Download PDF
Horm Metab Res 2012; 44(02): 114-122
DOI: 10.1055/s-0031-1299747
Animals
© Georg Thieme Verlag KG Stuttgart · New York

Postnatal Low Protein Diet Programs Leptin Signaling in the Hypothalamic-Pituitary-Thyroid Axis and Pituitary TSH Response to Leptin in Adult Male Rats

P. C. Lisboa
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
,
E. Oliveira
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
,
A.T. S. Fagundes
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
,
A. P. Santos-Silva
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
,
E.P. S. Conceição
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
,
M.C. F. Passos
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
,
E. G. Moura
1   Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
› Author Affiliations
Further Information

Publication History

received 23 July 2011

accepted after second revision 13 December 2011

Publication Date:
07 February 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Maternal protein restriction (PR) during lactation programs a lower body weight, hyperthyroidism, leptin resistance, and over-expression of leptin receptor in the pituitary gland at adulthood. Because leptin regulates energy homeo­stasis and the hypothalamus-pituitary-thyroid (HPT) axis, we evaluated adipocyte morpho­logy, the leptin signaling pathway in the HPT axis and the in vitro thyrotropin (TSH) response to leptin in adult progeny in this model. At birth, dams were separated in control diet with 23% protein or PR diet with 8% protein. After weaning, offspring received a normal diet. Adult PR offspring showed lower adipocytes area, higher leptin:visceral fat ratio, lower hypothalamic signal transducer and activator of transcription 3 (STAT3), higher pituitary leptin receptor (Ob-R) and lower thyroid janus tyrosine kinase 2 (JAK2) contents. Regarding the in vitro study, 10 − 7  M leptin stimulated TSH secretion in C offspring at 30 min, but had no effect in PR offspring. At 120 min, 10 − 7  M leptin decreased TSH secretion in C offspring and increased in PR offspring. Maternal nutritional status during lactation programs for adipocyte atrophy, higher relative leptin secretion and changes in the downstream leptin signaling in the HPT axis and the TSH response to leptin, suggesting a role for leptin in the development of the HPT axis and helping to explain thyroid dysfunction and leptin resistance in this programming model. Because leptin stimulates thyroid function, it is unlikely that these alterations were responsible for the increased in serum T4 and T3. Therefore, neonatal PR programs a hyperthyroidism, lower adipogenesis, and impairment of leptin action.

Key words

developmental programming - leptin - TSH
 

  • References

  • 1 Lucas A. Role of nutritional programming in determining adult morbidity. Arch Dis Child 1994; 71: 288-290
    CrossrefPubMedGoogle Scholar
  • 2 de Moura EG, Lisboa PC, Passos MC. Neonatal programming of neuroimmunomodulation – role of adipocytokines and neuropeptides. Neuroimmunomodulation 2008; 15: 176-188
    CrossrefPubMedGoogle Scholar
  • 3 Barker DJ. The developmental origins of adult disease. Eur J Epidemiol 2003; 18: 733-736
    PubMedGoogle Scholar
  • 4 Kajantie E, Phillips DI, Osmond C, Barker DJ, Forsén T, Eriksson JG. Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab 2006; 91: 4953-4956
    CrossrefPubMedGoogle Scholar
  • 5 Passos MC, da Fonte Ramos C, Dutra SC, Mouço T, de Moura EG. Long-term effects of malnutrition during lactation on the thyroid function of offspring. Horm Metab Res 2002; 34: 40-43
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Dutra SC, Passos MC, Lisboa PC, Santos RS, Cabanelas AP, Pazos-Moura CC, Moura EG. Liver deiodinase activity is increased in adult rats whose mothers were submitted to malnutrition during lactation. Horm Metab Res 2003; 35: 268-270
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Lisboa PC, Fagundes AT, Denolato AT, Oliveira E, Bonomo IT, Alves SB, Curty FH, Passos MC, Moura EG. Neonatal low-protein diet changes deiodinase activities and pituitary TSH response to TRH in adult rats. Exp Biol Med (Maywood) 2008; 233: 57-63
    CrossrefPubMedGoogle Scholar
  • 8 Passos MC, Vicente LL, Lisboa PC, de Moura EG. Absence of anorectic effect to acute peripheral leptin treatment in adult rats whose mothers were malnourished during lactation. Horm Metab Res 2004; 36: 625-629
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Vicente LL, de Moura EG, Lisboa PC, Monte Alto Costa A, Amadeu T, Mandarim-de-Lacerda CA, Passos MC. Malnutrition during lactation is associated with higher expression of leptin receptor in pituitary of the adult offspring. Nutrition 2004; 20: 924-928
    CrossrefPubMedGoogle Scholar
  • 10 Schwartz MW, Seeley RJ, Campfield LA, Burn P, Baskin DG. Identification of targets of leptin action in rat hypothalamus. J Clin Invest 1996; 98: 1101-1106
    CrossrefPubMedGoogle Scholar
  • 11 Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763-770
    CrossrefPubMedGoogle Scholar
  • 12 Bjørbaek C. Central leptin receptor action and resistance in obesity. J Investig Med 2009; 57: 789-794
    PubMedGoogle Scholar
  • 13 Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996; 379: 632-635
    CrossrefPubMedGoogle Scholar
  • 14 Vaisse C, Halaas JL, Horvath CM, Darnell Jr JE, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nature Genetics 1996; 14: 95-97
    CrossrefPubMedGoogle Scholar
  • 15 Bjorbaek C, Kahn BB. Leptin signaling in the central nervous system and the periphery. Recent Prog Horm Res 2004; 59: 305-331
    CrossrefPubMedGoogle Scholar
  • 16 Muoio DM, Lynis Dohm G. Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab 2002; 16: 653-666
    CrossrefPubMedGoogle Scholar
  • 17 Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382: 250-252
    CrossrefPubMedGoogle Scholar
  • 18 Légrádi G, Emerson CH, Ahima RS, Flier JS, Lechan RM. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 1997; 138: 2569-2576
    CrossrefPubMedGoogle Scholar
  • 19 Seoane LM, Carro E, Tovar S, Casanueva FF, Dieguez C. Regulation in vivo TSH secretion by leptin. Regul Pept 2000; 92: 25-29
    CrossrefPubMedGoogle Scholar
  • 20 Ortiga-Carvalho TM, Oliveira KJ, Soares BA, Pazos-Moura CC. Leptin role in the regulation of thyrotropin secretion in fed state: in vivo and in vitro studies. J Endocrinol 2002; 174: 121-125
    CrossrefPubMedGoogle Scholar
  • 21 Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV. Leptin and leptin receptor expression in the normal and neoplastic human pituitary: evidence of a regulatory role of leptin on pituitary cell proliferation. J Clin Endocrinol Metab 1999; 84: 2903-2911
    CrossrefPubMedGoogle Scholar
  • 22 Knerr I, Schuster S, Nomikos P, Buchfelder M, Dötsch J, Schoof E, Fahlbusch R, Rascher W. Gene expression of adrenomedullin, leptin, their receptors and neuropeptide Y in hormone-secreting and non-functioning pituitary adenomas, meningiomas and malignant intracranial tumours in humans. Neuropathol Appl Neurobiol 2001; 27: 215-222
    CrossrefPubMedGoogle Scholar
  • 23 Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV. Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 2000; 141: 333-339
    CrossrefPubMedGoogle Scholar
  • 24 Sone M, Nagata H, Takekoshi S. Expression and localization of leptin receptor in normal pituitary gland. Cell Tissue Res 2001; 305: 351-356
    CrossrefPubMedGoogle Scholar
  • 25 Nowak KW, Kaczmarek P, Mackowiak P, Ziolkowska A, Albertin G, Ginda WJ, Trejter M, Nussdorfer GG, Malendowicz LK. Rat thyroid gland expresses the long form of leptin receptors, and leptin stimulates the function of the gland in euthyroid non-fasted animals. Int J Mol Med 2002; 9: 31-34
    PubMedGoogle Scholar
  • 26 Rodrigues AL, de Moura EG, Passos MC, Dutra SC, Lisboa PC. Postnatal early overnutrition changes the leptin signalling pathway in the hypothalamic-pituitary-thyrois axis of young and adult rats. J Physiol 2009; 587: 2647-2661
    CrossrefPubMedGoogle Scholar
  • 27 Santos-Silva AP, Moura EG, Pinheiro CR, Rios AS, Abreu-Villaça Y, Passos MC, Oliveira E, Lisboa PC. Neonatal nicotine exposure alters leptin signaling in the hypothalamus-pituitary-thyroid axis in the late postnatal period and adulthood in rats. Life Sci 2010; 87: 187-195
    CrossrefPubMedGoogle Scholar
  • 28 da Veiga MA, Oliveira Kde J, Curty FH, de Moura CC. Thyroid hormones modulate the endocrine and autocrine/paracrine actions of leptin on thyrotropin secretion. J Endocrinol 2004; 183: 243-247
    CrossrefPubMedGoogle Scholar
  • 29 Marques RG, Morales MM, Petroianu A. Brazilian Law for scientific use of animals. Acta Cir Bras 2009; 24: 69-74
    CrossrefPubMedGoogle Scholar
  • 30 Lisboa PC, Passos MC, Dutra SC, Santos RS, Bonomo IT, Cabanelas AP, Pazos-Moura CC, Moura EG. Increased 5'-iodothyronine deiodinase activity is a maternal adaptive mechanism in response to protein restriction during lactation. J Endocrinol 2003; 177: 261-267
    CrossrefPubMedGoogle Scholar
  • 31 Fagundes AT, Moura EG, Passos MCF, Oliveira E, Toste FP, Bonomo IT, Trevenzoli IH, Garcia RM, Lisboa PC. Maternal low-protein diet during lactation programmes body composition and glucose homeostasis in the adult rat offspring. Br J Nutr 2007; 98: 922-928
    PubMedGoogle Scholar
  • 32 de Moura EG, Lisboa PC, Custódio CM, Nunes MT, de Picoli Souza K, Passos MC. Malnutrition during lactation changes growth hormone mRNA expression in the offspring at weaning and at adulthood. J Nutr Biochem 2007; 18: 134-139
    CrossrefPubMedGoogle Scholar
  • 33 Fagundes AT, Moura EG, Passos MC, Santos-Silva AP, de Oliveira E, Trevenzoli IH, Casimiro-Lopes G, Nogueira-Neto JF, Lisboa PC. Temporal evaluation of body composition, glucose homeostasis and lipid profile of male rats programmed by maternal protein restriction during lactation. Horm Metab Res 2009; 41: 866-873
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Reeves PG, Nielsen FH, Fahey GC. AIN-93 Purified diets for laboratory rodents: final report of the American Institute of Nutrition Ad Hoc Writing Committee on the reformulation of the AIN-76 rodent diet. J Nutr 1993; 123: 1939-1951
    PubMedGoogle Scholar
  • 35 de Oliveira E, Moura EG, Santos-Silva AP, Pinheiro CR, Lima NS, Nogueira-Neto JF, Nunes-Freitas AL, Abreu-Villaça Y, Passos MC, Lisboa PC. Neonatal nicotine exposure causes insulin and leptin resistance and inhibits hypothalamic leptin signaling in adult rat offspring. J Endocrinol 2010; 206: 55-63
    CrossrefPubMedGoogle Scholar
  • 36 Moura EG, Santos CV, Santos RM, Pazos-Moura CC. Interaction between substance P and gastrin-releasing peptide on thyrotropin secretion by rat pituitary in vitro. Braz J Med Biol Res 1999; 32: 1155-1160
    CrossrefPubMedGoogle Scholar
  • 37 Oliveira E, Fagundes AT, Alves SB, Pazos-Moura CC, Moura EG, Passos MC, Lisboa PC. Chronic leptin treatment inhibits liver mitochondrial alpha-glycerol-beta-phosphate dehydrogenase in euthyroid rats. Horm Metab Res 2007; 39: 867-870
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 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
    CrossrefPubMedGoogle Scholar
  • 39 Passos MCF, Ramos CF, Moura EG. Short and long term effects of malnutrition in rats during lactation on the body weight of offspring. Nutr Res 2000; 20: 1603-1612
    CrossrefPubMedGoogle Scholar
  • 40 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
  • 41 Voldstedlund M, Tranum-Jensen J, Handberg A, Vinten J. Quantity of Na/K-ATPase and glucose transporters in the plasma membrane of rat adipocytes is reduced by in vivo triiodothyronine. Eur J Endocrinol 1995; 133: 626-634
    CrossrefPubMedGoogle Scholar
  • 42 Trevenzoli IH, Rodrigues AL, Oliveira E, Thole AA, Carvalho L, Figueiredo MS, Toste FP, Neto JF, Passos MC, Lisboa PC, Moura EG. Leptin treatment during lactation programs leptin synthesis, intermediate metabolism, and liver microsteatosis in adult rats. Horm Metab Res 2010; 42: 483-490
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 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
    CrossrefPubMedGoogle Scholar
  • 44 Conceição EP, Trevenzoli IH, Oliveira E, Franco JG, Carlos AS, Nascimento-Saba CC, Moura EG, Lisboa PC. Higher white adipocyte area and lower leptin production in adult rats overfed during lactation. Horm Metab Res 2011; 43: 513-516
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Fernandez-Twinn DS, Ozanne SE, Ekizoglou S, Doherty C, James L, Gusterson B, Hales CN. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction. Br J Nutr 2003; 90: 815-822
    CrossrefPubMedGoogle Scholar
  • 46 Cripps RL, Martin-Gronert MS, Archer ZA, Hales CN, Mercer JG, Ozanne SE. Programming of hypothalamic neuropeptide gene expression in rats by maternal dietary protein content during pregnancy and lactation. Clin Sci (Lond) 2009; 117: 85-93
    CrossrefPubMedGoogle Scholar
  • 47 Teixeira C, Passos M, Ramos C, Dutra S, Moura E. Leptin serum concentration, food intake and body weight in rats whose mothers were exposed to malnutrition during lactation. J Nutr Biochem 2002; 13: 493-498
    CrossrefPubMedGoogle Scholar
  • 48 Toste FP, de Moura EG, Lisboa PC, Fagundes AT, de Oliveira E, Passos MC. Neonatal leptin treatment programmes leptin hypothalamic resistance and intermediary metabolic parameters in adult rats. Br J Nutr 2010; 95: 830-837
    PubMedGoogle Scholar
  • 49 Lloyd RV, Jin L, Tsumanuma I, Vidal S, Kovacs K, Horvath E, Scheithauer BW, Couce ME, Burguera B. Leptin and leptin receptor in anterior pituitary function. Pituitary 2001; 4: 33-47
    CrossrefPubMedGoogle Scholar
  • 50 Ahima RS, Prabakaran D, Flier JS. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest 1998; 101: 1020-1027
    CrossrefPubMedGoogle Scholar
  • 51 Lisboa PC, Oliveira KJ, Cabanelas A, Ortiga-Carvalho TM, Pazos-Moura CC. Acute cold exposure, leptin, and somatostatin analog (octreotide) modulate thyroid 5'-deiodinase activity. Am J Physiol Endocrinol Metab 2003; 284: E1172-E1176
    PubMedGoogle Scholar
  • 52 Black MM, Walker SP, Wachs TD, Ulkuer N, Gardner JM, Grantham-McGregor S, Lozoff B, Engle PL, de Mello MC. Policies to reduce undernutrition include child development. Lancet 2008; 371 (9611) 454-455
    CrossrefPubMedGoogle Scholar