Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Adipocytokine and ghrelin levels in relation to cardiovascular disease risk factors in women at midlife: longitudinal associations

International Journal of Obesity volume 32, pages 740–748 (2008)Cite this article

Abstract

Background:

There are limited data concerning the relationships between changes in adipocytokines and cardiovascular disease (CVD) risk factors.

Objective:

To examine the longitudinal associations between leptin, adiponectin, resistin and ghrelin levels and CVD risk factor levels in women at midlife.

Design:

Prospective, observational study.

Subjects and measurements:

Leptin, adiponectin, resistin, ghrelin levels and CVD risk factors were measured in specimens collected from 40 women at 3 points in time corresponding to the pre-, peri- and postmenopause stages of their natural menopause transition.

Results:

In longitudinal analyses adjusted for CVD risk factors and leptin at the previous menopausal stage, aging, education, smoking and physical activity, greater increases in leptin over the menopause transition were associated with greater decreases in high-density lipoprotein cholesterol (HDL-c) and greater increases in diastolic blood pressure, glucose, insulin and insulin resistance (all P<0.05). Larger decreases in adiponectin over the menopause transition were associated with greater increases in systolic blood pressure, insulin and insulin resistance and with greater decreases in HDL-c. Greater increases in ghrelin levels over the menopausal transition were associated with greater low-density lipoprotein cholesterol increases (P=0.014). Resistin was not associated with CVD risk factor changes.

Conclusion:

There were significant adverse associations of adipocytokines and ghrelin with multiple CVD risk factor changes in women across midlife. Given that this time period is dynamic for CVD risk, these data underscore the need for additional prospective studies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Kurth T, Gaziano JM, Berger K, Kase CS, Rexrode KM, Cook NR et al. Body mass index and the risk of stroke in men. Arch Intern Med 2002; 162: 2557–2562.

    Article  Google Scholar 

  2. Dey DK, Rothenberg E, Sundh V, Bosaeus I, Steen B . Waist circumference, body mass index, and risk for stroke in older people: a 15 year longitudinal population study of 70-year-olds. J Am Geriatr Soc 2002; 50: 1510–1518.

    Article  Google Scholar 

  3. Wilson PW, D'Agostino RB, Sullivan L, Parise H, Kannel WB . Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 2002; 162: 1867–1872.

    Article  Google Scholar 

  4. Stevens J, Cai J, Evenson KR, Thomas R . Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the lipid research clinics study. Am J Epidemiol 2002; 156: 832–841.

    Article  Google Scholar 

  5. Soderberg S, Ahren B, Jansson JH, Johnson O, Hallmans G, Asplund K et al. Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999; 246: 409–418.

    Article  CAS  Google Scholar 

  6. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003; 23: 85–89.

    Article  CAS  Google Scholar 

  7. Ohmori R, Momiyama Y, Kato R, Taniguchi H, Ogura M, Ayaori M et al. Associations between serum resistin levels and insulin resistance, inflammation, and coronary artery disease. J Am Coll Cardiol 2005; 46: 379–380.

    Article  Google Scholar 

  8. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A et al. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation 2001; 104: 3052–3056.

    Article  CAS  Google Scholar 

  9. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB . Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291: 1730–1737.

    Article  CAS  Google Scholar 

  10. Nakamura K, Ueno T, Yamamoto H, Iguro Y, Yamada K, Sakata R . Relationship between cerebral injury and inflammatory responses in patients undergoing cardiac surgery with cardiopulmonary bypass. Cytokine 2005; 29: 95–104.

    Article  CAS  Google Scholar 

  11. Meier U, Gressner AM . Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004; 50: 1511–1525.

    Article  CAS  Google Scholar 

  12. Webber J . Energy balance in obesity. Proc Nutr Soc 2003; 62: 539–543.

    Article  Google Scholar 

  13. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K . cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (dioseost abundant gene transcript 1). Biochem Biophys Res Commun 1996; 221: 286–289.

    Article  CAS  Google Scholar 

  14. Kim KH, Lee K, Moon YS, Sul HS . A cysteine-rich adipose tissue-specific secretory factor inhibits adipocyte differentiation. J Biol Chem 2001; 276: 11252–11256.

    Article  CAS  Google Scholar 

  15. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV et al. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-{gamma} action in humans. Diabetes 2001; 50: 2199–2202.

    Article  CAS  Google Scholar 

  16. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM et al. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307–312.

    Article  CAS  Google Scholar 

  17. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276: 905–908.

    Article  CAS  Google Scholar 

  18. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409: 194–198.

    Article  CAS  Google Scholar 

  19. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87: 240–244.

    Article  CAS  Google Scholar 

  20. Sowers M, Zheng H, Tomey K, Karvonen-Gutierrez C, Jannausch M, Li X et al. Changes in body composition in women over six years at midlife: ovarian and chronological aging. J Clin Endocrinol Metab 2007; 92: 895–901.

    Article  CAS  Google Scholar 

  21. Matthews KA, Kuller LH, Sutton-Tyrrell K, Chang YF . Changes in cardiovascular risk factors during the perimenopause and postmenopause and carotid artery atherosclerosis in healthy women. Stroke 2001; 32: 1104–1111.

    Article  CAS  Google Scholar 

  22. Otsuki M, Kasayama S, Morita S, Asanuma N, Saito H, Mukai M et al. Menopause, but not age, is an independent risk factor for fasting plasma glucose levels in nondiabetic women. Menopause 2007; 14: 404–407.

    Article  Google Scholar 

  23. Mesch VR, Boero LE, Siseles NO, Royer M, Prada M, Sayegh F et al. Metabolic syndrome throughout the menopausal transition: influence of age and menopausal status. Climacteric 2006; 9: 40–48.

    Article  CAS  Google Scholar 

  24. Warnick GR, Albers JJ . A comprehensive evaluation of heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol. J Lipid Res 1978; 19: 65.

    CAS  PubMed  Google Scholar 

  25. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

    Article  CAS  Google Scholar 

  26. Boulier A, Fricker J, Thomasset AL, Apfelbaum M . Fat-free mass estimation by the two-electrode impedance method. Am J Clin Nutr 1990; 52: 581–585.

    Article  CAS  Google Scholar 

  27. Sallis JF, Haskell WL, Wood PD, Fortmann SP, Rogers T, Blair SN et al. Physical activity assessment methodology in the Five-City Project. Am J Epidemiol 1985; 121: 91–106.

    Article  CAS  Google Scholar 

  28. Franks PW, Brage S, Luan J, Ekelund U, Rahman M, Farooqi IS et al. Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity. Obes Res 2005; 13: 1476–1484.

    Article  CAS  Google Scholar 

  29. Canatan H, Bakan I, Akbulut M, Baydas G, Halifeoglu I, Gursu MF . Comparative analysis of plasma leptin levels in both genders of patients with essential hypertension and healthy subjects. Endocr Res 2004; 30: 95–105.

    Article  CAS  Google Scholar 

  30. Matsubara M, Chiba H, Maruoka S, Katayose S . Elevated serum leptin concentrations in women with components of multiple risk factor clustering syndrome. J Atheroscler Thromb 2000; 7: 231–237.

    Article  CAS  Google Scholar 

  31. Liuzzi A, Savia G, Tagliaferri M, Lucantoni R, Berselli ME, Petroni ML et al. Serum leptin concentration in moderate and severe obesity: relationship with clinical, anthropometric and metabolic factors. Int J Obes Relat Metab Disord 1999; 23: 1066–1073.

    Article  CAS  Google Scholar 

  32. El-Gharbawy AH, Kotchen JM, Grim CE, Kaldunski M, Hoffmann RG, Pausova Z et al. Gender-specific correlates of leptin with hypertension-related phenotypes in African Americans. Am J Hypertens 2002; 15: 989–993.

    Article  CAS  Google Scholar 

  33. Lyoussi B, Ragala MA, Mguil M, Chraibi A, Israili ZH . Gender-specific leptinemia and its relationship with some components of the metabolic syndrome in Moroccans. Clin Exp Hypertens 2005; 27: 377–394.

    Article  CAS  Google Scholar 

  34. Hu FB, Chen C, Wang B, Stampfer MJ, Xu X . Leptin concentrations in relation to overall adiposity, fat distribution, and blood pressure in a rural Chinese population. Int J Obes Relat Metab Disord 2001; 25: 121–125.

    Article  CAS  Google Scholar 

  35. Baratta R, Amato S, Degano C, Farina MG, Patane G, Vigneri R et al. Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies. J Clin Endocrinol Metab 2004; 89: 2665–2671.

    Article  CAS  Google Scholar 

  36. Della MP, Lupia M, Bandolin V, Guzzon S, Sonino N, Vettor R et al. Adiponectin, insulin resistance, and left ventricular structure in dipper and nondipper essential hypertensive patients. Am J Hypertens 2005; 18: 30–35.

    Article  Google Scholar 

  37. Zietz B, Herfarth H, Paul G, Ehling A, Muller-Ladner U, Scholmerich J et al. Adiponectin represents an independent cardiovascular risk factor predicting serum HDL-cholesterol levels in type 2 diabetes. FEBS Lett 2003; 545: 103–104.

    Article  CAS  Google Scholar 

  38. Choi KM, Lee J, Lee KW, Seo JA, Oh JH, Kim SG et al. The associations between plasma adiponectin, ghrelin levels and cardiovascular risk factors. Eur J Endocrinol 2004; 150: 715–718.

    Article  CAS  Google Scholar 

  39. Yu JG, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M et al. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 2002; 51: 2968–2974.

    Article  CAS  Google Scholar 

  40. Pellme F, Smith U, Funahashi T, Matsuzawa Y, Brekke H, Wiklund O et al. Circulating adiponectin levels are reduced in nonobese but insulin-resistant first-degree relatives of type 2 diabetic patients. Diabetes 2003; 52: 1182–1186.

    Article  CAS  Google Scholar 

  41. Rajala MW, Scherer PE . Minireview: the adipocyte—at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 2003; 144: 3765–3773.

    Article  CAS  Google Scholar 

  42. Kim MS, Lee KU . Role of hypothalamic 5′-AMP-activated protein kinase in the regulation of food intake and energy homeostasis. J Mol Med 2005; 83: 514–520.

    Article  CAS  Google Scholar 

  43. Ahima RS, Flier JS . Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327–332.

    Article  CAS  Google Scholar 

  44. Beltowski J . Leptin and atherosclerosis. Atherosclerosis 2006; 189: 47–60.

    Article  CAS  Google Scholar 

  45. Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 2004; 145: 367–383.

    Article  CAS  Google Scholar 

  46. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI et al. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 2002; 99: 16309–16313.

    Article  CAS  Google Scholar 

  47. Ohashi K, Kihara S, Ouchi N, Kumada M, Fujita K, Hiuge A et al. Adiponectin replenishment ameliorates obesity-related hypertension. Hypertension 2006; 47: 1108–1116.

    Article  CAS  Google Scholar 

  48. Fagerberg B, Hulten LM, Hulthe J . Plasma ghrelin, body fat, insulin resistance, and smoking in clinically healthy men: the atherosclerosis and insulin resistance study. Metabolism 2003; 52: 1460–1463.

    Article  CAS  Google Scholar 

  49. Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A et al. Correlation between serum resistin level and adiposity in obese individuals. Obes Res 2003; 11: 997–1001.

    Article  CAS  Google Scholar 

  50. Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R et al. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab 2003; 88: 5452–5455.

    Article  CAS  Google Scholar 

  51. Chan DC, Watts GF, Ng TW, Uchida Y, Sakai N, Yamashita S et al. Adiponectin and other adipocytokines as predictors of markers of triglyceride-rich lipoprotein metabolism. Clin Chem 2005; 51: 578–585.

    Article  CAS  Google Scholar 

  52. Bo S, Gambino R, Pagani A, Guidi S, Gentile L, Cassader M et al. Relationships between human serum resistin, inflammatory markers and insulin resistance. Int J Obes (Lond) 2005; 29: 1315–1320.

    Article  CAS  Google Scholar 

  53. Kunnari A, Ukkola O, Paivansalo M, Kesaniemi YA . High plasma resistin level is associated with enhanced highly sensitive C-reactive protein and leukocytes. J Clin Endocrinol Metab 2006; 91: 2755–2760.

    Article  CAS  Google Scholar 

  54. Youn BS, Yu KY, Park HJ, Lee NS, Min SS, Youn MY et al. Plasma resistin concentrations measured by enzyme-linked immunosorbent assay using a newly developed monoclonal antibody are elevated in individuals with type 2 diabetes mellitus. J Clin Endocrinol Metab 2004; 89: 150–156.

    Article  CAS  Google Scholar 

  55. Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab 2003; 88: 4848–4856.

    Article  CAS  Google Scholar 

  56. Lavoie HB, Taylor AE, Sharpless JL, Anderson EJ, Strauss CC, Hall JE . Effects of short-term hormone replacement on serum leptin levels in postmenopausal women. Clin Endocrinol (Oxf) 1999; 51: 415–422.

    Article  CAS  Google Scholar 

  57. Elbers JMH, de Roo GW, Popp-Snijders C, Nicolaas-Merkus A, Westerveen E, Joenje BW et al. Effects of administration of 17beta-oestradiol on serum leptin levels in healthy postmenopausal women. Clin Endocrinol 1999; 51: 449–454.

    Article  CAS  Google Scholar 

  58. Haffner SM, Mykkanen L, Stern MP . Leptin concentrations in women in the San Antonio Heart Study: effect of menopausal status and postmenopausal hormone replacement therapy. Am J Epidemiol 1997; 146: 581–585.

    Article  CAS  Google Scholar 

  59. Im JA, Lee JW, Lee HR, Lee DC . Plasma adiponectin levels in postmenopausal women with or without long-term hormone therapy. Maturitas 2006; 54: 65–71.

    Article  CAS  Google Scholar 

  60. Expert panel on the identification, evaluation, and treatment of overweight and obesity in adults. Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med 1998; 158: 1855–1867.

    Article  Google Scholar 

  61. Wildman RP, Schott LL, Brockwell S, Kuller LH, Sutton-Tyrrell K . A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima–media thickness of the carotid arteries. J Am Coll Cardiol 2004; 44: 579–585.

    Article  Google Scholar 

  62. Wildman RP, Colvin AB, Powell LH, Matthews KA, Everson-Rose SA, Hollenberg SM et al. Associations of endogenous sex hormones with the vasculature in menopausal women: the Study of Women's Health Across the Nation (SWAN). Menopause 2007 (in press).

Download references

Acknowledgements

This work was supported by NIH Grant AR041384 (Sowers, PI). Dr Mancuso has grant support from NIH Grant HL077417.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    R P Wildman, C Wang & M Kim

  2. Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    P Mancuso

  3. Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    P E Scherer

  4. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    M R Sowers

  5. Center for Integrated Approaches to Complex Diseases, University of Michigan, Ann Arbor, MI, USA

    M R Sowers

Authors
  1. R P Wildman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Mancuso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P E Scherer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M R Sowers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R P Wildman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wildman, R., Mancuso, P., Wang, C. et al. Adipocytokine and ghrelin levels in relation to cardiovascular disease risk factors in women at midlife: longitudinal associations. Int J Obes 32, 740–748 (2008). https://doi.org/10.1038/sj.ijo.0803782

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803782

Keywords

This article is cited by

Search

Advanced search

Quick links