The Role of Leptinemia State as a Mediator of Inflammation in Obese Adults

A. dos Santos Moraes; L. P. Pisani; F. C. Corgosinho; L. O. Testa Carvalho; D.C. L. Masquio; G. Jamar; R. B. Sanches; L. M. Oyama; A. R. Dâmaso; C. Belote; D. A. Caranti

doi:10.1055/s-0033-1343450

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2013; 45(08): 605-610
DOI: 10.1055/s-0033-1343450

Humans, Clinical

The Role of Leptinemia State as a Mediator of Inflammation in Obese Adults

A. dos Santos Moraes

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

,

L. P. Pisani

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

³Post Graduate Program of Nutrition, Federal University of São Paulo – UNIFESP – São Paulo (SP), Brazil

,

F. C. Corgosinho

³Post Graduate Program of Nutrition, Federal University of São Paulo – UNIFESP – São Paulo (SP), Brazil

,

L. O. Testa Carvalho

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

,

D.C. L. Masquio

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

,

G. Jamar

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

,

R. B. Sanches

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

,

L. M. Oyama

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

³Post Graduate Program of Nutrition, Federal University of São Paulo – UNIFESP – São Paulo (SP), Brazil

,

A. R. Dâmaso

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

³Post Graduate Program of Nutrition, Federal University of São Paulo – UNIFESP – São Paulo (SP), Brazil

⁴Department of Biosciences, Federal University of São Paulo – UNIFESP –Santos (SP), Brazil

,

C. Belote

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

,

D. A. Caranti

¹Post Graduate Program of Interdisciplinary Health Sciences, Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

²Obesity Study Group (GEO), Federal University of São Paulo – UNIFESP – Santos (SP), Brazil

⁴Department of Biosciences, Federal University of São Paulo – UNIFESP –Santos (SP), Brazil

› Author Affiliations

Abstract

Hyperleptinemia has emerged as a marker of proinflammatory status, while the adiponectin/leptin ratio has been used to identify anti-inflammatory state. In this context, the aims of the present study were to investigate the role of leptinemia, adjusted by tertiles, on inflammatory state in obese adults according to obesity degree. This is a cross-sectional study comprised of 43 obese adults. The anthropometric variables and body composition were analyzed, as well as markers of inflammation such as leptin, adiponectin, and plasminogen activator inhibitor. Subjects were grouped using adjusted tertiles of the leptin levels. The major finding was the negative correlation between leptin concentration with adiponectin/leptin ratio (r=−0.622, p=0.000) and the positive correlation with leptin/adiponectin ratio (r=0.622, p=0.000). Indeed, both ratios were decreased and increased, respectively, according to the obesity degree. Furthermore, in the stepwise multiple linear regression analysis, the high degree of obesity was an independent predictor of leptinemia when adjusted for age and BMI (β=0.588, p=0.000 and β=0.778, p=0.005). Finally, the strong negatively correlation between the leptinemia with adiponectin/leptin ratio and the positive correlation with leptin/adiponectin ratio reinforce the role of this adipokine as a biomarker of inflammation in obese adults, according to obesity degree. Our findings can elucidate that hyperleptinemic status was a major factor in the proinflammatory status related to higher obesity degree. All together, these data reinforce the role of leptinemia state as a mediator of inflammation in obese adults.

Key words

hyperleptinemia - obesity - body composition - inflammatory status

Full Text

References

References
1 Popkin BM. Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am J Clin Nutr 2006; 84: 289-298
2 World Health Organization . Obesity: Preventing and Managing the Global Epidemic. Geneva: WHO Technical Report Series 894; 2000
3 Auwerx J, Staels B. Leptin. Lancet 1998; 351: 737-742
4 Israel PA, Park CR, Schwartz MW, Green PK, Sipols AJ, Woods SC, Porte Jr D, Figewicz DP. Effect of diet-induced obesity and experimental hyperinsulinemia on insulin uptake into CSF of the rat. Brain Res Bull 1993; 30: 571-575
5 Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 1998; 19: 155-157
6 Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 1996; 348: 159-161
7 McGregor GP, Desaga JF, Ehlenz K, Fisher A, Heese F, Hegele A, Lammer C, Peiser C, Lang RE. Radioimmunological measurement of leptin in plasma of obese and diabetic human subjects. Endocrinology 1996; 137: 1501-1504
8 Dardeno TA, Chou SH, Moon H-S, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in Human Physiology and Therapeutics. Front Neuroendocrinoly 2010; 31: 377-393
9 Mirza S, Qu HQ, Li Q, Martinez PJ, Rentfro AR, McCormick JB, Fisher-Hoch SP. Adiponectin/leptin ratio and metabolic syndrome in a Mexican American population. Clin Invest Med 2011; 34: 290
10 Callaway CW, Chumlea WC, Bouchard C, Himes JH, Lohman TG, Martin AD, Mitchell CD, Mueller WH, Roche AF, Seefeldt VD. Circumferences. In: Lohman TG, Roche AF, Martorell R. (eds.). Anthropometric standardization reference manual. Champaign: Human Kinetics, Books; 1988: 39-54
11 Botton J, Heude B, Kettaneh A, Borys JM, Lommez A, Bresson JL, Ducimetiere P, Charles MA. Cardiovascular risk factor levels and their relationships with overweight and fat distribution in children: the Fleurbaix Laventie Ville Sante II Study. Metabolism 2007; 56: 614-622
12 Jamar G, Pisani LP, Oyama C, Belote C, Masquio DCL, Furuya VA, Carvalho-Ferreira J, Andrade-Silva SG, Dâmaso AR, Caranti D. Is the neck circumference an emergent predictor for inflammatory status in obese adults?. Int J Clin Pract 2012;
13 Lean M, Lara J, O’Hill J. Strategies for preventing obesity. BMJ 2006; 333: 959-962
14 Sociedade Brasileira de Cardiologia Sociedade Brasileira de Hipertensão e Sociedade Brasileira de Nefrologia (SBC, SBH, SBN). V Diretrizes Brasileiras de Hipertensão Arterial 2006
15 Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005; 115: 911-919
16 Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S. The metabolically obese, normal-weight individual revisited. Diabetes 1998; 47: 699-713
17 Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell 1996; 87: 377-389
18 Kabir M, Catalano KJ, Ananthnarayan S, Kim S, Citters VGWV, Dea MK, Bergman RN. Molecular evidence supporting the portal theory: a causative e link between visceral adiposity and hepatic insulin resistance. Am J Physiol Endocrinol Metab 2005; 288: E454-E461
19 Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, Lago F, Gualillo O. Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Biofactors 2011; 37: 413-420
20 Maury E, Brichard SM. Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol 2010; 314: 1-16
21 Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000; 11: 327-332
22 Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-214
23 Klein S, Fontana YL, Leroy V, Coggan AR, Kilo C, Patterson BW, Mohammed BS. Absence of an Effect of Liposoluction on Insulin Action and Risk factors for Coronary Heart Disease. N Engl J Med 2004; 350: 2549-2557
24 Ahima RS, Flier JS. Leptin. Annu Rev Physiol 2000; 62: 413
25 Bastard J-P, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, Capeau J, Feve B. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006; 17: 4-12
26 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7: 941-946
27 Ailhaud G. Adipose tissue as a secretory organ: from adipogenesis to the metabolic syndrome. C R Biol 2006; 329: 570-597
28 Bahceci M, Gokalp D, Bahceci S, Tuzcu A, Atmaca S, Arikan S. The correlation between adiposity and adiponectin, tumor necrosis factor alpha, interleukin-6 and high sensitivity C-reactive protein levels. Is adipocyte size associated with inflammation in adults?. J Endocrinol Invest 2007; 30: 210-214
29 Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab 2007; 92: 1023-1033
30 Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005; 115: 1111-1119
31 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796-1808
32 Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004; 114: 1752-1761
33 Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RL, Zhang J, Xu A. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes. Biochem Biophys Res Commun 2006; 341: 549-556
34 Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 2007; 293: 1118-1128
35 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 2007; 56: 901-911
36 Pachler C, Ikeoka D, Plank J, Weinhandl H, Suppan M, Mader JK, Bodenlenz M, Regittnig W, Mangge H, Pieber TR, Ellmerer M. Subcutaneous adipose tissue exerts proinflammatory cytokines after minimal trauma in humans. Am J Physiol Endocrinol Metab 2007; 293: 690-696
37 Adamczak M, Wiecek A. The Adipose Tissue as an Endocrine Organ. Seminars in Nephrology 2013; 33: 12-13
38 Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzman 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: 25096-25100
39 O’Rourke L, Gronning LM, Yeaman SJ, Shepherd PR. Glucosedependent regulation of cholesterol ester metabolism in macrophages by insulin and leptin. J Biol Chem 2002; 277: 42557-42562
40 Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 2007; 4: 1-13
41 Matsubara M, Maruoka S, Katayose S. Inverse relationship between plasma adiponectin and leptin concentrations in normal-weight and obese women. Eur J Endocrinol 2002; 147: 173-180
42 Ajuwon KM, Spurlock ME. Adiponectin inhibits LPS-induced NFkappaB activation and IL-6 production and increases PPARgamma2 expression in adipocytes. Am J Physiol Regul Integr Comp Physiol 2005; 288: R1220-R1225
43 Tsatsanis C, Zacharioudaki V, Androulidaki A, Dermitzaki E, Charalampopoulos I, Minas V, Gravanis A, Margioris AN. Adiponectin induces TNF-alpha and IL-6 in macrophages and promotes tolerance to itself and other pro-inflammatory stimuli. Biochem Biophys Res Commun 2005; 335: 1254-1263
44 Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, Ishigami M, Kuriyama H, Kishida K, Nishizawa H, Hotta K, Muraguchi M, Ohmoto Y, Yamashita S, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 2001; 103: 1057-1063
45 Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 2003; 107: 671-674
46 Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001; 98: 2005-2010
47 Considine RV, Sinha MK, Heiman ML, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, Mckee LJ, Bauer TL, Caro JF. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292-295
48 Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM. Leptin levels in human and rodent: measurement of plasma leptin and ob rna in obese and weight-reduced subjects. Nat Med 1995; 1: 1155-1161
49 Janečková R. The Role of Leptin in Human Physiology and Pathophysiology. Physiol Res 2001; 50: 443-459
50 Dâmaso AR, de Piano A, Sanches PL, Corgosinho F, Tock L, Oyama LM, Tock L, do Nascimento CM, Tufik S, de Mello MT. Hyperinsulinemia in obese adolescents deregulates neuropeptides during weight loss. Peptides 2011; 32: 1384-1391
51 You T, Nicklas BJ, Ding J, Penninx BW, Goodpaster BH, Bauer DC, Tylavsky FA, Harris TB, Kritchevsky SB. The metabolic syndrome is associated with circulating adipokines in older adults across a wide range of adiposity. J Gerontol A Biol Sci Med Sci 2008; 63: 414-419
52 Jung C-H, Rhee E-J, Choi J-H, Bae J-C, Yoo S-H, Kim W-J, Park C-Y, Mok JO, Kim CH, Lee W-Y, Oh K-G, Park S-W, Kim S-W. The relationship of adiponectin/leptin ratio with homeostasis model assessment insulin resistance index and metabolic syndrome in apparently healthy Korean male adults. Korean Diabetes J 2010; 34: 237-243
53 Lee JM, Kim SR, Yoo SJ, Hong OK, Son HS, Chang SA. The relationship between adipokines, metabolic parameters and insulin resistance in patients with metabolic syndrome and type 2 diabetes. J Int Med Res 2009; 37: 1803-1812
54 Zhuo Q, Wang Z, Fu P, Piao J, Tian Y, Xu J, Yang X. Comparison of adiponectin, leptin and leptin to adiponectin ratio as diagnostic marker for metabolic syndrome in older adults of Chinese major cities. Diabetes Res Clin Pract 2009; 84: 27-33
55 Masquio DC, de Piano A, Sanches PL, Corgosinho FC, Campos RM, Carnier J, Silva PL, Caranti DA, Tock L, Oyama LM, Nascimento CM, de Mello MT, Tufik S, Dâmaso AR. The effect of weight loss magnitude on pro/anti-inflammatory adipokines and carotid intima-media thickness in obese adolescents engaged in interdisciplinary weight-loss therapy. Clin Endocrinol (Oxf) 2012;
56 Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 2008; 52: 1201-1210
57 Hamdy O, Porramatikul S, Al-Ozairi E. Metabolic Obesity: The paradox Between Visceral and Subcutaneous Fat. Curr Diabetes Rev 2006; 367-373