Download PDF
Horm Metab Res 2014; 46(10): 728-735
DOI: 10.1055/s-0034-1375688
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Resveratrol Prevents Hyperleptinemia and Central Leptin Resistance in Adult Rats Programmed by Early Weaning

J. G. Franco
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
P. C. Lisboa
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
N. da Silva Lima
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
N. Peixoto-Silva
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
L. A. Maia
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
E. Oliveira
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
M. C. F. Passos
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
,
E. G. de Moura
1   Department of Physiological Sciences, Roberto Alcantara Gomes Biology Institute, State University of Rio de Janeiro, Rio de Janeiro, Brazil
› Author Affiliations
Further Information

Publication History

received 07 January 2014

accepted 24 April 2014

Publication Date:
23 June 2014 (online)

Also available at
    Permissions and Reprints

Abstract

We have previously shown that early weaning in rats increases the risk of obesity and insulin resistance at adulthood, and leptin resistance can be a prime factor leading to these changes. Resveratrol is reported to decrease oxidative stress, insulin resistance, and cardiovascular risk. However, there is no report about its effect on leptin resistance. Thus, in this study we have evaluated resveratrol-preventing effect on the development of visceral obesity, insulin, and leptin resistance in rats programmed by early weaning. To induce early weaning, lactating dams were separated into 2 groups: early weaning (EW) – dams were wrapped with a bandage to interrupt lactation in the last 3 days of lactation and control (C) – dams whose pups had free access to milk during throughout lactation period (21 days). At 150 days-old, EW offspring were subdivided into 2 groups: EW+res – treated with resveratrol solution (30 mg/kg BW/day) or EW – receiving equal volume of vehicle solution, both given by gavage during 30 days. Control group received vehicle solution. Resveratrol prevented the higher body weight, hyperphagia, visceral obesity, hyperleptinemia, hyperglycemia, insulin resistance, and hypoadiponectinemia at adulthood in animals that were early weaned. Leptin resistance, associated with lower JAK2 and pSTAT3 and higher NPY in hypothalamus of EW rats were also normalized by resveratrol. The present results suggest that resveratrol is useful as therapeutic tool in treating obesity, mainly because it prevents the development of central leptin resistance.

Key words

metabolic programming - polyphenol - appetite control - visceral adiposity
 

  • References

  • 1 de Moura EG, Lisboa PC, Passos MC. Neonatal programming of neuroimmunomodulation-role of adipocytokines and neuropeptides. Neuroimmunomodulation 2008; 15: 176-188
    CrossrefPubMedGoogle Scholar
  • 2 Fernandez-Twinn DS, Ozanne SE. Early life nutrition and metabolic programming. Ann New York Acad Sci 2010; 1212: 78-96
    CrossrefPubMedGoogle Scholar
  • 3 Barker DJ. The origins of the developmental origins theory. J Intern Med 2007; 261: 412-417
    CrossrefPubMedGoogle Scholar
  • 4 Gluckman PD, Hanson MA. Developmental plasticity and human disease: research directions. J Intern Med 2007; 261: 461-471
    CrossrefPubMedGoogle Scholar
  • 5 Passos MCF, Ramos CF, Moura EG. Short and long term effects of malnutrition in rats during lactation on the body weight of offspring. Nutrition 2000; 20: 1603-1612
    PubMedGoogle Scholar
  • 6 de Moura EG, Bonomo IT, Nogueira-Neto JF, de Oliveira E, Trevenzoli IH, Reis AM, Passos MC, Lisboa PC. Maternal prolactin inhibition during lactation programs for metabolic syndrome in adult progeny. J Physiol 2009; 587: 4919-4129
    CrossrefPubMedGoogle Scholar
  • 7 Lisboa PC, Pires L, de Oliveira E, Lima NS, Bonomo IT, Reis AM, Passos MC, Moura EG. Prolactin inhibition at mid-lactation influences adiposity and thyroid function in adult rats. Horm Metab Res 2010; 42: 562-569
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Bonomo IT, Lisboa PC, Pereira AR, Passos MC, de Moura EG. Prolactin inhibition in dams during lactation programs for overweight and leptin resistance in adult offspring. J Endocrinol 2007; 192: 339-344
    CrossrefPubMedGoogle Scholar
  • 9 Lisboa PC, Passos MC, Dutra SC, Bonomo IT, Denolato AT, Reis AM, Moura EG. Leptin and prolactin, but not corticosterone, modulate body weight and thyroid function in protein-malnourished lactating rats. Horm Metab Res 2006; 38: 295-299
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Lima NS, Moura EG, Franco JG, Pinheiro CR, Pazos-Moura CC, Cabanelas A, Carlos AS, Nascimento-Saba CC, de Oliveira E, Lisboa PC. Developmental plasticity of endocrine disorders in obesity model primed by early weaning in dams. Horm Metab Res 2013; 45: 22-30
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Kelishadi R, Farajian S. The protective effects of breastfeeding on chronic non-communicable diseases in adulthood: A review of evidence. Adv Biomed Res 2014; 3: 3
    CrossrefPubMedGoogle Scholar
  • 12 Arenz S, Rückerl R, Koletzko B, von Kries R. Breast-feeding and childhood obesity-a systematic review. Int J Obes Relat Metab Disord 2004; 28: 1247-1256
    CrossrefPubMedGoogle Scholar
  • 13 Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr 2006; 84: 1043-1054
    CrossrefPubMedGoogle Scholar
  • 14 de Armas MG, Megías SM, Modino SC, Bolaños PI, Guardiola PD, Alvarez TM. Importance of breastfeeding in the prevalence of metabolic syndrome and degree of childhood obesity. Endocrinol Nutr 2009; 56: 400-403
    CrossrefPubMedGoogle Scholar
  • 15 Lima Nda S, de Moura EG, Passos MC, Nogueira Neto FJ, Reis AM, de Oliveira E, Lisboa PC. Early weaning causes undernutrition for a short period and programmes some metabolic syndrome components and leptin resistance in adult rat offspring. Br J Nutr 2011; 105: 1405-1413
    CrossrefPubMedGoogle Scholar
  • 16 Rahmouni K. Leptin-Induced Sympathetic Nerve Activation: Signaling Mechanisms and Cardiovascular Consequences in Obesity. Curr Hypertens Rev 2010; 6: 104-209
    CrossrefPubMedGoogle Scholar
  • 17 Friedman JM. Leptin and the regulation of body weight. Keio J Med 2011; 60: 1-9
    CrossrefPubMedGoogle Scholar
  • 18 Ahima RS, Antwi DA. Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am 2008; 37: 811-823
    CrossrefPubMedGoogle Scholar
  • 19 Sahu A. Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. Front Neuroendocrinol 2003; 24: 225-253
    CrossrefPubMedGoogle Scholar
  • 20 Ahima RS, Osei SY. Leptin signaling. Physiol Behav 2004; 81: 223-241
    CrossrefPubMedGoogle Scholar
  • 21 Morton GJ, Schwartz MW. Leptin and the central nervous system control of glucose metabolism. Physiol Rev 2011; 91: 389-411
    CrossrefPubMedGoogle Scholar
  • 22 El-Haschimi K, Pierroz DD, Hileman SM, Bjørbaek C, Flier JS. Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. J Clin Invest 2000; 105: 1827-1832
    CrossrefPubMedGoogle Scholar
  • 23 Renaud S. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992; 339: 1523-1526
    CrossrefPubMedGoogle Scholar
  • 24 Juhasz B, Varga B, Gesztelyi R, Kemeny-Beke A, Zsuga J, Tosaki A. Resveratrol: a multifunctional cytoprotective molecule. Free Radic Biol Med 2007; 43: 720-729
    CrossrefPubMedGoogle Scholar
  • 25 Juhasz B, Das DK, Kertesz A, Juhasz A, Gesztelyi R, Varga B. Reduction of blood cholesterol and ischemic injury in the hypercholesteromic rabbits with modified resveratrol, longevinex (corrected). Curr Pharm Biotechnol 2010; 11: 810-818
    CrossrefPubMedGoogle Scholar
  • 26 Thirunavukkarasu ML, Penumathsa SV, Koneru S, Juhasz B, Zhan L, Otani H, Bagchi D, Das DK, Maulik N. Resveratrol alleviates cardiac dysfunction in streptozotocin-induced diabetes: Role of nitric oxide, thioredoxin, and heme oxygenase. J Mol Cell Cardiol 2007; 42: 508-516
    CrossrefPubMedGoogle Scholar
  • 27 Penumathsa SVL, Thirunavukkarasu M, Koneru S, Juhasz B, Zhan L, Pant R, Menon VP, Otani H, Maulik N. Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol 2007; 42: 508-516
    CrossrefPubMedGoogle Scholar
  • 28 Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444: 337-342
    CrossrefPubMedGoogle Scholar
  • 29 Lekli I, Szabo G, Juhasz B, Das S, Das M, Varga E, Szendrei L, Gesztelyi R, Varadi J, Bak I, Das DK, Tosaki A. A Protective mechanism of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol 2008; 294: 859-866
    CrossrefPubMedGoogle Scholar
  • 30 Sharma S, Misra CS, Arumugam S, Roy S, Shah V, Davis JA, Shirumalla RK, Ray A. Antidiabetic activity of resveratrol, a known SIRT1 activator in a genetic model for type-2 diabetes. Phytother Res 2010; 25: 67-73
    PubMedGoogle Scholar
  • 31 Kim S, Jin Y, Park T. Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice. Biochem Pharmacol 2011; 81: 1343-1351
    CrossrefPubMedGoogle Scholar
  • 32 Gómez-Zorita S, Fernández-Quintela A, Macarulla MT, Aguirre L, Hijona E, Bujanda L, Milagro F, Martínez JA, Portillo MP. Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. British J Nutr 2009; 107: 202-210
    PubMedGoogle Scholar
  • 33 Marques RG, Morales MM, Petroianu A. Brazilian law for scientific use of animals. Acta Cir Bras 2009; 24: 69-74
    CrossrefPubMedGoogle Scholar
  • 34 Macarulla MT, Alberdi G, Gómez S, Tueros I, Bald C, Rodríguez VM, Martínez JA, Portillo MP. Effects of different doses of resveratrol on body fat and serum parameters in rats fed a hypercaloric diet. J Physiol Biochem 2009; 65: 369-376
    CrossrefPubMedGoogle Scholar
  • 35 Franco JG, de Moura EG, Koury JC, Trotta PA, Cordeiro A, Souza LL, Almeida NA, Lima Nda S, Pazos-Moura CC, Lisboa PC, Passos MC. Resveratrol reduces lipid peroxidation and increases sirtuin 1 expression in adult animals programmed by neonatal protein restriction. J Endocrinol 2010; 207: 319-328
    CrossrefPubMedGoogle Scholar
  • 36 Franco JG, Lisboa PC, Lima NS, Amaral TA, Peixoto-Silva N, Resende AC, Oliveira E, Passos MC, Moura EG. Resveratrol attenuates oxidative stress and prevents steatosis and hypertension in obese rats programmed by early weaning. J Nutr Biochem 2013; 24: 960-966
    CrossrefPubMedGoogle Scholar
  • 37 Das S, Lin HS, Ho PC, Ng KY. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res 2008; 25: 2593-2600
    CrossrefPubMedGoogle Scholar
  • 38 World Health Organization (WHO). 2011 Obesity and Overweight. Fact sheet no 311.   http://www.who.int/mediacentre/factsheets/fs311/en/index.html
    PubMed
  • 39 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
    CrossrefPubMedGoogle Scholar
  • 40 Sarzani R, Salvi F, Dessì-Fulgheri P, Rappelli A. Renin-angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: an integrated view in humans. J Hypertens 2008; 26: 831-843
    CrossrefPubMedGoogle Scholar
  • 41 Samson SL, Garber AJ. Metabolic Syndrome. Endocrinol Metab Clin North Am 2014; 43: 1-23
    CrossrefPubMedGoogle Scholar
  • 42 Xia X, Weng J. Targeting metabolic syndrome: candidate natural agents. J Diabetes 2010; 2: 243-249
    CrossrefPubMedGoogle Scholar
  • 43 Prasad K. Natural products in regression and slowing of progression of atherosclerosis. Curr Pharm Biotechnol 2010; 11: 794-800
    CrossrefPubMedGoogle Scholar
  • 44 Chachay VS, Kirkpatrick CM, Hickman IJ, Ferguson M, Prins JB, Martin JH. Resveratrol-pills to replace a healthy diet?. Br J Clin Pharmacol 2011; 72: 27-38
    CrossrefPubMedGoogle Scholar
  • 45 Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother Res 2008; 22: 1367-1371
    CrossrefPubMedGoogle Scholar
  • 46 Szkudelska K, Nogowski L, Szkudelski T. Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and the antilipolytic action of insulin in isolated rat adipocytes. J Steroid Biochem Mol Biol 2009; 113: 17-24
    CrossrefPubMedGoogle Scholar
  • 47 Baile CA, Yang JY, Rayalam S, Hartzell DL, Lai CY, Andersen C, Della-Fera MA. Effect of resveratrol on fat mobilization. Ann N Y Acad Sci 2011; 1215: 40-47
    CrossrefPubMedGoogle Scholar
  • 48 Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127: 1109-1122
    CrossrefPubMedGoogle Scholar
  • 49 Tauriainen E, Luostarinen M, Martonen E, Finckenberg P, Kovalainen M, Huotari A, Herzig KH, Lecklin A, Mervaala E. Distinct effects of calorie restriction and resveratrol on diet-induced obesity and Fatty liver formation. J Nutr Metab 2011; 2011: 525094
    PubMedGoogle Scholar
  • 50 Zhang J. Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem J 2006; 397: 519-527
    CrossrefPubMedGoogle Scholar
  • 51 Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. Embo J 2007; 26: 1913-1923
    CrossrefPubMedGoogle Scholar
  • 52 Costa Cdos S, Rohden F, Hammes TO, Margis R, Bortolotto JW, Padoin AV, Mottin CC, Guaragna RM. Resveratrol upregulated SIRT1, FOXO1, and adiponectin and downregulated PPARγ1-3 mRNA expression in human visceral adipocytes. Obes Surg 2011; 21: 356-361
    CrossrefPubMedGoogle Scholar
  • 53 Rivera L, Morón R, Zarzuelo A, Galisteo M. Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol 2009; 77: 1053-1063
    CrossrefPubMedGoogle Scholar
  • 54 Rogers CQ, Ajmo JM, You M. Adiponectin and alcoholic fatty liver disease. IUBMB Life 2008; 60: 790-797
    CrossrefPubMedGoogle Scholar
  • 55 Nobre JL, Lisboa PC, Lima Nda S, Franco JG, Nogueira Neto JF, de Moura EG, de Oliveira E. Calcium supplementation prevents obesity, hyperleptinaemia and hyperglycaemia in adult rats programmed by early weaning. Br J Nutr 2011; 9: 1-10
    PubMedGoogle Scholar
  • 56 Minakawa M, Kawano A, Miura Y, Yagasaki K. Hypoglycemic effect of resveratrol in type 2 diabetic model db/db mice and its actions in cultured L6 myotubes and RIN-5F pancreatic β-cells. J Clin Biochem Nutr 2011; 48: 237-244
    CrossrefPubMedGoogle Scholar
  • 57 Lönnqvist F, Wennlund A, Arner P. Relationship between circulating leptin and peripheral fat distribution in obese subjects. Int J Obes Relat Metab Disord 1997; 21: 255-260
    CrossrefPubMedGoogle Scholar
  • 58 Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol 2010; 316: 129-139
    CrossrefPubMedGoogle Scholar
  • 59 Szkudelska K, Nogowski L, Szkudelski T. The inhibitory effect of resveratrol on leptin secretion from rat adipocytes. Eur J Clin Invest 2009; b 39: 899-905
    CrossrefPubMedGoogle Scholar
  • 60 Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG. PTP1B regulates leptin signal transduction in vivo. Dev Cell 2002; 2: 489-495
    CrossrefPubMedGoogle Scholar
  • 61 Ghanim H, Sia CL, Abuaysheh S, Korzeniewski K, Patnaik P, Marumganti A, Chaudhuri A, Dandona P. An antiinflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. J Clin Endocrinol Metab 2010; 95: 1-8
    CrossrefPubMedGoogle Scholar
  • 62 Konstantinides S, Schäfer K, Koschnick S, Loskutoff DJ. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540
    CrossrefPubMedGoogle Scholar
  • 63 Singhal A, Farooqi IS, Cole TJ, O’Rahilly S, Fewtrell M, Kattenhorn M, Lucas A, Deanfield J. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease?. Circulation 2002; 106: 1919-1924
    CrossrefPubMedGoogle Scholar
  • 64 Moro C, Grauzam S, Ormezzano O, Toufektsian MC, Tanguy S, Calabrese P, Coll JL, Bak I, Juhasz B, Tosaki A, de Leiris J, Boucher F. Inhibition of cardiac leptin expression after infarction reduces subsequent dysfunction. Cell Mol Med 2011; 15: 1688-1694
    CrossrefPubMedGoogle Scholar
  • 65 Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, Romanatto T, Pascoal LB, Caricilli AM, Torsoni MA, Prada PO, Saad MJ, Velloso LA. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes 2012; 61: 1455-1462
    CrossrefPubMedGoogle Scholar
  • 66 Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS. Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes 2012; 61: 1444-1454
    CrossrefPubMedGoogle Scholar
  • 67 Valassi E, Scacchi M, Cavagnini F. Neuroendocrine control of food intake. Nutr Metab Cardiovasc Dis 2008; 18: 158-168
    CrossrefPubMedGoogle Scholar
  • 68 Kim SJ, Lee YH, Han MD, Mar W, Kim WK, Nam KW. Resveratrol, purified from the stem of Vitis coignetiae Pulliat, inhibits food intake in C57BL/6J Mice. Arch Pharm Res 2010; 33: 775-780
    CrossrefPubMedGoogle Scholar