This Article Abstract Full Text (PDF) All Versions of this Article: 109/18/2181    most recent 01.CIR.0000127960.28627.75v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shamsuzzaman, A. S.M. Articles by Somers, V. K. Search for Related Content PubMed PubMed Citation Articles by Shamsuzzaman, A. S.M. Articles by Somers, V. K. Pubmed/NCBI databases Substance via MeSH Related Collections Obesity Pathophysiology Risk Factors Calcium cycling/excitation-contraction coupling Growth factors/cytokines

(Circulation. 2004;109:2181-2185.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Independent Association Between Plasma Leptin and C-Reactive Protein in Healthy Humans

Abu S.M. Shamsuzzaman, MBBS, PhD; Mikolaj Winnicki, MD, PhD; Robert Wolk, MD, PhD; Anna Svatikova, BA; Bradley G. Phillips, BSc, PharmD; Diane E. Davison, RN, MA; Peter B. Berger, MD; Virend K. Somers, MD, PhD

From the Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minn (A.S.M.S., M.W., R.W., A.S., D.E.D., V.K.S.); Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland (M.W.); Division of Clinical and Administrative Pharmacy, University of Iowa, Iowa City (B.G.P.); and Duke University Medical Center and Duke Clinical Research Institute, Durham, NC (P.B.B.).

Correspondence to Virend K. Somers, MD, DPhil, Division of Cardiovascular Diseases, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. E-mail somers.virend{at}mayo.edu

Received October 7, 2003; revision received February 5, 2004; accepted February 6, 2004.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— C-reactive protein (CRP) is synthesized from the liver and is regulated by cytokines, especially interleukin-6. Leptin, the adipocyte-derived protein product of the ob gene, is related to amount of body fat. The long form of the leptin receptor resembles cytokine receptors, which include the interleukin-6 receptor. Both leptin and CRP may be increased in women, in obesity, and in inflammation, and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. We tested the hypothesis that leptin is associated with CRP levels independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables.

Methods and Results— We studied 100 healthy volunteers (48 men, and 52 women). For all subjects, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P=0.0007). There was a strong and significant positive relationship between leptin and CRP in both women (R=0.61, P<0.0001) and men (R=0.55, P<0.0001) considered separately. The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P=0.01) and men (F=5.69, P=0.02). When only subjects with BMI <25 kg/m² were considered (n=47), CRP was not linked to BMI (R=0.02, P=0.96), but a significant association between leptin and CRP was still evident (R=0.55, P<0.0001).

Conclusions— Leptin and CRP levels are independently associated in normal humans, providing further evidence linking metabolic and inflammatory cardiovascular disease mechanisms.

Key Words: C-reactive protein • cardiovascular diseases • inflammation • leptin • obesity • risk factors

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Inflammation may contribute importantly to cardiovascular disease, particularly ischemic heart disease and heart failure.¹ C-reactive protein (CRP), a marker of inflammation, is emerging as an important indicator of cardiovascular risk^2–4 and is associated with future cardiovascular events in patients with acute coronary artery disease, stable angina pectoris, and history of myocardial infarction.⁵ Elevated CRP is also a strong predictor of cardiovascular risk in apparently healthy men and women.¹ CRP may itself contribute to vascular disease by inhibiting nitric oxide synthase,⁶ increasing cell adhesion molecule expression,⁷ increasing plasminogen activator inhibitor-1,⁸ activating vascular smooth muscle cells,⁹ and eliciting direct proinflammatory effects on endothelial cells.¹⁰

Leptin, the adipocyte-derived protein product of the ob gene, is involved in appetite regulation and obesity through central effects at the hypothalamus.¹¹ Leptin is related to amount of body fat.¹² Leptin is also associated with increased heart rate,¹³ blood pressure,¹³ and sympathetic neural activity¹⁴ and may contribute to platelet aggregation.^15,16 Recent data have implicated leptin as an independent risk factor for cardiovascular diseases^17–19 even after adjustment for traditional risk factors.²⁰

CRP is synthesized by the liver and regulated by cytokines, especially interleukin (IL)-6.²¹ The long form of the leptin receptor resembles the gp120 family of cytokine receptors, which includes the IL-6 receptor.^11,22 Leptin also activates Janus kinases and certain signal transducers and activators of transcription, downstream components in the signaling pathways of several proinflammatory cytokines. Other important intracellular pathways related to possible proinflammatory effects of leptin are MAPK (ERK1/2), p38, and nuclear factor-.^23,24

Both leptin and CRP may be increased in women, in obesity,¹² and in inflammation,^25–27 and both have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk. There is little information on any interaction between leptin and CRP, particularly in healthy normal subjects. We tested the hypothesis that plasma leptin is associated with CRP independently of the influences of gender, body mass index (BMI), waist-to-hip ratio, and other variables.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
We studied 100 healthy volunteers (48 men, 52 women). All subjects were free of any acute or chronic disease conditions, including sleep disorders, and on no medications. Occult obstructive sleep apnea was excluded by complete overnight polysomnography in all subjects >25 years of age and/or with a BMI >22 kg/m²; thus, of all 100 subjects, 83 underwent overnight polysomnography. Baseline demographic data, body fat, BMI, heart rate, blood pressure (Dinamap MPS, Critikon), and venous blood were collected between 8 and 10 AM. Leptin and high-sensitivity CRP levels were measured with radioimmunoassay kits (leptin, Linco Research Inc; CRP, Kamiya Biomedical Corp). Written informed consent was obtained from all subjects. The institutional Human Subjects Review Committee approved the study.

Statistical Analysis
Data are expressed as mean±SEM or median and range. Categorical variables were compared by use of a ² test. Group comparisons were performed by an unpaired Student’s t test or the Wilcoxon rank-sum test. Because of the positive skewed distribution of leptin and CRP levels, data were logarithmically transformed, and the relationships were analyzed by logarithmic regression analysis. The independent association between leptin and CRP was analyzed by use of multivariate analysis with CRP as the dependent variable and leptin, age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption as covariates. A value of P<0.05 was considered significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
There were similar right-sided skewed distributions for both CRP and leptin levels (Figure 1). Subjects were divided according to the quartiles of leptin levels, with increased levels of leptin accompanied by increased CRP levels (Figure 2).

View larger version (33K): [in this window] [in a new window]   Figure 1. Comparable distribution of CRP and leptin in normal subjects.

View larger version (29K): [in this window] [in a new window]   Figure 2. CRP levels for each quartile of leptin.

There were positive correlations (Table 1) between BMI and CRP (R=0.47, P<0.0001) and between BMI and leptin (R=0.58, P<0.0001). In bivariate analysis, there was a strong and significant positive relationship between leptin and CRP levels (R=0.64, P<0.0001). In multivariate analysis, leptin was independently associated with CRP after adjustment for age, gender, BMI, waist-to-hip ratio, smoking, and alcohol consumption (F=12.39, P=0.0007). When only subjects with BMI <25 kg/m² were considered (n=47), CRP was not linked to BMI (R=0.02, P=0.96), but a significant association between leptin and CRP was still evident (R=0.55, P<0.0001; Figure 3).

View this table: [in this window] [in a new window]   TABLE 1. Linear Correlations of Subjects’ Characteristics With Log Leptin and Log CRP

View larger version (24K): [in this window] [in a new window]   Figure 3. Correlations between log leptin and log CRP in normal-weight (BMI <25 kg/m2) and overweight/obese (BMI 25 kg/m2) subjects. Significant positive relationships are observed in both groups even though CRP did not correlate with BMI in normal-weight subjects, suggesting that leptin-CRP interaction is not explained by effects of BMI.

Men and women were further considered separately, and the characteristics of each group are described in the Table 2. CRP (0.33±0.05 versus 0.08±0.01 mg/dL, P<0.0002) and leptin (17±2 versus 6±1 ng/mL, P<0.0001) levels were significantly higher in women than men. Significant positive relationships between BMI and CRP (R=0.51, P<0.001 for women; R=0.44, P<0.001 for men) and between BMI and leptin (R=0.75, P<0.0001 for women; R=0.58, P<0.0001 for men) were evident in both women and men. There was a strong and significant positive relationship between leptin and CRP in both women (R=0.61, P<0.0001) and men (R=0.55, P<0.0001). The association between leptin and CRP was significant even after adjustment for age, BMI, waist-to-hip ratio, smoking, and alcohol consumption in women (F=7.13, P=0.01) and men (F=5.69, P=0.02).

View this table: [in this window] [in a new window]   TABLE 2. Subject Characteristics

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The novel finding of the present study is the independent association between leptin and CRP in healthy humans. Although both leptin and CRP levels were significantly higher in women, there was an independent association between leptin and CRP in both men and women considered separately. It is unlikely that the leptin-CRP association we describe is secondary to BMI because the relationship was clear and significant even after adjustment for BMI. Furthermore, in subjects with BMI <25 kg/m², CRP was significantly linked to leptin but not to BMI. Thus, the leptin-CRP association cannot be secondary to any common influence of BMI on each of these measures.

The mechanisms linking leptin and CRP are not clear. Adipose tissue is the source of circulating leptin.²⁸ CRP is synthesized by the liver, largely under the regulation of the proinflammatory cytokines, primarily IL-6.²¹ Other proinflammatory cytokines such as IL-1 and tumor necrosis factor- (TNF-) may contribute to hepatic synthesis of CRP. Adipocytes are important sources of circulating IL-6²⁹ and express TNF-.³⁰ Hence, adipocytes, by serving as a common source for both leptin and inflammatory cytokines contributing to CRP synthesis, may explain in part the interaction between CRP levels and leptin. Moreover, IL-1, IL-6, and TNF-, which contribute to increases in CRP, may act directly on fat cells to increase leptin secretion in settings of acute inflammation,^31–33 further supporting adipose tissue as a potential common pathway contributing to the leptin-CRP interaction. Nevertheless, the strong relationship between leptin and CRP in the present study was independent of several measures of adiposity (eg, BMI and waist-to-hip ratio).

Thus, another possibility may be that leptin, either directly or indirectly through the immune system, may alter CRP levels. First, leptin can actually induce the production of various cytokines, including IL-6.³⁴ Second, IL-6 induces CRP. Third, the leptin receptor has been shown to have signaling capabilities of IL-6-type cytokine receptors.²² It is conceivable then that leptin may act via IL-6, or perhaps even via the leptin receptor, to upregulate CRP production.

Leptin also has an important role in modulating the immune response.^35,36 Subcutaneous injection of recombinant leptin in humans consistently produces inflammation at the site of injection, suggesting an immunomodulatory role of leptin.³⁷ Exogenous leptin upregulates both phagocytosis and the production of inflammatory cytokines and thus regulates proinflammatory immune responses.³⁸ Leptin also promotes and sustains immune responses mediated by Th1 CD +4 lymphocytes.³⁹ Surges of leptin have been observed at the onset of experimental autoimmune encephalomyelitis, and these leptin surges correlate with the development of pathogenic T-cell responses.⁴⁰ Leptin-deficient ob/ob mice develop defects in immune function.^41–43 Reduced leptin levels are related to impairment of immune function, characterized by lymphoid atrophy and T-cell dysfunction; these may be restored by administration of exogenous leptin.³⁹ Therefore, there is compelling evidence implicating leptin as an important modulator of the inflammatory process. Our data now raise the possibility that leptin may also conceivably act to increase levels of CRP, even in healthy normal subjects. If leptin does indeed induce CRP, this may be a mechanism whereby leptin would increase cardiovascular risk.

The clinical significance of the positive and independent relationship that we describe between leptin and CRP is that higher levels of one of these measures of inflammation/cardiovascular risk are linked to elevation in the other. However, both leptin and CRP each act directly and independently through a number of pathophysiological mechanisms to increase cardiovascular risk. Leptin stimulates vascular smooth muscle proliferation,⁴⁴ accelerates vascular calcification,⁴⁵ induces oxidative stress in endothelial cells⁴⁶ that may contribute to atherogenesis, and promotes coagulation by increasing platelet adhesiveness.¹⁵ CRP promotes secretion of inflammatory mediators by vascular endothelium,⁴⁷ increases cell adhesion molecule expression,¹⁰ opsonizes LDL for uptake by macrophages in atherosclerotic plaque,⁴⁸ decreases endothelial nitric oxide synthase expression and activity,⁶ and activates vascular smooth muscle cells.⁹ With few exceptions,²⁰ studies examining the cardiovascular risk associated with CRP have not considered the potential additional risk attributable to increased leptin levels.

Furthermore, conditions in which both leptin and CRP may be increased simultaneously, such as obesity and obstructive sleep apnea,⁴⁹ may be associated with additive or perhaps synergistic increases in cardiovascular risk. However, whether the pathophysiological processes induced by leptin or CRP are enhanced or redundant when both are elevated is unknown.

The strengths of the present study are the exclusion of occult obstructive sleep apnea and the absence of disease and drug therapy in our subject population, suggesting that the association we describe is physiological. Our data further suggest that any such interaction may be active very early, even before any evidence of overt cardiovascular disease.

In summary, we have demonstrated in healthy humans that increased leptin is associated with increased CRP independently of gender, measures of adiposity, and other variables. Both leptin and CRP have been linked to inflammatory and cardiovascular disease processes. These data provide further evidence linking the metabolic and inflammatory mediators of cardiovascular disease processes.

	Acknowledgments

 
We were supported by a Perkins Memorial Award and by National Institutes of Health grants TW05463, TW05399, HL-65176, HL-61560, HL-70602, HL-73211, and M01-RR00585.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Ridker PM. High-sensitivity C-reactive protein: potential adjunct for global risk assessment in the primary prevention of cardiovascular disease. Circulation. 2001; 103: 1813–1818.[Abstract/Free Full Text]
   
2. Ridker PM, Buring JE, Cook NR, et al. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation. 2003; 107: 391–397.[Abstract/Free Full Text]
   
3. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003; 107: 363–369.[Free Full Text]
   
4. Jialal I, Devaraj S. Role of C-reactive protein in the assessment of cardiovascular risk. Am J Cardiol. 2003; 91: 200–202.[CrossRef][Medline] [Order article via Infotrieve]
   
5. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein: the Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999; 100: 230–235.[Abstract/Free Full Text]
   
6. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002; 106: 1439–1441.[Abstract/Free Full Text]
   
7. Woollard KJ, Phillips DC, Griffiths HR. Direct modulatory effect of C-reactive protein on primary human monocyte adhesion to human endothelial cells. Clin Exp Immunol. 2002; 130: 256–262.[CrossRef][Medline] [Order article via Infotrieve]
   
8. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation. 2003; 107: 398–404.[Abstract/Free Full Text]
   
9. Hattori Y, Matsumura M, Kasai K. Vascular smooth muscle cell activation by C-reactive protein. Cardiovasc Res. 2003; 58: 186–195.[Abstract/Free Full Text]
   
10. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.[Abstract/Free Full Text]
    
11. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995; 269: 543–546.[Abstract/Free Full Text]
    
12. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996; 334: 292–295.[Abstract/Free Full Text]
    
13. Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases arterial pressure. Hypertension. 1998; 31: 409–414.[Abstract/Free Full Text]
    
14. Haynes WG, Morgan DA, Walsh SA, et al. Receptor-mediated regional sympathetic nerve activation by leptin. J Clin Invest. 1997; 100: 270–278.[Medline] [Order article via Infotrieve]
    
15. Konstantinides S, Schafer K, Koschnick S, et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest. 2001; 108: 1533–1540.[CrossRef][Medline] [Order article via Infotrieve]
    
16. Corsonello A, Malara A, Ientile R, et al. Leptin enhances adenosine diphosphate-induced platelet aggregation in healthy subjects. Obes Res. 2002; 10: 306.[Medline] [Order article via Infotrieve]
    
17. Sader S, Nian M, Liu P. Leptin: a novel link between obesity, diabetes, cardiovascular risk, and ventricular hypertrophy. Circulation. 2003; 108: 644–646.[Free Full Text]
    
18. Leyva F, Godsland IF, Ghatei M, et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol. 1998; 18: 928–933.[Abstract/Free Full Text]
    
19. Soderberg S, Ahren B, Jansson JH, et al. Leptin is associated with increased risk of myocardial infarction. J Intern Med. 1999; 246: 409–418.[CrossRef][Medline] [Order article via Infotrieve]
    
20. Wallace AM, McMahon AD, Packard CJ, et al. Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 2001; 104: 3052–3056.[Abstract/Free Full Text]
    
21. Castell J, Gomez-Lechion M, David M. Acute phase response of human hepatocyte: regulation of acute-phase protein synthesis by interleukin-6. Hepatology. 1990; 12: 1179–1186.[Medline] [Order article via Infotrieve]
    
22. Baumann H, Morella KK, White DW, et al. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci U S A. 1996; 93: 8374–8378.[Abstract/Free Full Text]
    
23. Machinal-Quelin F, Dieudonne MN, Leneveu MC, et al. Proadipogenic effect of leptin on rat preadipocytes in vitro: activation of MAPK and STAT3 signaling pathways. Am J Physiol Cell Physiol. 2002; 282: C853–C863.[Abstract/Free Full Text]
    
24. Martin-Romero C, Sanchez-Margalet V. Human leptin activates PI3K and MAPK pathways in human peripheral blood mononuclear cells: possible role of Sam68. Cell Immunol. 2001; 212: 83–91.[CrossRef][Medline] [Order article via Infotrieve]
    
25. Gualillo O, Eiras S, Lago F, et al. Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci. 2000; 67: 2433–2441.[CrossRef][Medline] [Order article via Infotrieve]
    
26. van Dielen FM, van’t Veer C, Schols AM, et al. Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int J Obes Relat Metab Disord. 2001; 25: 1759–1766.[CrossRef][Medline] [Order article via Infotrieve]
    
27. Sarraf P, Frederich RC, Turner EM, et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med. 1997; 185: 171–175.[Abstract/Free Full Text]
    
28. Lonnqvist F, Nordfors L, Jansson M, et al. Leptin secretion from adipose tissue in women: relationship to plasma levels and gene expression. J Clin Invest. 1997; 99: 2398–2404.[Medline] [Order article via Infotrieve]
    
29. Mohamed-Ali V, Goodrick S, Rawesh A, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab. 1997; 82: 4196–4200.[Abstract/Free Full Text]
    
30. Hotamisligil GS, Arner P, Caro JF, et al. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95: 2409–2415.[Medline] [Order article via Infotrieve]
    
31. Grunfeld C, Zhao C, Fuller J, et al. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest. 1996; 97: 2152–2157.[Medline] [Order article via Infotrieve]
    
32. Kirchgessner TG, Uysal KT, Wiesbrock SM, et al. Tumor necrosis factor-alpha contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes. J Clin Invest. 1997; 100: 2777–2782.[Medline] [Order article via Infotrieve]
    
33. Janik JE, Curti BD, Considine RV, et al. Interleukin 1 alpha increases serum leptin concentrations in humans. J Clin Endocrinol Metab. 1997; 82: 3084–3086.[Abstract/Free Full Text]
    
34. Santos-Alvarez J, Goberna R, Sanchez-Margalet V. Human leptin stimulates proliferation and activation of human circulating monocytes. Cell Immunol. 1999; 194: 6–11.[CrossRef][Medline] [Order article via Infotrieve]
    
35. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol. 2000; 68: 437–446.[Abstract/Free Full Text]
    
36. Juge-Aubry CE, Meier CA. Immunomodulatory actions of leptin. Mol Cell Endocrinol. 2002; 194: 1–7.[CrossRef][Medline] [Order article via Infotrieve]
    
37. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA. 1999; 282: 1568–1575.[Abstract/Free Full Text]
    
38. Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates proinflammatory immune responses. FASEB J. 1998; 12: 57–65.[Abstract/Free Full Text]
    
39. Lord GM, Matarese G, Howard JK, et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998; 394: 897–901.[CrossRef][Medline] [Order article via Infotrieve]
    
40. Sanna V, Di Giacomo A, La Cava A, et al. Leptin surge precedes onset of autoimmune encephalomyelitis and correlates with development of pathogenic T cell responses. J Clin Invest. 2003; 111: 241–250.[CrossRef][Medline] [Order article via Infotrieve]
    
41. Tian Z, Sun R, Wei H, et al. Impaired natural killer (NK) cell activity in leptin receptor deficient mice: leptin as a critical regulator in NK cell development and activation. Biochem Biophys Res Commun. 2002; 298: 297–302.[CrossRef][Medline] [Order article via Infotrieve]
    
42. Mancuso P, Gottschalk A, Phare SM, et al. Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol. 2002; 168: 4018–4024.[Abstract/Free Full Text]
    
43. Busso N, So A, Chobaz-Peclat V, et al. Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. J Immunol. 2002; 168: 875–882.[Abstract/Free Full Text]
    
44. Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci. 2001; 47: 141–150.[Medline] [Order article via Infotrieve]
    
45. Parhami F, Tintut Y, Ballard A, et al. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res. 2001; 88: 954–960.[Abstract/Free Full Text]
    
46. Yamagishi SI, Edelstein D, Du XL, et al. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem. 2001; 276: 25096–25100.[Abstract/Free Full Text]
    
47. Lagrand WK, Visser CA, Hermens WT, et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation. 1999; 100: 96–102.[Abstract/Free Full Text]
    
48. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low-density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103: 1194–1197.[Abstract/Free Full Text]
    
49. Shamsuzzaman AS, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation. 2002; 105: 2462–2464.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				T Lappalainen, M Kolehmainen, U Schwab, L Pulkkinen, D E Laaksonen, R Rauramaa, M Uusitupa, and H Gylling Serum concentrations and expressions of serum amyloid A and leptin in adipose tissue are interrelated: the Genobin Study Eur. J. Endocrinol., March 1, 2008; 158(3): 333 - 341. [Abstract] [Full Text] [PDF]

				R. J Kaaja Metabolic syndrome and the menopause Menopause Int, March 1, 2008; 14(1): 21 - 25. [Abstract] [Full Text] [PDF]

				L. A. Viikari, R. K. Huupponen, J. S. A. Viikari, J. Marniemi, C. Eklund, M. Hurme, T. Lehtimaki, M. Kivimaki, and O. T. Raitakari Relationship between Leptin and C-Reactive Protein in Young Finnish Adults J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4753 - 4758. [Abstract] [Full Text] [PDF]

				J. Golledge, P. Clancy, K. Jamrozik, and P. E. Norman Obesity, Adipokines, and Abdominal Aortic Aneurysm: Health in Men Study Circulation, November 13, 2007; 116(20): 2275 - 2279. [Abstract] [Full Text] [PDF]

				S. Djurovic, K. E. Berge, B. Birkenes, O. Braaten, and L. Retterstol The effect of red wine on plasma leptin levels and vasoactive factors from adipose tissue: A randomized crossover trial Alcohol Alcohol., November 1, 2007; 42(6): 525 - 528. [Abstract] [Full Text] [PDF]

				P. Singh, M. Hoffmann, R. Wolk, A. S.M. Shamsuzzaman, and V. K. Somers Leptin Induces C-Reactive Protein Expression in Vascular Endothelial Cells Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): e302 - e307. [Abstract] [Full Text] [PDF]

				J. D. Knudson, G. M. Dick, and J. D. Tune Adipokines and Coronary Vasomotor Dysfunction Experimental Biology and Medicine, June 1, 2007; 232(6): 727 - 736. [Abstract] [Full Text] [PDF]

				E. Oda Criteria for diagnosing the metabolic syndrome. Am. J. Clinical Nutrition, November 1, 2006; 84(5): 1251 - 1252. [Full Text] [PDF]

				E. Oda The metabolic syndrome (emperor) wears no clothes: response to kahn. Diabetes Care, November 1, 2006; 29(11): 2566 - 2566. [Full Text] [PDF]

				A. U. Momin, N. Melikian, A. M. Shah, D. J. Grieve, S. B. Wheatcroft, L. John, A. El Gamel, J. B. Desai, T. Nelson, C. Driver, et al. Leptin is an endothelial-independent vasodilator in humans with coronary artery disease: evidence for tissue specificity of leptin resistance Eur. Heart J., October 1, 2006; 27(19): 2294 - 2299. [Abstract] [Full Text] [PDF]

				R. Wolk and V. K. Somers Leptin and vascular function: friend or foe? Eur. Heart J., October 1, 2006; 27(19): 2263 - 2265. [Full Text] [PDF]

				D M Wunder, M Yared, N A Bersinger, D Widmer, R Kretschmer, and M H Birkhauser Serum leptin and C-reactive protein levels in the physiological spontaneous menstrual cycle in reproductive age women. Eur. J. Endocrinol., July 1, 2006; 155(1): 137 - 142. [Abstract] [Full Text] [PDF]

				S. Mora, I-M. Lee, J. E. Buring, and P. M Ridker Association of Physical Activity and Body Mass Index With Novel and Traditional Cardiovascular Biomarkers in Women JAMA, March 22, 2006; 295(12): 1412 - 1419. [Abstract] [Full Text] [PDF]

				S. Andreas, S. D. Anker, P. D. Scanlon, and V. K. Somers Neurohumoral Activation as a Link to Systemic Manifestations of Chronic Lung Disease Chest, November 1, 2005; 128(5): 3618 - 3624. [Abstract] [Full Text] [PDF]

				B. Canavan, R. O. Salem, S. Schurgin, P. Koutkia, I. Lipinska, M. Laposata, and S. Grinspoon Effects of Physiological Leptin Administration on Markers of Inflammation, Platelet Activation, and Platelet Aggregation during Caloric Deprivation J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5779 - 5785. [Abstract] [Full Text] [PDF]

				S. Devaraj, G. O'Keefe, and I. Jialal Defining the Proinflammatory Phenotype Using High Sensitive C-Reactive Protein Levels as the Biomarker J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4549 - 4554. [Abstract] [Full Text] [PDF]

				J. Gomez-Ambrosi, J. Salvador, C. Silva, F. Rotellar, M. J. Gil, J. A. Cienfuegos, and G. Fruhbeck Leptin Therapy Does Not Affect Inflammatory Markers J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3803 - 3803. [Full Text] [PDF]

				C. Kasapis and P. D. Thompson The Effects of Physical Activity on Serum C-Reactive Protein and Inflammatory Markers: A Systematic Review J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1563 - 1569. [Abstract] [Full Text] [PDF]

				A. H. Berg and P. E. Scherer Adipose Tissue, Inflammation, and Cardiovascular Disease Circ. Res., May 13, 2005; 96(9): 939 - 949. [Abstract] [Full Text] [PDF]

				D.M. Wunder, R. Kretschmer, and N.A. Bersinger Concentrations of leptin and C-reactive protein in serum and follicular fluid during assisted reproductive cycles Hum. Reprod., May 1, 2005; 20(5): 1266 - 1271. [Abstract] [Full Text] [PDF]

				G. Matarese, S. Moschos, and C. S. Mantzoros Leptin in Immunology J. Immunol., March 15, 2005; 174(6): 3137 - 3142. [Abstract] [Full Text] [PDF]

				M. von Eynatten, J. G. Schneider, S. Hadziselimovic, A. Hamann, A. Bierhaus, P. P. Nawroth, and K. A. Dugi Adipocytokines as a Novel Target for the Anti-inflammatory Effect of Atorvastatin in Patients With Type 2 Diabetes Diabetes Care, March 1, 2005; 28(3): 754 - 755. [Full Text] [PDF]

				J. L. Chan, J. Bullen, V. Stoyneva, A. M. DePaoli, C. Addy, and C. S. Mantzoros Recombinant Methionyl Human Leptin Administration to Achieve High Physiologic or Pharmacologic Leptin Levels Does Not Alter Circulating Inflammatory Marker Levels in Humans with Leptin Sufficiency or Excess J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1618 - 1624. [Abstract] [Full Text] [PDF]

				K. Tsuda, I. Nishio, A. S.M. Shamsuzzaman, M. Winnicki, R. Wolk, A. Svatikova, D. E. Davison, V. K. Somers, B. G. Phillips, and P. B. Berger Leptin, C-Reactive Protein, and Nitric Oxide Production in Healthy Humans * Response Circulation, September 28, 2004; 110(13): e330 - e330. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 109/18/2181    most recent 01.CIR.0000127960.28627.75v1 Alert me when this article is cited