRF mRNA in hypothalamic tissue and leptin mRNA in adipose tissue from a representative animal for each age. Lanes 1, 2, 3, and 4 represent 106-day-old fetus, 7-day-old, 3.5-mo-old, and 6-mo-old female pig, respectively

DISCUSSION

The ob and db genes encode leptin [13] and its receptor [14], respectively. The action of leptin is mediated via Ob-Rl in the hypothalamus [15]. Leptin mRNA expression in adipose tissue was detectable in 106-day-old fetuses as was Ob-Rl expression in hypothalamic tissue. We previously observed Ob-Rl expression in adipose tissue from a 50-day-old fetus [16]. Taken together these data suggest that leptin may play a role during fetal development. The Ob-Rl mRNA expression in the hypothalamus increased by 3.5 mo of age and remained elevated at 6 mo of age relative to 106-day-old fetuses and 7-day-old gilts, demonstrating an age-dependent increase in Ob-Rl expression. This occurred at a time when serum leptin concentrations increased in the developing pig [17]. In the pig a constant ad libitum intake of feed was established between 4 and 6 mo of age, in advance of attainment of mature size [18]. Thus, changes in serum leptin concentrations, coupled with Ob-Rl expression in the hypothalamus, may, in part, explain the age-related change in feed intake.

The early growth pattern of the gilt is linear. Growth sharply increased from the postnatal to the peripubertal period [19]. However, serum GH concentrations and pituitary response to GH releasing factor declined with age in the pig [20]. Greater hypothalamic somatostatin mRNA expression at 3.5 mo of age compared to the other ages supports the idea of an age-related decline in GH secretion related to increased somatostatin secretion. Furthermore, Drisko et al. [21] reported a temporal relationship between hypophyseal-portal blood concentration of somatostatin and generation of serum GH pulses in the pig.

In general, in the gilt, mean serum LH concentration and serum LH pulse frequency increased from 15 days of age to maximum levels between 110 and 125 days of ages, then decreased until 150 days of age and remained suppressed (juvenile nadir) until the peripuberal period [7–10]. There is little information regarding mechanisms within the brain that brings the various components of the reproductive axis together in a proper temporal relationship to initiate puberty [22–25]. Several studies have characterized LH secretion in the pig during pubertal development. In the present study, GnRH mRNA expression increased markedly by 3.5 mo of age and declined by 6 mo of age. This expression pattern is consistent with the LH secretory pattern observed during development; particularly around the time of the juvenile nadir. A recent report by Morash et al. [26] demonstrated that leptin mRNA is selectively expressed in specific areas in the brain and pituitary in the rat. Leptin gene was expressed in the hypothalamus, and expression was regulated by nutrient availability. The authors suggested that central leptin mRNA expression may play a role in appetite control. It is possible that central leptin may be involved in maturation of the GnRH/LH secretory axis.

In the present study, CRF expression did not change over the ages studied. This is consistent with an early report by Emanuel et al. [27] indicating that CRF mRNA expression in the rat hypothalamus did not change during development. However, there could be posttranscriptional regulation of the CRF gene product in rats [27] as well as in pigs.

Other substances may be intermediates in the signal transduction pathway between leptin and GnRH secretion. Neurons containing POMC and its products, i.e., ACTH, ß-endorphin, and melanocyte stimulating hormones (MSHs), are located in areas within the hypothalamus that are involved in GnRH secretion and feed intake regulation in the pig [28, 29]. Direct synaptic contacts between POMC- and GnRH-containing neurons were found in the arcuate nucleus of the hypothalamus, a region high in Ob-Rl mRNA [30–32]. Leptin treatment reduced feed intake and increased POMC mRNA in ob/ob mice [33] and fasting decreased POMC mRNA expression in rodents [34, 35]. In the pig, morphine suppressed LH secretion after intracerebroventricular (ICV) administration [36] and inhibited GnRH release from hypothalamic tissue in vitro [37]. Thus, the potential exists for leptin, through activation of the POMC gene, to influence LH secretion. Furthermore, recent studies demonstrated that MSH acts to inhibit feed intake via the melanocortin-4-receptor [38]. In the present study, POMC mRNA expression increased by 6 mo of age, a time when GnRH expression was suppressed. This increased expression in POMC may contribute to changes in feed intake and the juvenile nadir in LH secretion described above.

Orexins (Orexin-A and -B) are neuropeptides synthesized in the hypothalamus and derived from preproorexin. Preproorexin mRNA expression is located in the dorsal and lateral hypothalamic areas of the rat brain [39]. Orexin neurons send projections to multiple targets including the arcuate nucleus and the preoptic area [39, 40]. Horvathe et al. [41] colocalized Ob-R on orexin-containing neurons. In addition, orexin neurons innervate POMC and NPY neurons, suggesting that orexin not only modulates feed intake but also regulates neuroendocrine function. Orexin treatment stimulated food intake while fasting increased orexin expression in the rat [42]. Moreover, ICV administration of orexin stimulated LH secretion in steroid-treated ovariectomized rats [43]. Preproorexin gene expression was high at 3.5 mo of age compared to the other ages in the current study. This occurred at a time when LH secretion is relatively high in the pig [8].

In summary, although these findings are correlative in nature, the data suggest that Ob-Rl and a number of hypothalamic and peripheral peptides may be associated with development of the neuroendocrine axis and may serve as messengers that link mechanisms that regulate reproduction and energy balance. However, future studies are needed to demonstrate that the mRNA is translated into protein product before definitive conclusions can be made.

ACKNOWLEDGMENTS

The authors are grateful to Dr. Rick Meinersmann for using his facilities and Mr. Benny Barrett for his technical help.

FOOTNOTES

First decision: 25 April 2000.

1 This research was supported by USDA funds and State and Hatch funds allocated to the Georgia Agricultural Experiment Station. Mention of a trade name, proprietary product, or specific equipment does not constitute a guarantee or warranty by the U.S. Department of Agriculture or the University of Georgia and does not imply its approval to the exclusion of other products that may be suitable. Back

2 Correspondence: C. Richard Barb, Animal Physiology Unit, USDA, ARS, R.B. Russell Research Center, P.O. Box 5677, Athens, GA 30604-5677. FAX: 706 542 0399; rbarb{at}saa.ars.usda.gov Back

Accepted: January 16, 2001.

Received: March 17, 2000.

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