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The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

International Journal of Obesity volume 31, pages 1199–1209 (2007)Cite this article

Abstract

Background:

There is epidemiological evidence that perinatal nutritional factors may have long-term effects on obesity. Which nutrients or food components are involved in this programming mechanism are unknown. Breast milk contains leptin, a hormone that regulates food intake and energy expenditure, and previous studies in rats have shown that leptin orally administered during lactation exerts anorexigenic effects.

Objective:

To evaluate whether supplementation with physiological doses of oral leptin during lactation has long-term effects on body weight regulation.

Design:

A daily oral dose of leptin (equivalent to five times the amount of leptin ingested normally from maternal milk during the suckling period) or the vehicle was given to suckling male rats during lactation. Animals were fed after weaning with a normal fat (NF) or a high-fat (HF) diet. We followed body weight and food intake of animals until the age of 6 months, and measured the size of adipose tissue depots, the thermogenic capacity, the expression of leptin in the stomach and adipose tissues and the expression of two appetite-related peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)), leptin receptor (OB-Rb) and suppressor of cytokine signalling 3 (SOCS-3) in the hypothalamus at the age of 6 months.

Results:

Leptin-treated animals had, in adulthood, lower body weight and fat content and ate fewer calories than their untreated controls. Unlike adipocitary leptin production, adult animals that were leptin-treated during lactation displayed higher gastric leptin production without changes in OB-Rb mRNA levels. In addition, in response to HF diet, leptin-treated animals (contrary to controls) showed lower hypothalamic NPY/POMC mRNA ratio. Hypothalamic OB-Rb mRNA levels decreased in control animals as an effect of HF diet feeding, but remained unchanged in leptin-treated animals; SOCS-3 mRNA levels were lower in leptin-treated animals than in their controls, both under normal or HF diet.

Conclusion:

The animals that received leptin during lactation become more protected against fat accumulation in adult life and seem to be more sensitive to the short- and long-term regulation of food intake by leptin. Thus, leptin plays an important role in the earlier stages of neonatal life, as a component of breast milk, in the prevention of later obesity.

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References

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–432.

    Article  CAS  Google Scholar 

  2. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y et al. 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.

    Article  CAS  Google Scholar 

  3. Ostlund Jr RE, Yang JW, Klein S, Gingerich R . Relation between plasma leptin concentration and body fat, gender, diet, age, and metabolic covariates. J Clin Endocrinol Metab 1996; 81: 3909–3913.

    CAS  PubMed  Google Scholar 

  4. Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P . Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995; 269: 546–549.

    Article  CAS  Google Scholar 

  5. Banks AS, Davis SM, Bates SH, Myers Jr MG . Activation of downstream signals by the long form of the leptin receptor. J Biol Chem 2000; 275: 14563–14572.

    Article  CAS  Google Scholar 

  6. Himms-Hagen J . Physiological roles of the leptin endocrine system: differences between mice and humans. Crit Rev Clin Lab Sci 1999; 36: 575–655.

    Article  CAS  Google Scholar 

  7. Ahima RS, Flier JS . Leptin. Annu Rev Physiol 2000; 62: 413–437.

    Article  CAS  Google Scholar 

  8. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546.

    Article  CAS  Google Scholar 

  9. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540–543.

    Article  CAS  Google Scholar 

  10. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879–884.

    Article  CAS  Google Scholar 

  11. Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN et al. The stomach is a source of leptin. Nature 1998; 394: 790–793.

    Article  CAS  Google Scholar 

  12. Cinti S, Matteis RD, Pico C, Ceresi E, Obrador A, Maffeis C et al. Secretory granules of endocrine and chief cells of human stomach mucosa contain leptin. Int J Obes Relat Metab Disord 2000; 24: 789–793.

    Article  CAS  Google Scholar 

  13. Cinti S, de Matteis R, Ceresi E, Pico C, Oliver J, Oliver P et al. Leptin in the human stomach. Gut 2001; 49: 155.

    Article  CAS  Google Scholar 

  14. Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG . Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc Natl Acad Sci USA 1997; 94: 11073–11078.

    Article  CAS  Google Scholar 

  15. Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H et al. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nat Med 1997; 3: 1029–1033.

    Article  CAS  Google Scholar 

  16. Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L . A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998; 393: 684–688.

    Article  CAS  Google Scholar 

  17. Smith-Kirwin SM, O'Connor DM, De Johnston J, Lancey ED, Hassink SG, Funanage VL . Leptin expression in human mammary epithelial cells and breast milk. J Clin Endocrinol Metab 1998; 83: 1810–1813.

    Article  CAS  Google Scholar 

  18. Casabiell X, Pineiro V, Tome MA, Peino R, Dieguez C, Casanueva FF . Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake. J Clin Endocrinol Metab 1997; 82: 4270–4273.

    Article  CAS  Google Scholar 

  19. Houseknecht KL, McGuire MK, Portocarrero CP, McGuire MA, Beerman K . Leptin is present in human milk and is related to maternal plasma leptin concentration and adiposity. Biochem Biophys Res Commun 1997; 240: 742–747.

    Article  CAS  Google Scholar 

  20. Pico C, Oliver P, Sanchez J, Palou A . Gastric leptin: a putative role in the short-term regulation of food intake. Br J Nutr 2003; 90: 735–741.

    Article  CAS  Google Scholar 

  21. Pico C, Sanchez J, Oliver P, Palou A . Leptin production by the stomach is up-regulated in obese (fa/fa) Zucker rats. Obes Res 2002; 10: 932–938.

    Article  CAS  Google Scholar 

  22. Breidert M, Miehlke S, Glasow A, Orban Z, Stolte M, Ehninger G et al. Leptin and its receptor in normal human gastric mucosa and in Helicobacter pylori-associated gastritis. Scand J Gastroenterol 1999; 34: 954–961.

    Article  CAS  Google Scholar 

  23. Mix H, Widjaja A, Jandl O, Cornberg M, Kaul A, Goke M et al. Expression of leptin and leptin receptor isoforms in the human stomach. Gut 2000; 47: 481–486.

    Article  CAS  Google Scholar 

  24. Sobhani I, Bado A, Vissuzaine C, Buyse M, Kermorgant S, Laigneau JP et al. Leptin secretion and leptin receptor in the human stomach. Gut 2000; 47: 178–183.

    Article  CAS  Google Scholar 

  25. Morton NM, Emilsson V, Liu YL, Cawthorne MA . Leptin action in intestinal cells. J Biol Chem 1998; 273: 26194–26201.

    Article  CAS  Google Scholar 

  26. Yuan CS, Attele AS, Wu JA, Zhang L, Shi ZQ . Peripheral gastric leptin modulates brain stem neuronal activity in neonates. Am J Physiol 1999; 277: G626–630.

    CAS  PubMed  Google Scholar 

  27. Oliver P, Pico C, De Matteis R, Cinti S, Palou A . Perinatal expression of leptin in rat stomach. Dev Dyn 2002; 223: 148–154.

    Article  CAS  Google Scholar 

  28. Sanchez J, Oliver P, Miralles O, Ceresi E, Pico C, Palou A . Leptin orally supplied to neonate rats is directly uptaken by the immature stomach and may regulate short-term feeding. Endocrinology 2005; 146: 2575–2582.

    Article  CAS  Google Scholar 

  29. Armstrong J, Reilly JJ . Breastfeeding and lowering the risk of childhood obesity. Lancet 2002; 359: 2003–2004.

    Article  Google Scholar 

  30. O'Connor D, Funanage V, Locke R, Spear M, Leef K . Leptin is not present in infant formulas. J Endocrinol Invest 2003; 26: 490.

    Article  CAS  Google Scholar 

  31. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 2001; 25: 402–408.

    Article  CAS  Google Scholar 

  32. Oliver P, Pico C, Martinez N, Bonet ML, Palou A . In vivo effects of CGP-12177 on the expression of leptin and uncoupling protein genes in mouse brown and white adipose tissues. Int J Obes Relat Metab Disord 2000; 24: 423–428.

    Article  CAS  Google Scholar 

  33. Bradford MM . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72: 248–254.

    Article  CAS  Google Scholar 

  34. Laemmli UK . Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680–685.

    Article  CAS  Google Scholar 

  35. Sanchez J, Oliver P, Pico C, Palou A . Diurnal rhythms of leptin and ghrelin in the systemic circulation and in the gastric mucosa are related to food intake in rats. Pflugers Arch 2004; 448: 500–506.

    Article  CAS  Google Scholar 

  36. Oliver P, Ribot J, Rodriguez AM, Sanchez J, Pico C, Palou A . Resistin as a putative modulator of insulin action in the daily feeding/fasting rhythm. Pflugers Arch 2006; 452: 260–267.

    Article  CAS  Google Scholar 

  37. Freedman DS, Srinivasan SR, Valdez RA, Williamson DF, Berenson GS . Secular increases in relative weight and adiposity among children over two decades: the Bogalusa Heart Study. Pediatrics 1997; 99: 420–426.

    Article  CAS  Google Scholar 

  38. Levin BE . The obesity epidemic: metabolic imprinting on genetically susceptible neural circuits. Obes Res 2000; 8: 342–347.

    Article  CAS  Google Scholar 

  39. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD . Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition. Am J Physiol Endocrinol Metab 2000; 279: E83–E87.

    Article  CAS  Google Scholar 

  40. Schmidt I, Fritz A, Scholch C, Schneider D, Simon E, Plagemann A . The effect of leptin treatment on the development of obesity in overfed suckling Wistar rats. Int J Obes Relat Metab Disord 2001; 25: 1168–1174.

    Article  CAS  Google Scholar 

  41. Palou A, Pico C, Bonet ML, Oliver P . The uncoupling protein, thermogenin. Int J Biochem Cell Biol 1998; 30: 7–11.

    Article  CAS  Google Scholar 

  42. Dryden S, Frankish H, Wang Q, Williams G . Neuropeptide Y and energy balance: one way ahead for the treatment of obesity? Eur J Clin Invest 1994; 24: 293–308.

    Article  CAS  Google Scholar 

  43. Beck B, Burlet A, Bazin R, Nicolas JP, Burlet C . Elevated neuropeptide Y in the arcuate nucleus of young obese Zucker rats may contribute to the development of their overeating. J Nutr 1993; 123: 1168–1172.

    CAS  PubMed  Google Scholar 

  44. Park ES, Yi SJ, Kim JS, Lee HS, Lee IS, Seong JK et al. Changes in orexin-A and neuropeptide Y expression in the hypothalamus of the fasted and high-fat diet fed rats. J Vet Sci 2004; 5: 295–302.

    Article  Google Scholar 

  45. Bell ME, Bhatnagar S, Akana SF, Choi S, Dallman MF . Disruption of arcuate/paraventricular nucleus connections changes body energy balance and response to acute stress. J Neurosci 2000; 20: 6707–6713.

    Article  CAS  Google Scholar 

  46. Bergen HT, Mizuno T, Taylor J, Mobbs CV . Resistance to diet-induced obesity is associated with increased proopiomelanocortin mRNA and decreased neuropeptide Y mRNA in the hypothalamus. Brain Res 1999; 851: 198–203.

    Article  CAS  Google Scholar 

  47. Baskin DG, Seeley RJ, Kuijper JL, Lok S, Weigle DS, Erickson JC et al. Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting. Diabetes 1998; 47: 538–543.

    Article  CAS  Google Scholar 

  48. Peiser C, McGregor GP, Lang RE . Leptin receptor expression and suppressor of cytokine signaling transcript levels in high-fat-fed rats. Life Sci 2000; 67: 2971–2981.

    Article  CAS  Google Scholar 

  49. Lin S, Storlien LH, Huang XF . Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain. Brain Res 2000; 875: 89–95.

    Article  CAS  Google Scholar 

  50. Proulx K, Richard D, Walker CD . Leptin regulates appetite-related neuropeptides in the hypothalamus of developing rats without affecting food intake. Endocrinology 2002; 143: 4683–4692.

    Article  CAS  Google Scholar 

  51. Madiehe AM, Schaffhauser AO, Braymer DH, Bray GA, York DA . Differential expression of leptin receptor in high- and low-fat-fed Osborne–Mendel and S5B/Pl rats. Obes Res 2000; 8: 467–474.

    Article  CAS  Google Scholar 

  52. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS . Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1998; 1: 619–625.

    Article  CAS  Google Scholar 

  53. Howard JK, Cave BJ, Oksanen LJ, Tzameli I, Bjorbaek C, Flier JS . Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 2004; 10: 734–738.

    Article  CAS  Google Scholar 

  54. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E . SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 2000; 275: 15985–15991.

    Article  CAS  Google Scholar 

  55. Niswender KD, Morrison CD, Clegg DJ, Olson R, Baskin DG, Myers Jr MG et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 2003; 52: 227–231.

    Article  CAS  Google Scholar 

  56. Bouret SG, Simerly RB . Minireview: leptin and development of hypothalamic feeding circuits. Endocrinology 2004; 145: 2621–2626.

    Article  CAS  Google Scholar 

  57. Bouret SG, Draper SJ, Simerly RB . Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004; 304: 108–110.

    Article  CAS  Google Scholar 

  58. Uysal FK, Onal EE, Aral YZ, Adam B, Dilmen U, Ardicolu Y . Breast milk leptin: its relationship to maternal and infant adiposity. Clin Nutr 2002; 21: 157–160.

    Article  CAS  Google Scholar 

  59. Miralles O, Sánchez J, Palou A, Pico C . A physiological role of milk leptin in body weight control in developing infants. Obesity 2006; 14: 1371–1377.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Spanish Government (Grants G03/028, BFI2003-04439, AGL2004-07496/ALI, and AGL2006-04887/ALI). Our Laboratory is a member of the European Research Network of Excellence NuGO (The European Nutrigenomics Organization, EU Contract: no FP6-506360).

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Authors and Affiliations

  1. Departamento de Biología Fundamental y Ciencias de la Salud, Bioquímica, Biología Molecular, Nutrición y Biotecnología (Nutrigenómica), Universitat de les Illes Balears, Palma de Mallorca, and Ciber Fisiopatología obesidad y nutrición (CB06/03) Instituto Salud Carlos III, Spain,

    C Picó, P Oliver, J Sánchez, O Miralles, A Caimari, T Priego & A Palou

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  1. C Picó
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Correspondence to A Palou.

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Picó, C., Oliver, P., Sánchez, J. et al. The intake of physiological doses of leptin during lactation in rats prevents obesity in later life. Int J Obes 31, 1199–1209 (2007). https://doi.org/10.1038/sj.ijo.0803585

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