Download PDF
Horm Metab Res 2018; 50(07): 509-520
DOI: 10.1055/a-0620-8671
Review
© Georg Thieme Verlag KG Stuttgart · New York

Association of Serum Leptin with All-Cause and Disease Specific Mortality: A Meta-Analysis of Prospective Observational Studies

Hamed Kord-Varkaneh
1   Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
,
Somaye Fatahi
1   Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
,
Shahab Alizadeh
1   Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
,
Ehsan Ghaedi
1   Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
2   Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
,
Sakineh Shab-Bidar
1   Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
› Author Affiliations
Further Information

Publication History

received 01 April 2018

accepted 19 April 2018

Publication Date:
10 July 2018 (online)

Also available at
    Permissions and Reprints

Abstract

Leptin levels may affect mortality through its link to inflammation and obesity. However, data are inconclusive. This meta-analysis was performed to investigate the association of leptin with mortality. The PubMed, Scopus, Google scholar, and reference lists of the included studies were searched for all published prospective observational studies that described the associations of serum leptin and mortality up to August 2017. Two reviewers independently assessed all potentially relevant studies for inclusion and methodological quality using standardized abstraction forms. Of 518 studies identified, 19 studies considered the association of leptin with all-cause mortality (16 208 subjects) and 12 studies evaluated the association of leptin with disease-specific mortality (13 680 subjects). In the overall analysis, no significant association was found between leptin and all-cause mortality (HR=1.028; 95% CI: 0.908–1.165; p=0.659), with a high between study heterogeneity (p˂0.001, I2=61). Subgroup analysis found that high leptin is associated with increased all-cause mortality in healthy people (HR=1.159 (95% CI, 1.032, 1.302), p=0.012), in men (HR=1.162; 95% CI: 1.036–1.302; p=0.010), and in subjects with ≥60 years old (HR=1.129; 95% CI: 1.030–1.238; p=0.010); whereas, increased leptin levels was related to the decreased cancer-specific mortality ((HR=0.550; 95% CI: 0.418–0.724), p˂0.001). Higher leptin levels in healthy people, old people, and males were associated with increased all-cause mortality, while increased leptin level was related to the reduced risk of death among patients with cancer.

Key words

leptin - mortality - obesity - meta-analysis

Supplementary Material

 

  • References

  • 1 Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity among adults: United States. NCHS Data Brief 2012; 2013: 1-8
    PubMedGoogle Scholar
  • 2 Flegal KM, Graubard BI, Williamson DF, Gail MH. Excess deaths associated with underweight, overweight, and obesity. JAMA 2005; 293: 1861-1867
    CrossrefPubMedGoogle Scholar
  • 3 Shimokawa I, Higami Y. Leptin signaling and aging: insight from caloric restriction. Mech Age Develop 2001; 122: 1511-1519
    CrossrefPubMedGoogle Scholar
  • 4 Hukshorn CJ, Lindeman JH, Toet KH, Saris WH, Eilers PH, Westerterp-Plantenga MS, Kooistra T. Leptin and the proinflammatory state associated with human obesity. J Clin Endocrinol Metab 2004; 89: 1773-1778
    CrossrefPubMedGoogle Scholar
  • 5 Waelput W, Brouckaert P, Broekaert D, Tavernier J. A role for leptin in the systemic inflammatory response syndrome (SIRS) and in immune response, an update. Curr Med Chem 2006; 13: 465-475
    CrossrefPubMedGoogle Scholar
  • 6 Yamagishi S-i, Edelstein D, Du X-l, Kaneda Y, Guzmán M, Brownlee M. 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: 25096-250100
    CrossrefPubMedGoogle Scholar
  • 7 Gualillo O, Eiras S, Lago F, Diéguez C, Casanueva FF. Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci 2000; 67: 2433-2441
    CrossrefPubMedGoogle Scholar
  • 8 BouloumiÉ A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells. FASEB J 1999; 13: 1231-1238
    CrossrefPubMedGoogle Scholar
  • 9 Van Dielen F, Van't Veer C, Schols A, Soeters P, Buurman W, Greve J. Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals. Int J Obes 2001; 25: 1759
    CrossrefPubMedGoogle Scholar
  • 10 Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Hematol 2001; 8: 131-136
    CrossrefPubMedGoogle Scholar
  • 11 Bian X, Liu N, Bai Y, Zheng L, He P, Su X, Du F, Yang X, Li D. Association of leptin with mortality in patients on maintenance hemodialysis: A prospective study. Iran J Kidney Dis 2014; 8: 314-320
    PubMedGoogle Scholar
  • 12 Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Papacosta O, Sattar N. The obesity paradox in men with coronary heart disease and heart failure: The role of muscle mass and leptin. Int J Cardiol 2014; 171: 49-55
    CrossrefPubMedGoogle Scholar
  • 13 Siegel AB, Goyal A, Salomao M, Wang S, Lee V, Hsu C, Rodriguez R, Hershman DL, Brown Jr. RS, Neugut AI, Emond J, Kato T, Samstein B, Faleck D, Karagozian R. Serum adiponectin is associated with worsened overall survival in a prospective cohort of hepatocellular carcinoma patients. Oncology (Switzerland) 2015; 88: 57-68
    CrossrefPubMedGoogle Scholar
  • 14 Wulaningsih W, Holmberg L, Ng T, Rohrmann S, Van Hemelrijck M. Serum leptin, C-reactive protein, and cancer mortality in the NHANES III. Cancer Med 2016; 5: 120-128
    CrossrefPubMedGoogle Scholar
  • 15 Vecchione C, Maffei A, Colella S, Aretini A, Poulet R, Frati G, Gentile MT, Fratta L, Trimarco V, Trimarco B. Leptin effect on endothelial nitric oxide is mediated through Akt–endothelial nitric oxide synthase phosphorylation pathway. Diabetes 2002; 51: 168-173
    CrossrefPubMedGoogle Scholar
  • 16 Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N. Plasma leptin and the risk of cardiovascular disease in the west of Scotland coronary prevention study (WOSCOPS). Circulation 2001; 104: 3052-3056
    CrossrefPubMedGoogle Scholar
  • 17 Scholze A, Rattensperger D, Zidek W, Tepel M. Low serum leptin predicts mortality in patients with chronic kidney disease stage 5. Obesity 2007; 15: 1617-1622
    CrossrefPubMedGoogle Scholar
  • 18 Head GA, Lim K, Barzel B, Burke SL, Davern PJ. Central nervous system dysfunction in obesity-induced hypertension. Curr Hypertens Rep 2014; 16: 466
    CrossrefPubMedGoogle Scholar
  • 19 Langenberg C, Bergstrom J, Scheidt-Nave C, Pfeilschifter J, Barrett-Connor E. Cardiovascular death and the metabolic syndrome. Diabetes Care 2006; 29: 1363-1369
    CrossrefPubMedGoogle Scholar
  • 20 Franks PW, Brage S, Luan JA, Ekelund U, Rahman M, Farooqi IS, Halsall I, O'rahilly S, Wareham NJ. Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity. Obesity 2005; 13: 1476-1484
    CrossrefPubMedGoogle Scholar
  • 21 Couillard C, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien P-J, Després J-P. Leptinemia is not a risk factor for ischemic heart disease in men: prospective results from the Quebec Cardiovascular Study. Diabetes Care 1998; 21: 782-786
    CrossrefPubMedGoogle Scholar
  • 22 Brennan A, Li T, Kelesidis I, Gavrila A, Hu F, Mantzoros C. Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: a prospective cohort study. Diabetologia 2007; 50: 1178-1185
    CrossrefPubMedGoogle Scholar
  • 23 Kayacan SM, Yildiz A, Kazancioglu R, Sahin S, Sever MS, Ark E. The changes in serum leptin, body fat mass and insulin resistance after renal transplantation. Clin Transpl 2003; 17: 63-68
    CrossrefPubMedGoogle Scholar
  • 24 Mcneely MJ, Boyko EJ, Weigle DS, Shofer JB, Chessler SD, Leonnetti DL, Fujimoto WY. Association between baseline plasma leptin levels and subsequent development of diabetes in Japanese Americans. Diabetes Care 1999; 22: 65-70
    CrossrefPubMedGoogle Scholar
  • 25 Agras PI, Saatci U, Baskin E, Ozbek N, Cengiz N, Colak T, Karakayali H, Haberal A, Haberal M. Hyperleptinemia and its relation with peripheral C34+ CD7+ stem cells in renal transplant recipients. Transpl Immunol 2006; 15: 241-245
    CrossrefPubMedGoogle Scholar
  • 26 Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798
    CrossrefPubMedGoogle Scholar
  • 27 VanSaun MN. Molecular pathways: adiponectin and leptin signaling in cancer. Clin Cancer Res 2013; 19: 1926-1932
    CrossrefPubMedGoogle Scholar
  • 28 Niu J, Jiang L, Guo W, Shao L, Liu Y, Wang L. The association between leptin level and breast cancer: a meta-analysis. PloS One 2013; 8: e67349
    CrossrefPubMedGoogle Scholar
  • 29 Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res 2001; 88: 954-960
    CrossrefPubMedGoogle Scholar
  • 30 Oda A, Taniguchi T, Yokoyama M. Leptin stimulates rat aortic smooth muscle cell proliferation and migration. Kobe J Med Sci 2001; 47: 141-150
    PubMedGoogle Scholar
  • 31 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283: 2008-2012
    CrossrefPubMedGoogle Scholar
  • 32 Moher D, Liberati A, Tetzlaff J, Altman DG. Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6: e1000097
    Google Scholar
  • 33 Wells G, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013; http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
    PubMed
  • 34 Egger M, Davey-Smith G, Altman D. Systematic reviews in health care: meta-analysis in context. New York: Wiley; 2008
    Google Scholar
  • 35 Higgins J, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statist Med 2002; 21: 1539-1558
    CrossrefPubMedGoogle Scholar
  • 36 Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634
    CrossrefPubMedGoogle Scholar
  • 37 Molnar MZ, Nagy K, Remport A, Gaipov A, Fülöp T, Czira ME, Kovesdy CP, Mucsi I, Mathe Z. Association between serum leptin level and mortality in kidney transplant recipients. J Renal Nutr 2017; 27: 53-61
    CrossrefPubMedGoogle Scholar
  • 38 Dellas C, Lankeit M, Reiner C, Schäfer K, Hasenfuß G, Konstantinides S. BMI-independent inverse relationship of plasma leptin levels with outcome in patients with acute pulmonary embolism. Int J Obes 2013; 37: 204-210
    CrossrefPubMedGoogle Scholar
  • 39 Bracho-Riquelme RL, Reyes-Romero MA, Pescador N, Flores-García AI. A leptin serum concentration less than 10 ng/ml is a predictive marker of outcome in patients with moderate to severe secondary peritonitis. Eur Surg Res 2008; 41: 238-244
    CrossrefPubMedGoogle Scholar
  • 40 Bickel C, Schnabel RB, Zeller T, Lackner KJ, Rupprecht HJ, Blankenberg S, Sinning C, Westermann D. Predictors of leptin concentration and association with cardiovascular risk in patients with coronary artery disease: results from the AtheroGene study. Biomarkers 2017; 22: 210-218
    CrossrefPubMedGoogle Scholar
  • 41 Mishra S, Harris TB, Hsueh WC, Hue T, Leak TS, Li R, Mehta M, Vaisse C, Sahyoun NR. The association of serum leptin with mortality in older adults. PLoS One 2015; 10:
    PubMed
  • 42 Martin SS, Blaha MJ, Muse ED, Qasim AN, Reilly MP, Blumenthal RS, Nasir K, Criqui MH, McClelland RL, Hughes-Austin JM, Allison MA. Leptin and incident cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2015; 239: 67-72
    CrossrefPubMedGoogle Scholar
  • 43 Batsis JA, Sahakyan KR, Singh P, Bartels SJ, Somers VK, Lopez-Jimenez F. Leptin, adiposity, and mortality: Results from the national health and nutrition examination survey III, 1988 to 1994. Mayo Clin Proc 2015; 90: 481-491
    CrossrefPubMedGoogle Scholar
  • 44 Ku IA, Farzaneh-Far R, Vittinghoff E, Zhang MH, Na B, Whooley MA. Association of low leptin with cardiovascular events and mortality in patients with stable coronary artery disease: the Heart and Soul Study. Atherosclerosis 2011; 217: 503-508
    CrossrefPubMedGoogle Scholar
  • 45 Li H, Stampfer MJ, Mucci L, Rifai N, Qiu W, Kurth T, Ma J. A 25-year prospective study of plasma adiponectin and leptin concentrations and prostate cancer risk and survival. Clinical Chemistry. 2010; 56: 34-43
    CrossrefPubMedGoogle Scholar
  • 46 Brennan AM, Li TY, Kelesidis I, Gavrila A, Hu FB, Mantzoros CS. Circulating leptin levels are not associated with cardiovascular morbidity and mortality in women with diabetes: A prospective cohort study. Diabetologia 2007; 50: 1178-1185
    CrossrefPubMedGoogle Scholar
  • 47 Park JT, Yoo TH, Kim JK, Oh HJ, Kim SJ, Yoo DE, Lee MJ, Shin DH, Han SH, Han DS, Kang SW. Leptin/adiponectin ratio is an independent predictor of mortality in nondiabetic peritoneal dialysis patients. Periton Dial Int 2013; 33: 67-74
    PubMedGoogle Scholar
  • 48 Arai Y, Takayama M, Gondo Y, Inagaki H, Yamamura K, Nakazawa S, Kojima T, Ebihara Y, Shimizu K, Masui Y, Kitagawa K, Takebayashi T, Hirose N. Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age. J Gerontol Ser A 2008; 63: 1209-1218
    CrossrefPubMedGoogle Scholar
  • 49 Hellström L, Wahrenberg H, Hruska K, Reynisdottir S, Arner P. Mechanisms behind gender differences in circulating leptin levels. J Intern Med 2000; 247: 457-462
    CrossrefPubMedGoogle Scholar
  • 50 De Luis D, Perez CJ, Duenas A. Leptin and obesity. Minerva Med 2009; 100: 229-236
    PubMedGoogle Scholar
  • 51 McGee DL. Collaboration DP. Body mass index and mortality: a meta-analysis based on person-level data from twenty-six observational studies. Ann Epidemiol 2005; 15: 87-97
    CrossrefPubMedGoogle Scholar
  • 52 Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983; 67: 968-977
    CrossrefPubMedGoogle Scholar
  • 53 Björntorp P. The associations between obesity, adipose tissue distribution and disease. J Intern Med 1987; 222: 121-134
    PubMedGoogle Scholar
  • 54 Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798
    CrossrefPubMedGoogle Scholar
  • 55 Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140: 883-899
    CrossrefPubMedGoogle Scholar
  • 56 Trujillo ME, Lee M-J, Sullivan S, Feng J, Schneider SH, Greenberg AS, Fried SK. Tumor necrosis factor a and glucocorticoid synergistically increase leptin production in human adipose tissue: role for p38 mitogen-activated protein kinase. J Clin Endocrinol Metab 2006; 91: 1484-1490
    CrossrefPubMedGoogle Scholar
  • 57 Shamsuzzaman AS, Winnicki M, Wolk R, Svatikova A, Phillips BG, Davison DE, Berger PB, Somers VK. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation 2004; 109: 2181-2185
    CrossrefPubMedGoogle Scholar
  • 58 Ble A, Windham BG, Bandinelli S, Taub DD, Volpato S, Bartali B, Tracy RP, Guralnik JM, Ferrucci L. Relation of plasma leptin to C-reactive protein in older adults (from the Invecchiare nel Chianti study). Am J Cardiol 2005; 96: 991-995
    CrossrefPubMedGoogle Scholar
  • 59 Dagogo-Jack S, Selke G, Melson AK, Newcomer JW. Robust leptin secretory responses to dexamethasone in obese subjects. J Clin Endocrinol Metab 1997; 82: 3230-3233
    PubMedGoogle Scholar
  • 60 Fain JN, Leffler CW, Bahouth SW. Eicosanoids as endogenous regulators of leptin release and lipolysis by mouse adipose tissue in primary culture. J Lipid Res 2000; 41: 1689-1694
    PubMedGoogle Scholar
  • 61 Wang D, DuBois RN. Prostaglandins and cancer. Gut 2006; 55: 115-122
    CrossrefPubMedGoogle Scholar
  • 62 Ajisaka H, Koyama F, Uotani C. History of distal gastrectomy prevents metabolic syndrome and chronic kidney disease. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2014; 8: 30-32
    CrossrefPubMedGoogle Scholar
  • 63 Tong X, Ma Y, Zhou Q, He J, Peng B, Liu S, Yan Z, Yang X, Fan H. Serum and tissue leptin in lung cancer: A meta-analysis. Oncotarget 2017; 8: 19699
    PubMedGoogle Scholar
  • 64 Wang P-P, He X-Y, Wang R, Wang Z, Wang Y-G. High leptin level is an independent risk factor of endometrial cancer: a meta-analysis. Cell Physiol Biochem 2014; 34: 1477-1484
    CrossrefPubMedGoogle Scholar
  • 65 Rathmann W, Herder C. Adiponectin and cardiovascular mortality: evidence for “reverse epidemiology”. Horm Metab Res 2007; 39: 1-2
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Liu Z, Zhang T-T, Zhao J-J, Qi S-F, Du P, Liu D-W, Tian Q-B. The association between overweight, obesity and ovarian cancer: a meta-analysis. Jpn J Clin Oncol 2015; 45: 1107-1115
    PubMedGoogle Scholar
  • 67 Sun J-W, Zhao L-G, Yang Y, Ma X, Wang Y-Y, Xiang Y-B. Obesity and risk of bladder cancer: a dose-response meta-analysis of 15 cohort studies. PloS One 2015; 10: e0119313
    CrossrefPubMedGoogle Scholar
  • 68 Zhang X, Liu Y, Shao H, Zheng X. Obesity paradox in lung cancer prognosis: evolving biological insights and clinical implications. J Thorac Oncol 2017; 12: 1478-1488
    CrossrefPubMedGoogle Scholar
  • 69 Mishra S, Harris TB, Hsueh W-C, Hue T, Leak TS, Li R, Mehta M, Vaisse C, Sahyoun NR. The association of serum leptin with mortality in older adults. PloS One 2015; 10: e0140763
    CrossrefPubMedGoogle Scholar
  • 70 Casabiell Xs, Piñeiro Vn, Peino R, Lage M, Camiña Js, Gallego Ra, Vallejo LG, Dieguez C, Casanueva FF. Gender differences in both spontaneous and stimulated leptin secretion by human omental adipose tissue in vitro: dexamethasone and estradiol stimulate leptin release in women, but not in men. J Clin Endocrinol Metab 1998; 83: 2149-2155
    PubMedGoogle Scholar
  • 71 Castracane VD, Kraemer RR, Franken MA, Kraemer GR, Gimpel T. Serum leptin concentration in women: effect of age, obesity, and estrogen administration. Fertil Steril 1998; 70: 472-477
    CrossrefPubMedGoogle Scholar
  • 72 Doehner W, Von Haehling S, Anker SD. Protective overweight in cardiovascular disease: moving from ‘paradox’to ‘paradigm’. Oxford: Oxford University Press; 2015
    Google Scholar
  • 73 Tseng C-H. Obesity paradox: differential effects on cancer and noncancer mortality in patients with type 2 diabetes mellitus. Atherosclerosis 2013; 226: 186-192
    CrossrefPubMedGoogle Scholar