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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 7 3278-3283
Copyright © 2003 by The Endocrine Society

Changes in Diurnal Sympathoadrenal Balance and Pituitary Hormone Secretion in Subjects with Leu7Pro Polymorphism in the Prepro-Neuropeptide Y

Jaana Kallio, Ullamari Pesonen, Ulriikka Jaakkola, Matti K. Karvonen, Hans Helenius and Markku Koulu

Departments of Pharmacology and Clinical Pharmacology (J.K., U.P., U.J., M.K.) and Biostatistics (H.H.), University of Turku, and Hormos Medical Corporation (M.K.K.), FIN-20520 Turku, Finland

Address all correspondence and requests for reprints to: Jaana Kallio, M.D., Ph.D., Department of Pharmacology and Clinical Pharmacology, University of Turku, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland. E-mail: jaana.kallio{at}utu.fi.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Neuropeptide Y (NPY) is an important neurotransmitter in the central and peripheral nervous systems. It has a regulatory role in cardiovascular and metabolic functions and control of hormone release. The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of prepro-NPY is associated with increased blood lipid levels, accelerated atherosclerosis, and diabetic retinopathy. This study elucidated the role of this polymorphism in diurnal cardiovascular, metabolic, and hormonal functions of healthy subjects during rest. The two study groups comprised individuals with different genotype, but they were matched for age and body mass index. Subjects with the Leu7Pro polymorphism had significantly lower plasma NPY and norepinephrine concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin-glucose ratio in plasma than the controls. Heart rate was significantly higher during daytime in the subjects with Leu7Pro polymorphism. Furthermore, these subjects had significantly lower prolactin concentrations in plasma. Systolic and diastolic blood pressure, serum free fatty acid and plasma leptin, ACTH, cortisol, LH, FSH, TSH, free thyroxin, and melatonin concentrations were similar during the 24-h period, compared with controls. These results show that genetically determined changes in NPY levels lead to widespread consequences in the control of sympathoadrenal, metabolic, and hormonal balance in healthy subjects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
NEUROPEPTIDE Y (NPY) IS a neurotransmitter that is expressed together with its receptors (Y1-Y5) in many brain areas and peripheral tissues. It has many important functions in the mammalian central and peripheral nervous systems including control of blood pressure (BP), heart rate (HR), and hormone release (1, 2, 3, 4, 5, 6, 7, 8, 9). Early findings already indicated that NPY is abundant in the surroundings of blood vessels (10), and exogenously given NPY increases BP (7, 8). On the other hand, it has been shown quite recently that NPY may also counteract vasoconstriction by vascular endothelium-dependent mechanisms (11). In the heart, NPY inhibits vagal postganglionic nerves and thereby increases HR (12, 13). However, centrally administered NPY decreases HR and BP by decreasing sympathetic outflow from the brain stem (14). These effects show that NPY is an important physiological modulator of cardiovascular functions in the autonomic and central nervous systems and may be associated with pathophysiological mechanisms of vascular diseases.

In experimental animals, NPY has multiple effects on the control of hormone release in the brain (15, 16, 17). The effect of centrally administered NPY on gonadotropin release can be inhibitory or stimulatory, depending on the species studied and experimental conditions (16). NPY has been shown to inhibit TRH transcription and decrease circulating thyroid hormone levels in the rat (15). The effect of centrally administered NPY on prolactin (PRL) secretion is inhibitory with low concentrations and stimulatory with high concentration of NPY (17, 18). In addition, NPY has an acute stimulating effect on CRH release, which subsequently increases ACTH and 11ß,17,21-trihydroxypregn-4-ene-3,20-dione (cortisol) secretion, but chronically centrally administered NPY reduces CRH expression in the brain (19, 20, 21). Based on experimental data, NPY has also an increasing effect on melatonin production (22).

Because of lack of suitable pharmacological tools, it is difficult to study the effects of NPY on hormone secretion in the central nervous system in humans. However, there is evidence that NPY may control hormone levels by peripheral mechanisms in humans. In healthy subjects, exogenously given NPY has inhibitory effects on hypothalamo-pituitary-adrenocortical axis, decreasing the concentrations of ACTH and cortisol in plasma (23). However, no effects of iv NPY on plasma PRL or leptin concentrations were seen (24).

The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of prepro-NPY occurs in 6–13% in Caucasian subjects (25). Recent studies have indicated several physiological consequences of the Pro7 substitution. Healthy subjects with the Leu7Pro polymorphism have increased NPY and GH secretion, lower insulin and free fatty acid (FFA) concentrations, and higher HR during standardized physical exercise, compared with control subjects without the polymorphism (26, 27). Cellular mechanisms behind these changes are not completely clear but may include altered intracellular processing and secretion of NPY from cells to circulation or to paracrine targets because of the structural change in the signal peptide part of the nascent prepro-NPY (26). The detected changes in physiological responses may be related to the observed associations of the Leu7Pro polymorphism with high blood lipid levels in adults and children (25, 28) and accelerated atherosclerosis in middle-aged men and type 2 diabetic patients (29, 30) as well as with accelerated progression of diabetic retinopathy in type 2 diabetic patients (31). The current study was undertaken to clarify the role of the Leu7Pro polymorphism of prepro-NPY in the diurnal sympathoadrenal, metabolic, and hormonal physiology during rest in healthy subjects.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

The Ethical Committee of the Hospital District of Southwest Finland approved the study. Written informed consent was obtained from each subject for genotyping and participation in the diurnal study.

To exclude nonhealthy subjects, detailed medical history (including diseases, medication, smoking, trauma, and alcohol consumption) was taken, a physical examination (including electrocardiogram, cardiac and pulmonary auscultation, BP measurement, thyroid palpation, and screening for clinical signs of infection) conducted, and basic laboratory screening (blood hemoglobin, total cholesterol, low-density lipoprotein cholesterol, glucose, FFA and alanine amino transferase concentration, leukocyte count, and erythrocyte sedimentation rate) was done before the subjects entered the study.

Fourteen healthy, male, Caucasian, nonsmoking subjects were originally recruited in two study groups. The Leu7/Pro7 group comprised subjects having one wild-type allele and one polymorphic allele leading to Pro7 substitution in the signal peptide of prepro-NPY. The control Leu7/Leu7 group consisted of subjects with two wild-type alleles. The groups were matched for age and body mass index (BMI). One Leu7/Pro7 subject did not arrive to the study. The mean (SD) age was 22.5 (1.0) yr in the Leu7/Pro7 group (n = 6) and 21.3 (0.4) yr in the Leu7/Leu7 group (n = 7). The mean BMI was 23.9 (0.45) kg/m2 in the Leu7/Pro7 group and 23.3 (0.44) kg/m2 in the Leu7/Leu7 group. Nevertheless, the mean weight was significantly higher in the Leu7/Pro7 group [77.8 (6.9) kg] than in the Leu7/Leu7 group [70.5 (5.4) kg, P < 0.05, t test]. Quantitative insulin sensitivity check index, a recently defined parameter for insulin resistance (32), was similar in the two genotype groups [0.331 (0.014) in Leu7/Pro7 subjects and 0.327 (0.009) in Leu7/Leu7 subjects].

Genotyping

For genotyping, blood samples (10 ml) were drawn from an antecubital vein. Blood leukocyte DNA was extracted by using Puregene DNA isolation kit (Gentra Systems, Minneapolis, MN) following the manufacturer’s instructions. The genotype was determined as described earlier (25).

Diurnal study protocol

The study subjects were asked to refrain from any medication and alcohol-containing drinks for 48 h and any caffeine-containing food or drink for 10 h before the study period. They were asked to avoid strenuous physical exercise for 2 d preceding the study. The subjects were followed up in a clinical research unit for 24 h (from 0800 h to 0800 h). An iv cannula was inserted into an antecubital vein for blood sampling. Standard meals were offered for breakfast (at 0900 h), lunch (at 1200 h), snack (at 1500 h), dinner (at 1800 h), and evening snack (at 2200 h). The subjects stayed in the research unit for the whole study period during which they mostly remained recumbent but were allowed to sit and walk occasionally. However, before each blood sampling, the subjects were lying for at least 15 min. They were encouraged to sleep after 2300 h, at which time all lights were turned off and no activities were allowed. Blood samples were drawn hourly between 0800 and 2400 h and then at 0200, 0600, and 0800 h. The study subjects were monitored (electrocardiogram and BP) by Datex Engstrom AS/3 system (Datex Ohmeda, Oulu, Finland). HR and systolic and diastolic BP were recorded every time after blood sampling from the contralateral arm.

Analytical methods

Plasma concentrations of NPY was determined using commercial RIA kit EURIA-NPY (Euro-Diagnostica Inc., Malmö, Sweden), plasma insulin with INSIK-5 RIA kit (DiaSorin, Inc. S.r.l., Saluggia, Italy), plasma leptin with human leptin RIA kit (Linco Research, Inc., St. Charles, MO), plasma ACTH with ACTH immunoradiometric assay (IRMA) kit (DiaSorin, Inc., Stillwater, MN), and plasma FSH and LH with IRMA kits from DRG (DRG Diagnostics, Marburg, Germany). Plasma PRL was determined with Spectria PRL IRMA kit, cortisol with Spectria Cortisol RIA kit, TSH with Spectria TSH IRMA kit, and free T4 (fT4) with Spectria FT4 RIA kit, all supplied by Orion Diagnostica (Espoo, Finland). Plasma glucose was determined with a reflection photometer method (Reflotron, Roche Diagnostics, GmbH, Mannheim, Germany). FFA concentrations in serum were determined with NEFA-C reagent set (Wako Chemicals GmbH, Neuss, Germany). Plasma melatonin was determined with RIA as previously described (33). Norepinephrine (NE) concentrations in plasma were determined using HPLC with electrochemical detection as previously described (34). Other laboratory measurements were done by standard methods.

Statistical analysis

The data were analyzed using linear mixed models using MIXED-procedure in the SAS System for Windows (release 8.2/2001; SAS Institute Inc., Cary, NC). Comparisons between the two genotype groups in the average level of each response variable were done by formulating a model for analysis of repeated measurements recorded at different time points. The individual matching was taken into account by defining the pair as a random factor (35). The regression analyses for associations between variables, and differences in these associations between the genotype groups, were also analyzed taking into account the repeated measurements and matched pairs by defining a repeated factor and a random factor in the formulation of the models. In addition to testing the equality of the regression slopes, the regression coefficients were also estimated separately for both groups. A two-sided P value of less than 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The Leu7/Pro7 subjects had significantly lower NPY (Fig. 1AGo) and NE (Fig. 1BGo) concentrations (genotype group effect F(df1,df2) values 8.48(1,7.1) and 6.76(1,41.1), respectively, P < 0.05). HR was significantly higher (Fig. 1CGo, genotype group-by-time effect F(df1,df2) value 2.19(14,139), P < 0.05) during daytime (between 0800 and 2300 h) in the Leu7/Pro7 group. Systolic and diastolic BP, FFA, and leptin concentrations were not significantly different between the two study groups (Table 1Go). The Leu7/Pro7 subjects had significantly higher glucose concentrations (Fig. 2AGo, genotype group effect F(df1,df2) value 6.17(1,58.5), P < 0.05), lower insulin concentrations (Fig. 2BGo, genotype group effect F(df1,df2) value 7.10(1,58.2), P < 0.05), and lower insulin:glucose ratio (Fig. 2CGo, genotype group effect F(df1,df2) value 12.39(1,48.2), P < 0.05) than the control Leu7/Leu7 subjects.



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  		FIG. 1. NPY (A) and NE (B) concentrations were significantly lower in the Leu7/Pro7 subjects (open triangles) than in the Leu7/Leu7 subjects (solid triangles). HR (C) was significantly higher in the Leu7/Pro7 subjects between 0800 h and 2300 h. Standard meals (dashed vertical lines) were offered for breakfast (BF), lunch (LC), snack (SN), and dinner (DN). Errors bars represent SEM values. NPY: 1 pg/ml = 0.000234 nmol/liter; NE: 1 pg/ml = 0.005911 nmol/liter.

 

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  		TABLE 1. Genotype group effect and genotype group-by-time interaction effect on variables measured during a 24-h study period (MIXED-procedure)

 


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  		FIG. 2. Significantly higher glucose concentrations (A), lower insulin concentrations (B), and lower insulin:glucose ratio (C) were found in the Leu7/Pro7 subjects (open triangles) than in the Leu7/Leu7 subjects (solid triangles). Standard meals (dashed vertical lines) were offered for breakfast (BF), lunch (LC), snack (SN), and dinner (DN). Errors bars represent SEM values. Glucose: 1 mg/dl = 0.05551 mmol/liter; insulin: 1 µU/ml = 6 pmol/liter.

 
The Leu7/Pro7 subjects had significantly lower PRL concentrations (Fig. 3Go) in the peripheral plasma (genotype group effect F(df1,df2) value 22.52(1,24.8), P < 0.001). Plasma ACTH, cortisol, LH, FSH, TSH, and melatonin concentrations were similar between the two genotype groups (Table 1Go). There was a tendency for higher fT4 concentrations in the Leu7/Pro7 subjects (P = 0.064, Table 1Go).



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  		FIG. 3. Significantly lower PRL concentrations were found in the Leu7/Pro7 subjects (open triangles) than in the Leu7/Leu7 subjects (solid triangles). Standard meals (dashed vertical lines) were offered for breakfast (BF), lunch (LC), snack (SN), and dinner (DN). Errors bars represent SEM values. PRL: 1 ng/ml = 1 µg/liter.

 
Significant differences were observed in correlations of several cardiovascular and hormonal parameters with plasma NE or NPY concentrations between the study groups (Table 2Go). There was a significant positive correlation of plasma NPY concentration with HR and diastolic BP in subjects with the Pro7 substitution but not in the controls (Table 2Go). Plasma NE had a significantly stronger positive correlation with systolic and diastolic BP as well as plasma cortisol and ACTH concentrations in subjects with the Pro7 substitution than in the control subjects (Table 2Go).


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  		TABLE 2. Comparison of the linear regression coefficients of plasma concentration of NPY and NE vs. other measured variables between the Leu7/Pro7 and Leu7/Leu7 genotype groups

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The Leu7Pro polymorphism of prepro-NPY has been shown to lead to increased plasma NPY and GH levels, decreased plasma insulin and serum FFA levels, and increased HR in healthy subjects during high-intensity exercise (26, 27). The current study investigated the role of the Leu7Pro polymorphism in diurnal sympathoadrenal, metabolic, and hormonal functions in rest during a 24-h period in healthy male subjects. We found lower plasma NPY and NE concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin:glucose ratio in subjects with the Pro7 substitution than in the control subjects. We also found decreased plasma PRL concentrations in the Leu7/Pro7 subjects. Furthermore, higher HR during awake hours was detected in these subjects, compared with controls.

We observed decreased NPY concentrations in the Leu7/Pro7 subjects during rest in this study. On the other hand, increased NPY concentrations were observed in subjects with this genotype during high-intensity exercise in our earlier study (26). This indicates that the Leu7Pro polymorphism has different effects on the plasma NPY kinetics in rest and exercise. Because circulating NPY is derived mainly from perivascular sympathetic nerve bundles (36, 37, 38, 39), the mechanisms may be related to changed intraneuronal kinetics of NPY. It is possible that in rest, the Leu7Pro polymorphism leads to impaired release and intracellular retention of NPY, followed by an exaggerated release of NPY in high-intensity sympathetic stimulation. Also, the elimination of NPY from plasma by degradation or excretion through kidneys could be affected differently in rest and exercise in subjects with the prepro-NPY polymorphism. However, changed intracellular kinetics of NPY synthesis and processing seems a more plausible mechanism on the basis of known functions of signal peptides. Our earlier studies with genotyped human endothelial cells also support the hypothesis that there is increased intracellular storage of NPY because of the Leu7Pro polymorphism (26).

NE and NPY are coreleased in strong sympathetic stimulation from sympathetic nerves, in which these two transmitters are colocalized in large dense-cored vesicles (36, 37, 38, 39, 40). In this study, the plasma concentration of NE was also lower in Leu7/Pro7 subjects, compared with controls. This indicates that the Leu7Pro polymorphism of prepro-NPY also modifies the secretion of NE in rest. The mechanism is not known but may be related to the regulation of the release of the common storage vesicles in neurones.

We detected higher HR during daytime in subjects with the Pro7 substitution, compared with controls. The present study confirms the earlier finding during exercise (26). The effect on HR may be explained by the experimentally shown parasympatholytic action of NPY in the heart. NPY does not have direct effects on HR (41) but inhibits vagal postganglionic nerves through Y2 receptors and thereby increases HR (12, 13, 42, 43, 44). On the other hand, subjects with the Leu7/Pro7 genotype may have higher HR because of altered central regulation of autonomic balance because centrally given NPY has been shown to have effects on HR (14).

There was no difference in BP between the genotypes in this study, although NPY is thought to have a significant role in the regulation of BP. This may be because of opposing actions of NPY on vascular tone through different mechanisms, e.g. peripheral vs. central and postsynaptic vs. presynaptic (7, 8, 45, 46, 47), which may counteract each other in in vivo situations in young healthy subjects. An earlier study with 966 middle-aged men indicated that subjects with the Pro7 substitution have in average 2–3 mm Hg higher BP levels than the subjects without this polymorphism (30). The significance of the stronger positive relationships of plasma NE and NPY with systolic and/or diastolic BP in the Leu7/Pro7 subjects, compared with controls in the current study, is not known. This finding perhaps indicates higher responsiveness of the vascular tone for concentration changes of NE and NPY in the blood.

The Leu7/Pro7 subjects had lower insulin levels and higher glucose levels throughout the 24-h study period than the controls. Similar results, with lower insulin secretion, in Leu7/Pro7 individuals were obtained during exercise in our earlier study with matched genotyped subjects, who were given a standard meal 2 h before the exercise (26). The subjects were also given standard food portions in the present study, and they were matched for BMI. However, the Leu7/Pro7 individuals were heavier; therefore, it is not possible that the intake of caloric nutrients in relation to body weight was higher in these subjects. Because insulin sensitivity was similar in the study groups, the results suggest slightly impaired insulin release after meals in the Leu7/Pro7 subjects. The increased NPY levels detected in tissue level (26) could be a possible mechanism because NPY has been shown to inhibit glucose-stimulated insulin secretion in human pancreatic ß-cells (48). Also, a changed response to glucose in the brain and a changed central regulation of autonomic balance in the Leu7/Pro7 subjects are possible mechanisms. However, the association of altered NPY balance and insulin secretion needs further clarification.

FFA levels were similar between the genotypes in rest, although lower levels of FFAs in Leu7/Pro7 individuals were detected during exercise (26). NPY has been shown to inhibit lipolysis in human adipocytes by inhibiting the hormone-sensitive lipase (2, 49). This was not seen in the present study, maybe because there was no significant stimulation of lipolysis during rest in either study group as indicated by constantly low FFA concentrations. We also measured leptin, which is secreted by adipose tissue, in the present study. This peptide hormone acts centrally, decreasing appetite and increasing energy expenditure (50). There were no differences in plasma leptin concentrations during rest between the subjects with different prepro-NPY genotypes but similar BMI. This indicates that the Leu7Pro polymorphism does not have a major contribution to leptin levels in humans.

An outstanding finding of the present study is that the subjects with Pro7 substitution in the prepro-NPY have lower plasma PRL levels. The lower secretion of PRL in Leu7/Pro7 subjects was also detected in our earlier exercise study (Kallio, J., U. Pesonen, K. Kaipio, M. K. Karvonen, U. Jaakkola, O. J. Heinonen, M. I. J. Uusitupa, M. Koulu, unpublished results), where enhanced GH secretion was reported in these subjects (27). These findings may indicate a common mechanism of central regulation of the secretion of these pituitary hormones by NPY. This mechanism possibly includes the control of dopamine release into hypophyseal portal blood (24). On the basis of a very recent study (51), it is also possible that NPY could interfere with PRL-releasing peptides at their receptors.

There were no differences in the plasma levels of other pituitary hormones (i.e. ACTH, LH, FSH, or TSH) or cortisol between the genotype groups. The circadian variation in the concentrations of all studied hormones was identical, and melatonin levels were also similar throughout the study period. The results indicate that there are no disturbances in circadian rhythms in subjects with the Leu7Pro polymorphism. The tendency for increased fT4 levels in the Leu7/Pro7 subjects needs to be confirmed in future studies. The stronger correlation of plasma NE with plasma ACTH and cortisol observed in the Leu7/Pro7 subjects indicates that during rest these hormones may be coregulated more tightly in these subjects.

NPY is a multifunctional neurotransmitter with multiple modulator effects in the regulation of physiological functions and responses in the body. A change in its molecular structure, as in the Leu7Pro polymorphism, has been shown to associate with many diseases (25, 26, 27, 28, 29, 30, 31) and now with many changes in sympathoadrenal, hormonal, and metabolic balance in healthy subjects. The clinical significance of the current findings needs to be further clarified.

The exact molecular and cellular mechanisms by which the Leu7Pro polymorphism leads to the observed changes are not clear. Therefore, there is a possibility that the Leu7Pro polymorphism is a marker, which is in linkage disequilibrium with a yet-unknown functional mutation of the NPY gene.


   Acknowledgments
 
We thank Dr. Eriika Savontaus for valuable scientific comments and Raija Kaartosalmi for skillful technical assistance. The volunteers who participated in the study are also acknowledged.


   Footnotes
 
This work was supported by the National Technology Agency of Finland and the funds of Turku University Central Hospital.

Abbreviations: BMI, Body mass index; BP, blood pressure; cortisol, 11ß,17,21-trihydroxypregn-4-ene-3,20-dione; FFA, free fatty acid; fT4, free T4; HR, heart rate; IRMA, immunoradiometric assay; Leu7Pro, leucine 7 to proline 7; NE, norepinephrine; NPY, neuropeptide Y; PRL, prolactin.

Received December 12, 2002.

Accepted April 1, 2003.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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