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Program in Nutritional Metabolism (B.C., S.S., P.K., S.G.) and Laboratory Medicine Division, Pathology Department (R.O.S., M.L.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and Whitaker Cardiovascular Institute and Boston University Medical Center (I.L.), Boston, Massachusetts 02118
Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Program in Nutritional Metabolism, Massachusetts General Hospital, 55 Fruit Street, LON 207, Boston, Massachusetts 02114. E-mail: sgrinspoon{at}partners.org.
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Abstract |
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Objective: The objective of the study was to investigate markers of inflammation, platelet activation, and platelet aggregation in a model of caloric deprivation and increased leptin sensitivity.
Design: This study was a randomized, placebo-controlled study conducted between November 2002 and November 2003.
Setting: The study was conducted at an inpatient care setting at the General Clinical Research Center.
Participants: Twenty healthy, young (18–35 yr old), normal-weight (body mass index, 20–26 kg/m2) women were recruited from local advertisements. No subjects withdrew due to adverse effects.
Intervention: The effects of physiological recombinant methionyl human leptin or identical placebo administration were investigated over a 4-d fast.
Main Outcome Measures: The primary outcome measures for this study were C-reactive protein (CRP) and indices of platelet activity.
Results: Leptin administration prevented the fasting-induced decline in leptin (P < 0.05 vs. placebo at each time point). Leptin administration increased CRP (6.3 ± 2.4 vs. 0.7 ± 0.3 mg/liter; P = 0.04), circulating P-selectin (11.6 ± 10.2 vs. –28.9 ± 15.6 ng/ml; P = 0.04), and induction of platelet aggregation (5.8 ± 2.6 vs. –2.7 ± 2.9%, P = 0.04, percent maximum platelet aggregation) relative to placebo administration (change in leptin vs. change in placebo, respectively, for each variable). Leptin tended to increase serum amyloid A [0.1 ± 0.2 vs. –0.3 ± 0.1 log10 (ng/ml); P = 0.07], and the changes in serum amyloid A and CRP were highly correlated (r = 0.83; P < 0.0001). No changes in TNF
, IL-6, IL-10, plasminogen activator inhibitor-1, haptoglobin, intercellular adhesion molecule, or vascular cell adhesion molecule were seen between the groups.
Conclusions: Our data provide evidence that physiological leptin administration stimulates inflammatory and platelet responses in humans during caloric deprivation.
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Introduction |
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An independent correlation between leptin and CRP levels was observed in healthy men and women, which remained significant after adjustment for age, gender, body mass index (BMI), waist to hip ratio, smoking, and alcohol consumption (8). In subjects with normal BMI (<25 kg/m2), CRP was not linked to BMI but was significantly associated with leptin (8). Pegylated long-acting recombinant leptin, resulting in very supraphysiological leptin levels, was recently shown to increase CRP in obese humans (9), but the effects of physiological leptin administration on CRP have not been investigated in a human model. Furthermore, prior studies investigating leptin effects on inflammation have focused on obesity, and leptin effects have not been studied in a model of undernutrition, in which leptin sensitivity might be increased.
Leptin may play an additional role in inflammation by its effects on platelet function. Platelet activation is implicated as a regulator in the inflammatory cascade, resulting in thrombosis formation (10). The leptin receptor is present on platelets (11), and leptin has been shown to increase ADP-stimulated platelet aggregation in vitro and ex vivo using physiological concentrations of leptin (12, 13, 14). In obese subjects in whom leptin levels are elevated, leptin-dependent platelet aggregation and thrombosis formation may contribute to endothelial dysfunction and atherosclerotic disease (15). It is unknown whether leptin increases monocyte adhesion, soluble intercellular adhesion molecule (ICAM), and soluble vascular cell adhesion molecule (VCAM) as a mechanism of endothelial dysfunction in obesity. Studies suggest that platelet aggregation decreases with acute caloric deprivation (16, 17), but the effects of leptin replacement on platelet function in a human model of caloric deprivation are not known.
We therefore investigated the novel effects of leptin on markers of inflammation, platelet activation (using the activation marker of soluble P-selectin that is released from platelet granules), and platelet aggregation during short-term caloric restriction. Importantly, leptin was administered at physiological doses, sufficient only to prevent the fasting-induced decline in leptin levels, and thus, this model differs significantly from a model of the chronic overweight individual with increased leptin and leptin resistance.
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Subjects and Methods |
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Study design
Baseline testing.
Before baseline testing, calorie, protein and fat intake were determined from 4-d outpatient food records (version 8A/2.6; Minnesota Nutrition Data Systems, Minneapolis, MN). Baseline testing was carried out as an inpatient, during which time the subjects were maintained for 24 h on an isocaloric diet, with similar proportions of protein and carbohydrate to the prebaseline diet. Total body fat was determined using dual-energy x-ray absorptiometry (Hologic 4500, Hologic, Inc., Waltham, MA) at baseline and at the conclusion of the 4-d fast. Fasting blood was drawn for TNF, IL-6, IL-10, CRP, serum amyloid A (SAA), haptoglobin, ICAM, VCAM, plasminogen activator inhibitor (PAI)-1, P-selectin, triglycerides, free fatty acids, insulin, and glucose as well as white blood cell (WBC) and platelet counts. Platelet aggregation was measured in whole blood in response to patient plasma as described below.
Randomization
Subjects were randomly assigned to receive either r-metHuLeptin (Amgen, Inc., Thousand Oaks, CA) or identical placebo (total daily dose of 0.05 mg/kg sc, divided into four doses of 0.0125 mg/kg administered at 0800, 1400, 2000, and 0200 h). Study drug was stored at the Massachusetts General Hospital (MGH) research pharmacy at 2–8 C before reconstitution and administration by the nursing staff of the MGH General Clinical Research Center. r-metHuLeptin and placebo were supplied in a single-use vial and was reconstituted with sterile water immediately before sc injection.
The Massachusetts General Hospital pharmacy performed the randomization. All investigators, study staff, and subjects were blinded to drug assignment.
Fasting protocol
Study drug continued over 4 d, during which time subjects underwent a complete fast, except for water and a daily multivitamin, and had daily blood drawing at 0800 h for leptin and electrolytes. On the final morning of the protocol, while still fasting, repeat evaluations for TNF, IL-6, IL-10, CRP, SAA, haptoglobin, ICAM, VCAM, PAI-1, P-selectin, triglycerides, free fatty acids, insulin, and glucose as well as WBC and platelet count were performed and weight and body composition again determined. Platelet aggregation in response to patient plasma was again measured.
Biochemical assays
All samples from the same patient were run in duplicate in the same assay. Serum leptin levels were determined using a RIA kit [Linco Research, Inc., St. Charles, MO; intraassay coefficient of variation (CV) of 3.4%]. Serum TNF (intraassay CV 5.3–8.8%), serum IL-6 levels (intraassay CV 6.9–7.8%), plasma soluble P-selectin (intraassay CV 3%), serum soluble ICAM levels (intraassay CV < 6.0–7.4%), and serum soluble VCAM levels (intraassay CV < 7.8%) were determined using ELISA kits (R&D Systems, Inc., Minneapolis, MN). Serum IL-10 levels were determined using a sandwich EIA kit (R&D Systems; intraassay CV < 15.6%). Serum CRP levels were determined using an ELISA kit (Diagnostic Systems Laboratories, Inc., Webster, TX; intraassay CV 1.7–3.9%). Plasma PAI-1 levels were determined using an enzyme immunoassay kit (Biopool Chromolize kit, Trinity Biotech, St. Louis, MO; intraassay CV < 3.6–16.9%). SAA levels were measured by ELISA kit (Biosource International, Inc., Camarillo, CA; intraassay CV < 3.8%). Serum free fatty acids were assessed by an in vitro, enzymatic calorimetric method (Wako Chemicals USA, Inc., Richmond, VA; intraassay CV 1.1–2.7%). Serum insulin levels were run using RIA (Diagnostic Products Corp.; intraassay CV 3.1–9.3%). Haptoglobin levels were assessed by nephelometry, and serum glucose, triglycerides and ketone bodies were assessed by standard technique in MGH laboratories.
Platelet aggregation assay
Fifty microliters of plasma from each subject in the study was used as an agonist to determine the effect on platelet aggregation of normal donor platelets, using a well-established aggregation assay (19). The person performing this assay was blinded to the randomization status of each subject. Separate determinations of percent maximal platelet aggregation were made in response to plasma obtained at baseline and at the end of the study from each study subject, and the change in maximal platelet aggregation was compared between treatment assignments (r-metHuLeptin vs. placebo). To perform the platelet aggregation assay, whole blood (10 ml) was collected from normal-weight volunteers into vacuum tubes containing 3.2% sodium citrate. The blood was centrifuged at 120 g for 10 min to isolate platelet-rich plasma, and then a platelet count was performed on the suspension. To obtain platelet-poor plasma, the whole blood was centrifuged at 200 x g for 10 min, and 450 µl of normal donor platelet-rich plasma was added to cuvettes, which were transferred to a platelet aggregation chromogenic kinetic system (Helena Laboratories, Beaumont, TX). Plasma from study subjects (50 µl) was added to the sample to start aggregation to measure platelet aggregation.
Statistical analysis
Baseline comparisons were made by t test between the placebo and leptin-treated groups. Baseline comparison of ethnicity was made by likelihood ratio. Leptin levels were compared between treatment groups at baseline and on each day of the study by t test. Changes in other variables, including CRP, P-selectin, platelet aggregation, IL-6, IL-10, haptoglobin, SAA, VCAM, ICAM, PAI-1, and TNF, were compared between treatment groups by ANOVA and also within each treatment group by paired t test. End-of-study specimens were not available for one patient in the placebo group. Outlier analysis for change of total fat was performed using Dixon criteria and changes in primary end points, including CRP, and platelet aggregation indices were confirmed using the nonparametric Wilcoxon test. Statistical analyses were performed using SAS JMP software (SAS Institute, Inc., Cary, NC). Statistical significance was defined as a two-tailed alpha value of P 
0.05. Changes in platelet aggregation, platelet activation (P-selectin), CRP, SAA, and other metabolic variables were compared in univariate regression analysis. With 20 patients, the study had 80% power to determine a difference of 1.325 SD between the treatment groups at a two-sided 5% significance level. Multiple statistical comparisons were not used in this analysis.
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Results |
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Age (25.2 ± 1.4 vs. 26.7 ± 1.6 yr, leptin vs. placebo, P = 0.48) and ethnicity (60 vs. 50% Caucasian, leptin vs. placebo, P = 0.20) were similar in both groups. Baseline clinical characteristics were not significantly different between the two groups (P > 0.05) (Table 1
). Baseline leptin levels were similar in both groups (14.7 ± 2.2 vs. 11.4 ± 1.5 ng/ml, leptin vs. placebo, P = 0.24) (Fig. 1).
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Daily leptin levels were lower after baseline in the placebo, compared with the leptin-treated group (Fig. 1
, P < 0.05 for each time point after the baseline).
Body composition and metabolic parameters
Weight decreased in both groups, but the changes were not significant between groups. In contrast, fat mass decreased more in the leptin-treated than placebo group (Table 1). Insulin and glucose levels decreased, whereas free fatty acid and triglyceride levels increased in both the placebo and leptin-treated groups, but the changes were not significant between the groups (Table 1). Ketone bodies were undetectable at baseline and present in trace amounts at the end of the study in each subject, and no effects of leptin treatment were noted. There were no discernible side effects related to leptin treatment.
Inflammatory and metabolic parameters
CRP increased significantly in the r-metHuLeptin group, compared with the placebo-treated group (6.3 ± 2.4 vs. 0.7 ± 0.3 mg/liter, leptin vs. placebo, P = 0.04, Table 1). Change in CRP was also significant using nonparametric analysis [3.6 (0.7, 9.7) vs. 0.2 (0.0, 1.7) mg/liter, median (interquartile range), leptin vs. placebo, P = 0.04]. In contrast, changes in IL-6, IL-10, PAI-1, haptoglobin, and TNF were not significantly different between groups and did not correlate with the changes in CRP (Table 1). SAA tended to increase in the leptin-treated group, compared with placebo [0.1 ± 0.2 vs. –0.3 ± 0.1 log10 (ng/ml), P = 0.07]. Within the placebo-treated group, SAA decreased significantly with 4 d of fasting. Change in CRP correlated most strongly with change in SAA among all subjects (r = 0.83, P < 0.0001). Change in CRP correlated inversely with change in free fatty acids (r = –0.54, P = 0.02) among all subjects and with change in fat mass by dual-energy x-ray absorptiometry among subjects receiving leptin (r = 0.69, P = 0.03). Change in CRP did not correlate with change in triglyceride levels (data not shown).
Hematological parameters
The platelet count increased significantly more in the r-metHuLeptin group, compared with the placebo-treated group (72,000 ± 17,000 vs. 31,000 ± 10,000/µl, P = 0.05, Table 1). The change in P-selectin, a marker of platelet activation, was significant between the groups, with an increase in the leptin-treated and a decline among the placebo-treated patients undergoing caloric deprivation (11.6 ± 10.2 vs. –28.9 ± 15.6 ng/ml, P = 0.04, Table 1). Similarly, the change in percent maximal platelet aggregation differed significantly between the groups and increased in the leptin group and decreased in the placebo group (5.8 ± 2.6 vs. –2.7 ± 2.9% maximal platelet aggregation, P = 0.04, Table 1). Changes in P-selectin [15.8 (–13.0, 42.6) vs. –21.3 (–30.5, – 5.3) ng/ml, median (interquartile range), leptin vs. placebo, P = 0.03] and platelet aggregation [4.1 (0.7, 8.2) vs. –0.5 (–5.2, 3.4) % maximal platelet aggregation, median (interquartile range), leptin vs. placebo, P = 0.03] were also significant using nonparametric analysis. Furthermore, the change in platelet aggregation was highly correlated with the change in platelet activation (P-selectin, r = 0.88, P < 0.0001). Levels of P-selectin (r = 0.57, P = 0.01) and platelet aggregation (r = 0.57, P = 0.01) at the end of the study significantly correlated with leptin levels achieved. Changes in the WBC did not differ between the treatment groups.
Hemodynamic parameters and endothelial function
Diastolic blood pressure did not change significantly in the leptin-treated group, compared with the placebo-treated group (2 ± 2 vs. –4 ± 3 mm Hg, P = 0.08, Table 1). Changes in systolic blood pressure were not significantly different between the treatment groups. Markers of endothelial function, VCAM, ICAM, and PAI-I did not change significantly between the groups.
Safety
Leptin administration was safe, and no side effects were reported.
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Discussion |
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Prior studies suggest an association between leptin levels and CRP. For example, in the West of Scotland Coronary Prevention Study, leptin levels were shown to correlate significantly with CRP, even after adjustment for BMI (7). Kazumi et al. (22) demonstrated that CRP is positively correlated with percent fat mass but even more so with serum leptin in young, healthy men. Weight loss in obese subjects led to reductions in leptin that were correlated with BMI and highly sensitive CRP (23).
Our data suggest that physiological administration of leptin during acute caloric deprivation increases CRP. Our data stand in contrast to the more modest effects on CRP observed in response to very high doses of pegylated leptin in obese patients undergoing a 45-d, very low-calorie diet (9). In addition, these results stand in contrast to those recently reported by Chan et al. (21) in which CRP did not increase in response to leptin at 10 mg twice daily over 16 wk in patients with diabetes mellitus. In contrast, the leptin levels achieved in our study were physiological, but CRP increased significantly by approximately 6 ng/ml in the leptin-treated compared with placebo-treated subjects. CRP levels increased significantly between treatment groups (leptin vs. placebo) and within the leptin-treated group, despite the fact that final leptin levels achieved were at or below baseline values due to the very low doses of leptin administered. These data contrast with data from models of leptin administration in obesity and suggest that caloric deprivation may enhance the sensitivity of certain inflammatory markers to leptin.
The mechanism by which leptin increased CRP in this study is not known but may relate to an acute-phase response. In agreement with Chan et al. (24), we did not see an effect of recombinant human leptin on TNF, IL-10, or ICAM during caloric restriction. Similar to Hukshorn et al. (9), we did not see an effect on IL-6 or TNF, nor did we see changes in haptoglobin or PAI-1, but changes in SAA levels were highly associated with CRP. SAA has been shown to decrease with caloric deprivation, but previous studies in healthy normal-weight men not undergoing caloric deprivation did not show an effect of leptin on SAA (25). In contrast, we studied women undergoing caloric deprivation, in whom sensitivity may be greater. Furthermore, the design of our study contrasts with that of longer-term studies, in which chronic leptin administration over 2 months increased IL-10 and IL-4 in an obese child with leptin deficiency (26). Although it is possible that leptin may have resulted in a subacute, short-term inflammatory reaction, we did not see local skin reactions in patients. In other studies investigating cytokine administration, transient increases in CRP and SAA were seen in response to interferon-1ß injection in patients with multiple sclerosis (27), whereas long-term administration of GH (18 months) to GH-deficient subjects was associated with decreases in CRP and SAA (28). Taken together our data on CRP and SAA suggest that leptin may result in an acute-phase response during short-term administration during caloric deprivation. Further longer-term studies are needed to resolve the time course and mechanisms of increased CRP in response to physiological leptin administration and the implications of this finding with respect to elevated endogenous leptin levels in obesity.
In this study we demonstrate significant effects of leptin to increase both platelet aggregation and platelet activation. Leptin has been shown to increase ADP-stimulated platelet aggregation. Nakata et al. (11) demonstrated expression of the leptin receptor in platelets and demonstrated in nonobese patients with a BMI of less than 22 kg/m2 that leptin increased phosphorylation of platelet proteins and ADP-stimulated platelet aggregation at leptin concentrations seen in nonobese individuals. Lower concentrations of leptin less than 10 ng/ml did not increase ADP-stimulated aggregation. Konstantinides et al. (15) demonstrated that leptin increased platelet aggregation and thrombosis in ob/ob mice lacking leptin but not in db/db mice lacking the leptin receptor.
We demonstrate a significant effect of leptin to increase P-selectin is a marker of platelet activation and endothelial function that has been shown to correlate with cardiovascular events in healthy women (29). Ponthieux et al. (30) recently demonstrated that P-selectin was associated with increased platelet count and was negatively regulated by female gender and TNF. P-selectin has been shown to induce the expression of tissue factor on monocytes and mediate the binding of platelets and endothelial cells with monocytes and neutrophils and therefore may be an important factor regulating the initiation of thrombosis (10). In our study, changes in P-selectin and platelet aggregation were very highly correlated suggesting a potent effect of leptin on platelet function. In contrast to the effect on platelet aggregation, we did not see effects on markers of endothelial function (ICAM or VCAM) or fibrinolysis (PAI-1).
In contrast to obesity, characterized by leptin resistance, undernutrition is characterized by increased leptin sensitivity. It is therefore possible that normal-weight subjects undergoing complete caloric deprivation demonstrate greater sensitivity in hemostatic responses to leptin. Indeed, this phenomenon was recently suggested by Corsonello et al. (13), who investigated the ex vivo effects of leptin on platelet aggregation in healthy (BMI, 22.9 kg/m2), overweight (BMI, 27.4 kg/m2), and obese (BMI, 32.3 kg/m2) males. ADP-stimulated platelet aggregation was increased in response to leptin at a low 10 ng/ml concentration in the lower-weight controls but not the obese patients. In response to ex vivo exposure at higher leptin concentrations, ADP-stimulated platelet aggregation was increased in obese patients, suggesting a differential sensitivity of the leptin effect based on nutritional and weight status (13). The effects of leptin on platelet aggregation were completely inhibited by antileptin receptor antibody and were thought to be potentially mediated by phospholipase C, phospholipase A (2), calcium, and protein kinase C (12).
In our study, P-selectin tended to decrease in response to fasting alone in the placebo group, whereas leptin administration increased P-selectin in this model, suggesting effects of undernutrition on platelet activation that were prevented or reversed by physiological leptin administration in this setting. Similarly, platelet aggregation tended to decrease among the placebo-treated patients and increased significantly among the leptin-treated patients, for a significant difference between the treatment groups (leptin vs. placebo). Importantly, the changes in platelet aggregation and activation (P-selectin), determined using different techniques, were highly correlated, suggesting that the results are biological and not the result of the specific testing paradigms chosen. Prior studies of acute caloric deprivation suggest decreased platelet aggregation (16, 17). However, in our study, low-dose leptin administration not only prevented such a decrease but also significantly increased platelet aggregation. Our data extend those of Corsonello et al. (13) showing differential sensitivities of platelet aggregation to leptin exposure ex vivo, depending on nutritional status and weight. Our data suggest a potent effect of very low physiological leptin dosing on platelet aggregation in a model of acute caloric deprivation and heightened leptin sensitivity. Less pronounced effects on platelet aggregation might be seen in obese patients with leptin resistance.
This current study investigates the effects of treatment in the model of acute (4 d) caloric restriction. Our study was not designed specifically to discern whether the effects of leptin were direct or indirect and related to changes in other endocrine parameters. However, levels of P-selectin and platelet aggregation at the end of the study significantly correlated with leptin levels achieved, suggesting a direct effect of leptin on platelet function. In contrast, changes induced by leptin in endocrine and metabolic function, as reported in a prior publication, were not related to CRP and platelet aggregation. Leptin might also increase CRP via IL-6, but this mechanism is not supported by our present study. Further studies are needed to determine the direct mechanisms by which leptin increases CRP. The long-term effects of leptin in caloric restriction are unknown; however, the change in CRP level and effects on platelets could potentially impact cardiovascular parameters in long-term models. Leptin deficiency has been associated with impaired immune function, including cytokine release, which is reversed by leptin therapy (26). It is also possible that the changes in CRP seen in our placebo-controlled study are spurious and result from chance in the context of testing of multiple parameters, but correlations with SAA and effects on multiple indices of platelet aggregation make this less likely. Future studies are needed to determine long-term effects of leptin replacement on CRP, platelet aggregation, and activation. Local antileptin therapy may have a potential benefit for thromboembolic diseases, but this would require further investigation in this population. In addition, our study was limited to women, and different effects might be seen in men.
In summary, we have examined the effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation in a model of caloric deprivation. These data demonstrate an effect of leptin to increase CRP, P-selectin, and platelet aggregation in humans and may reflect heightened sensitivity to leptin in this model. In contrast, increased leptin levels may contribute to increased inflammation and thrombosis via effects on platelet activation and aggregation in obesity, contributing to cardiovascular disease, but such effects may be attenuated by leptin resistance. Further studies are necessary to understand the mechanisms of leptin effects on inflammation and platelet function in undernutrition and the effects of leptin on these endpoints in obesity.
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Acknowledgments |
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Footnotes |
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First Published Online August 2, 2005
Abbreviations: BMI, Body mass index; CRP, C-reactive protein; CV, coefficient of variation; ICAM, soluble intercellular adhesion molecule; PAI, plasminogen activator inhibitor; r-metHuLeptin, recombinant methionyl human leptin; SAA, serum amyloid A; VCAM, vascular cell adhesion molecule; WBC, white blood cell.
Received April 11, 2005.
Accepted July 27, 2005.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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receptor levels in humans with relative leptin deficiency. J Clin Endocrinol Metab 90:1625–1631This article has been cited by other articles:
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