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Activation of Dopamine D2 Receptors Lowers Circadian Leptin Concentrations in Obese Women

Departments of General Internal Medicine (P.K., A.E.M.), Endocrinology and Metabolic Diseases (F.R., H.P.), and Clinical Chemistry (M.F., J.v.P.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. Hanno Pijl, Leiden University Medical Center, Department of Internal Medicine (C4–83), P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: h.pijl{at}lumc.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Leptin release is regulated by factors other than fat mass alone. Previous observations provide indirect evidence for an inhibitory effect of dopaminergic neurotransmission on leptin secretion. This study was done to establish the effect of bromocriptine treatment on circadian plasma leptin concentrations in obese humans.

Objective: The objective of the study was to study the acute effects of bromocriptine (a D2R agonist) on circadian leptin levels in obese women, whereas body weight and caloric intake remained constant.

Design: This was a prospective, single-blind, crossover study (2004).

Setting: The study was conducted at a clinical research center.

Participants: Eighteen healthy obese women (body mass index 33.2 ± 0.6 kg/m²) were studied twice in the early follicular phase of their menstrual cycle.

Intervention(s): Treatment consisted of bromocriptine or placebo for 8 d.

Main Outcome Measure(s): Blood was collected during 24 h at 20-min intervals for determination of leptin concentrations at the last day of medical treatment (bromocriptine or placebo). Mean 24-h serum concentrations were determined for insulin, glucose, free fatty acids, and triglycerides.

Results: Short-term treatment with bromocriptine reduced leptin concentration (placebo 33.6 ± 2.5 vs. bromocriptine 30.5 ± 2.5 ng/liter, P = 0.03). Free fatty acid concentrations were increased by treatment with bromocriptine. The increase of free fatty acids was inversely related with the decline of leptin levels. The decline of glucose, insulin, or prolactin concentrations in response to bromocriptine was not correlated with the reduction of leptin.

Conclusion: Activation of dopamine D2 receptors by bromocriptine lowers circulating leptin levels in obese women, which suggests that dopaminergic neurotransmission is involved in the control of leptin release in humans.

	Introduction

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LEPTIN IS PRODUCED by adipocytes and serves as an endocrine signal to inform the brain about the size of body adipose tissue stores (1, 2, 3). Although circulating leptin levels are positively related to fat mass in groups of obese individuals (4), individual concentrations vary considerably for a given measure of adiposity (3). The fact that plasma leptin concentrations acutely change in response to fasting (5, 6), refeeding (6, 7), and increased food intake (7), even without any measurable alteration of body fat content, also supports the contention that leptin release and/or clearance are regulated by factors other than fat mass alone. Indeed, corticosteroids, insulin, prolactin, various cytokines, nutrient flux through adipocytes, and the sympathetic nervous system have all been shown to modulate leptin release by adipocytes (8).

In this context, previous observations provide indirect evidence for an inhibitory effect of dopaminergic neurotransmission on leptin secretion. In particular, it has been reported that treatment with bromocriptine, a dopamine D2 receptor agonist, significantly lowers the plasma leptin concentration in a single blood sample of humans with prolactinoma, even without affecting body weight (9). Furthermore, a single iv bolus injection of bromocriptine significantly reduced both basal and lipopolysaccharide-induced leptin release in rats (10). These data led us to hypothesize that short-term bromocriptine treatment would lower circadian plasma leptin concentrations in obese humans. To test this postulate, we measured plasma leptin concentrations in obese women who were treated with bromocriptine or placebo for 8 d. Because plasma leptin levels clearly exhibit circadian fluctuation, concentrations were measured over 24 h. Because bromocriptine significantly affected various metabolic and endocrine parameters that may impact on leptin secretion, including circulating insulin, glucose, and prolactin levels, we also report the statistical correlation between these parameters and leptin concentrations.

	Subjects and Methods

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Subjects

Eighteen healthy obese premenopausal women [body mass index (BMI) 30–35 kg/m², mean age 37.5 ± 1.7, range 22–51 yr] were enrolled. Before participation, all subjects underwent medical screening, including medical history taking, physical examination, standard laboratory hematology, blood chemistry, and urine tests. Acute or chronic disease, depression (present or in history), head trauma, smoking, alcohol abuse, recent transmeridian flights, night-shift work, weight change before the study (>5 kg in 3 months), recent blood donation or participation in another clinical trial (<3 months), and use of medication (including oral contraceptives) were exclusion criteria for participation. All participants were required to have regular menstrual cycles. All studies were performed in the early follicular phase of the menstrual cycle.

Drugs

Subjects were assigned to bromocriptine or placebo treatment for a period of 8 d in a single (patient) blind, crossover design, with a 4-wk time interval between each study occasion. To avoid potential crossover effects of bromocriptine treatment, all subjects received placebo during the first intervention period. All assays and analyses were performed by co-workers who were not aware of the type of intervention. A dose of 2.5 mg bromocriptine was prescribed on the first day. Thereafter, drug or placebo was taken twice daily (totaling 5.0 mg daily) at 0800 and 2000 h for 7 d. The drug was well tolerated, although 10 participants had gastrointestinal complaints (nausea, vomiting) on the first day of bromocriptine treatment only.

Diet

To limit confounding by nutritional factors, all subjects were prescribed a standard eucaloric diet, as from 1 d before admission until the end of each study occasion. All subjects received the same diet consisting of liquids (150 kcal per 100 ml, 16% proteins, 49% carbohydrates, and 35% fat). The caloric content and macronutrient composition of the diet was exactly the same (2100 kcal/d) for each individual participant at both study occasions. Intake of alcohol and caffeine/theine-containing beverages was not allowed. During the 24-h blood sampling period, meals were served according to a fixed time schedule (breakfast 0930 h, lunch 1300 h, dinner 1830 h) and were consumed within limited time periods (30 min). Compliance with the diet the day before admission was controlled; the next morning and during each admission, food intake was directly monitored by the investigators. No dietary restrictions were imposed between both study occasions.

Clinical protocol

The protocol was approved by the Medical Ethics Committee of the Leiden University Medical Center and was performed according the Helsinki Declaration. All subjects gave written acknowledgment of informed consent for participation and were admitted to the Clinical Research Unit of the Department of General Internal Medicine in the early follicular stage of their menstrual cycle. Subjects were studied twice with an interval of 4 wk, during which body weight remained stable and subjects were instructed to keep their physical activity level constant. The clinical set-up was the same during both occasions apart from the subject receiving the alternative treatment (bromocriptine or placebo). Subjects were admitted to the research center at 0700 h. A cannula for blood sampling was inserted into an antecubital vein, which was attached to a three-way stopcock and kept patent by a continuous 0.9% NaCl and heparin (1 U/ml) infusion (500 ml per 24 h). Blood samples for basal parameters were withdrawn and 24-h blood sampling started. Blood was collected with S-monovetten (Sarstedt, Etten-Leur, The Netherlands) at 20-min intervals for determination of leptin concentrations. Blood samples for the measurements of plasma insulin and glucose concentrations were taken at 10-min intervals and hourly for the assessment of plasma free fatty acid (FFA) and triglyceride levels. Subjects remained recumbent during the blood-sampling period, except for bathroom visits (24-h urine was collected). No daytime naps were allowed. Well-being and vital signs were recorded at regular time intervals (hourly). Lights were switched off at 2300 h, and great care was taken not to disturb and touch subjects during withdrawal of blood samples while they were sleeping. Lights were switched on and subjects were awakened at 0730 h.

Assays

Samples of each subject were determined in the same assay run. Plasma leptin concentrations were determined by RIA (Linco Research, St. Charles, MO). The detection limit was 0.5 ng/liter and the interassay coefficient of variation (CV) was 3.6–6.8%. Plasma prolactin (PRL) concentrations were measured with a sensitive time-resolved fluoroimmunoassay with a detection limit of 0.04 µg/liter (Delfia; Wallac Oy, Turku, Finland). Estradiol concentrations were determined by RIA (Diagnostic Systems Laboratory, Webster, TX). The detection limit was 10 pmol/liter and the interassay CV was 5.1–8.1%. Serum insulin was measured with immunoradiometric assay (Biosource Europe, Nivelles, Belgium) with a detection limit of 2 µU/liter and interassay CV of 4.4–5.9%. Plasma FFA levels were determined using a NEFA-C FFA kit (Wako Chemicals GmbH, Neuss, Germany) with a detection limit of 30 µmol/liter and interassay CV of 2.6%. Plasma triglyceride concentrations were measured using an enzymatic colorimetric kit (Roche Diagnostics GmbH, Mannheim, Germany) with a detection limit of 50 µmol/liter and interassay CV of 1.8%. Blood glucose concentrations were assessed using a blood glucose analyser (Accutrend; Boehringer, Mannheim, Germany). Basal serum glucose was measured using a fully automated Modular P 800 (Hitachi, Tokyo, Japan), and free T₄ concentrations were estimated using electrochemoluminescence immunoassay (Elecsys 2010; Roche Diagnostics Nederland BV, Almere, Netherlands).

Urine analysis

Urine was collected during the 24 h of blood sampling. Urinary epinephrine, norepinephrine, and dopamine concentrations were assessed by HPLC with electron capture detection.

Calculations and statistics

Area under the curve leptin profiles. Area under the curves of leptin concentration plots were calculated using the trapezoidal rule (SigmaPlot 2002, version 8.02; Systat Software, Inc., Point Richmond, CA).

Approximate entropy (ApEn). ApEn is a scale- and model-independent statistic that assigns a nonnegative number to time series data, reflecting regularity of these data (11). Higher ApEn values denote greater relative randomness of hormone patterns. Data are presented as normalized ApEn ratios, defined by the mean ratio of absolute ApEn to that of 1000 randomly shuffled versions of the same series. ApEn ratios close to 1.0 express high irregularity (maximum randomness) of pulsatile hormone patterns (12).

Circadian rhythmicity. Circadian characteristics of leptin concentration patterns were determined using a robust curve-fitting algorithm [LOWESS analysis, SYSTAT, version 11; Systat Inc., Richmond, CA, (13, 14)]. The acrophase (clock time during 24 h at which leptin concentration is maximal) is the maximal value of the fitted curve. The Mesor is the average value about which the diurnal rhythm oscillates. The amplitude of the rhythm was defined as half the difference of the nocturnal zenith and the daytime nadir. The relative amplitude is the maximal percentage increase of the Mesor value.

Statistics. Data are presented as means ± SEM, unless otherwise specified. Data were logarithmically transformed before statistical computations when appropriate and statistically analyzed using a parametric test (paired samples t test). Significance level was set at 0.05. Multiple regression analysis was performed to estimate the correlation between changes in metabolic parameters (mean 24-h glucose, insulin, triglyceride, and FFA plasma concentrations) vs. changes of mean circadian leptin concentrations induced by bromocriptine treatment in the obese subjects. Differences were calculated subtracting values during bromocriptine treatment from values during placebo treatment. Negative differences reflect a decrease and positive differences reflect an increase induced by bromocriptine treatment of the parameter.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Eighteen obese subjects were enrolled in the present study. Body weight and BMI were similar after placebo and bromocriptine treatment [weight, placebo (Pl) 94.1 ± 2.5 vs. bromocriptine (B) 94.4 ± 2.5 kg, P = 0.33; and BMI, Pl 33.2 ± 0.6 vs. B 33.3 ± 0.6 kg/m², P = 0.35]. All subjects were studied in the early follicular phase of their menstrual cycle (estradiol, Pl 163 ± 21 vs. B 209 ± 21 pmol/liter, P = 0.10; and progesterone, Pl 2.13 ± 0.64 vs. B 2.94 ± 1.13 nmol/liter, P = 0.56). Subjects were clinically euthyroid (free T₄ levels, Pl 14.6 ± 0.4 vs. B 14.4 ± 0.4 pmol/liter, P = 0.56). PRL concentrations were significantly reduced by bromocriptine (PRL, Pl 6.7 ± 1.1 vs. B 2.3 ± 0.4 µg/liter, P < 0.01).

Urine analysis

The total 24-h urine volume was not significantly different during both study occasions (Pl, 3202 ± 202 vs. B, 3075 ± 222 ml/24 h, P = 0.489). Urinary norepinephrine was significantly reduced after bromocriptine treatment (Pl, 0.184 ± 0.020 vs. B, 0.119 ± 0.015 µmol per 24 h, P < 0.001). Urinary epinephrine (Pl, 0.015 ± 0.005 vs. B, 0.011 ± 0.004 µmol per 24 h, P = 0.416) was not significantly different during placebo and bromocriptine treatment.

Leptin concentration parameters

Mean and area under the curves of 24-h leptin concentrations were significantly reduced by bromocriptine treatment (Table 1). A graphical illustration of mean 24-h plasma leptin concentrations during placebo and bromocriptine treatment vs. clock time is presented in Fig. 1.

View larger version (29K): [in this window] [in a new window]   FIG. 1. Mean diurnal serum leptin concentration time series in the obese subjects (n = 18) during placebo (-•-) and bromocriptine treatment (--). Data reflect sampling of blood every 20 min for 24 h. Blood sampling started at 0900 h. Lights were switched off and subjects went to sleep at 2300 h until 0730 h next morning, when lights were switched on (gray horizontal bar indicates sleeping period).

Correlations between leptin concentrations and metabolic parameters

Mean 24-h plasma glucose and insulin concentrations were significantly reduced by bromocriptine (10 and 24%, respectively), whereas mean 24-h plasma FFA concentrations were 30% higher during bromocriptine treatment. Multiple regression analysis, including differences () of mean 24-h glucose, insulin, FFA, and triglyceride concentrations as independent variables, revealed that differences in mean 24-h FFA concentrations (range FFA –0.04 to 0.48 mmol/liter) were significantly correlated with differences in mean 24-h leptin concentrations (partial correlation R² = 0.46, range leptin –14.7 to 8.2 ng/liter, P = 0.03, Fig. 2). Changes in mean 24-h circulating glucose (range glucose –1.22 to 0.72 mmol/liter, P = 0.23), insulin (range insulin –34.16 to 6.97 mU/liter, P = 0.40) and triglyceride concentrations (range triglyceride –0.41 to 0.63 mmol/liter, P = 0.23) were not related to changes in leptin concentrations.

View larger version (11K): [in this window] [in a new window]   FIG. 2. Differences in mean FFA concentrations were significantly inversely related to differences in mean 24-h leptin concentrations (R2 = 0.46, P = 0.03) during placebo and bromocriptine in obese women. The range of differences in mean 24-h leptin concentrations was –14.7 to 8.2 ng/liter.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Circulating leptin concentrations are the net result of concerted influences of prior and ongoing hormone secretion, distribution, and elimination. Because there is no evidence indicating that bromocriptine alters leptin clearance from the circulation, our observations suggest that activation of dopamine 2 receptors, directly or indirectly modulates leptin release by adipocytes.

The brain is involved in the control of (circadian) leptin levels (15), perhaps via modulation of adipocyte metabolism by autonomic nerves (16), in which sympathetic input inhibits leptin synthesis (8). Bromocriptine acts on presynaptic D2 receptors to inhibit (sympathetic) norepinephrine release (17, 18). Furthermore, dopamine 2 receptors activation inhibits norepinephrine gene expression and release in the arcuate nucleus and peripheral nerves (19, 20). The fact that urinary norepinephrine excretion was reduced during bromocriptine treatment in our study corroborates these data. Thus, because sympathetic signals reduce leptin release by adipocytes (8), the reduction of circulating leptin levels we observe here was not due to the inhibitory effects of bromocriptine on sympathetic activity.

Alternatively, the decline of leptin during bromocriptine treatment was brought about via effects on other metabolic parameters that modulate leptin release. Glucose, insulin, and PRL all stimulate leptin synthesis (8, 21, 22, 23). However, the decline of the concentration of either glucose or these hormones in response to bromocriptine was not correlated with the reduction of circulating leptin in the present study, which does not support the possibility that these factors are involved in the effect of bromocriptine.

Interestingly, the decline of leptin in response to bromocriptine was correlated with the concomitant increase of circulating FFAs. Fuel flux through adipocytes is instrumental in the control of leptin synthesis, in which net influx of glucose and/or FFA promotes leptin gene expression (24), and net efflux therefore may down-regulate gene transcription. The rise of FFA levels may be due to inhibition of the net influx of FFA in adipocytes by bromocriptine (25). Thus, the fact that changes of FFA and leptin in response to bromocriptine were inversely related supports the view that the drug reduces circulating leptin concentration via modulation of FFA flux in adipocytes. This postulate clearly requires further investigation.

Leptin levels are clearly increased in obese humans in proportion to fat mass, whereas dopamine D2 receptor availability in the brain is reduced in obese humans in proportion to body adiposity (26). The present findings allow for the postulate that these phenomena are related.

The hypoleptinemic effect attributable to bromocriptine is quite modest (10% reduction, compared with placebo) and lower than the effect induced by fasting (27) or ß-adrenergic stimulation (28). The physiological significance of such a modest change in humans is currently unknown and remains to be established.

In conclusion, short-term bromocriptine treatment lowers circulating leptin levels in obese women, which suggests that dopaminergic neurotransmission is involved in the control of leptin release in humans.

	Acknowledgments

 
We gratefully thank R. J. W. de Wilde, the analysts of the clinical chemistry department (M. van Dijk-Besling and J. H. G. Haasnoot-van der Bent), and the clinical research assistants (E. J. M. Ladan-Eijgenraam and I. A. Sierat-van der Steen) for their assistance during the performance of the study.

	Footnotes

 
Disclosure of potential conflicts of interest: The authors of this manuscript have no conflicts of interest to declare that are directly related to the material being published.

First Published Online May 16, 2006

Abbreviations: ApEn, Approximate entropy; B, bromocriptine; BMI, body mass index; CV, coefficient of variation; FFA, free fatty acid; Pl, placebo; PRL, prolactin.

Received November 21, 2005.

Accepted May 10, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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