Hostname: page-component-78c5997874-lj6df Total loading time: 0 Render date: 2024-11-19T20:19:35.558Z Has data issue: false hasContentIssue false
  • English
  • Français

The role of leptin in the transition from fetus to neonate

Published online by Cambridge University Press:  28 February 2007

A. Mostyn ,
D. H. Keisler ,
R. Webb ,
T. Stephenson  and
M. E. Symonds
A. Mostyn*
Affiliation:
Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, UK
D. H. Keisler
Affiliation:
Department of Animal Sciences, University of Missouri, Columbia, Missouri 65211–5300, USA
R. Webb
Affiliation:
Division of Agriculture and Horticulture, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK
T. Stephenson
Affiliation:
Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, UK
M. E. Symonds
Affiliation:
Academic Division of Child Health, School of Human Development, University Hospital, Nottingham NG7 2UH, UK
*
*Corresponding Author: Miss Alison Mostyn, fax +44 115 9709382, email [email protected]
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Leptin is a 16 kDa hormone which has been shown to have a major physiological role in the control of energy balance. Leptin is produced primarily in white adipose tissue, although there is evidence for its production in brown adipose tissue (BAT) and the placenta. BAT is critically important for the initiation of non-shivering thermogenesis in the newborn through the BAT-specific uncoupling protein (UCP), UCP1. This factor is particularly important in lambs in which levels of UCP1 peak at birth, concomitant with a rapid decline in plasma leptin levels. Our studies have examined the effect of acute and chronic administration of leptin to neonatal lambs, investigating effects on colonic temperature, UCP1 and thermogenic potential of BAT. Administration of leptin in sequential physiological doses of 10, 100 and 100 µg to neonatal lambs caused a modest increase in colonic temperature which was not observed in weight-matched vehicle-treated controls. This increase in colonic temperature was not mediated by an increase in either abundance or thermogenic potential of UCP1, as previously shown in adult rodents. UCP1 mRNA levels were 30 % lower in leptin-treated lambs, which is also contradictory to findings in adult rodents. Leptin treatment resulted in a dose-dependent rise in plasma leptin, with levels at the end of the study being almost twenty times greater in leptin-treated animals. To determine whether these findings in neonatal lambs were transient due to the complex milieu of hormones present after birth, we examined the effect of chronic leptin treatment over 6 d. Pairs of lambs were treated daily, from the second to seventh day of life with 100 µg leptin or vehicle. Colonic temperatures of leptin- and vehicle-treated animals remained similar throughout the study. UCP1 abundance was significantly lower in the leptin-treated animals, suggesting that the drop in UCP1 mRNA seen in the previous study had been translated to protein levels. In conclusion, the decline in plasma leptin levels at birth may be a signal to initiate enteral feeding. In lambs, the rapid loss of UCP1 mRNA, which occurs within the first few days of life, appears to be accelerated by leptin administration, possibly stimulating the development of white adipose tissue and generation of body heat through mechanisms other than non-shivering thermogenesis by UCP1 in BAT.

Keywords

LeptinBrown adipose tissueNeonateUncoupling protein
Type
Postgraduate Symposium
Information
Proceedings of the Nutrition Society , Volume 60 , Issue 2 , May 2001 , pp. 187 - 194
Copyright
Copyright © The Nutrition Society 2001

References

Ahima, RS, Prabakaran, D, Mantzoros, C, Qu, D, Lowell, B, Maratos‐Flier, E & Flier, J (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252.Google Scholar
Ashworth, CJ, Hoggard, N, Thomas, L, Mercer, JG, Wallace, JM & Lea, RG (2000) Placental leptin. Reviews of Reproduction 5, 18–24.CrossRefGoogle ScholarPubMed
Bado, A, Levasseur, S, Attoub, S, Kermorgant, S, Laigneau, J, Bortoluzzi, M, Moizo, L, Lehy, T, Guerre-Millo, M, Le Marchand-Brustel, Y & Lewin, MJM (1998) The stomach is a source of leptin. Nature 394, 790–793.Google Scholar
Behre, HM, Simoni, M & Nieschlag, E (1997) Strong association between serum levels of leptin and testosterone in men. Clinical Endocrinology 47, 237–240.CrossRefGoogle ScholarPubMed
Bispham, J, Mostyn, A, Dastoor, EJ, Keisler, DH, Stephenson, T, Webb, R & Symonds, ME (1999) Effect of acute leptin administration in day old lambs on uncoupling protein-1 messenger RNA expression in brown adipose tissue. Early Human Development 56, 251–252 Abstr.Google Scholar
Cannon, B & Nedergaard, J (1985) The biochemistry of an inefficient adipose tissue. Essays in Biochemistry 20, 110–164.Google Scholar
Carmona, MC, Valmaseda, A, Brun, S, Vinas, O, Mampel, T, Iglesias, R, Giralt, M & Villarroya, F (1998) Differential regulation of uncoupling protein-2 and uncoupling protein-3 gene expression in brown adipose tissue during development and cold exposure. Biochemical and Biophysical Research Communications 243, 224–228.Google Scholar
Chen, H, Charlat, O, Tartaglia, LA, Woolf, EA, Weng, X, Ellis, SJ, Lakey, ND, Culpepper, J, Moore, KJ, Breitbart, R E, Duyk, GM, Tepper, RI & Morgenstern, JP (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495.CrossRefGoogle ScholarPubMed
Cinaz, P, Sen, E, Bideci, A, Ezgu, FS, Atalay, Y & Koca, E (1999) Plasma leptin levels of large for gestational age and small for gestational age infants. Acta Paediatrica 88, 753–756.Google Scholar
Cinti, S, Frederich, RC, Zingaretti, MC, de Matteis, R, Flier, JS & Lowell, BB (1997) Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue. Endocrinology 138, 797–804.Google Scholar
Clapham, JC, Arch, JRS, Chapman, H, Haynes, A, Lister, C, Moore, GBT et al. (2000) Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406, 415–418.CrossRefGoogle ScholarPubMed
Clarke, L, Buss, DS, Juniper, DT, Lomax, MA & Symonds, ME (1997 a) Adipose tissue development during early postnatal life in ewe-reared lambs. Experimental Physiology 82, 1015–1027.Google ScholarPubMed
Clarke, L, Heasman, L, Firth, K & Symonds, ME (1997 b) Influence of route of delivery and ambient temperature on thermoregulation in newborn lambs. American Journal of Physiology 272, R1931–R1939.Google ScholarPubMed
Collins, S, Kuhn, CM, Petro, AE, Swick, AG, Chrunyk, BA & Surwit, RS (1996) Role of leptin in fat regulation. Nature 380, 677.CrossRefGoogle ScholarPubMed
Damon, M, Vincent, A, Lombardi, A & Herpin, P (2000) First evidence of uncoupling protein-2 (UCP2) and -3 (UCP3) gene expression in piglet skeletal muscle and adipose tissue. Gene 246, 133–141.CrossRefGoogle ScholarPubMed
Dandrea, J, Keisler, DH, Morrison, C, Stephenson, T & Symonds, ME (2000) Effect of moderate undernutrition during early- to mid-gestation followed by refeeding to appetite until term on maternal plasma leptin concentration in sheep. Journal of Physiology 528P, 25P.Google Scholar
Delavaud, C, Bocquier, F, Chilliard, Y, Keisler, DH, Gertler, A & Kann, G (2000) Plasma leptin determination in ruminants: effect of nutritional status and body fatness on plasma leptin concentration assessed by a specific RIA in sheep. Journal of Endocrinology 165, 519–526.Google Scholar
Denjean, F, Lachuer, J, Geloen, A, Cohen-Adad, F, Moulin, C, Barre, H & Duchamp, C (1999) Differential regulation of uncoupling protein-1, -2 and -3 gene expression by sympathetic innervation in brown adipose tissue of thermoneutral or cold-exposed rats. FEBS Letters 444, 181–185.CrossRefGoogle ScholarPubMed
Dessolin, S, Schalling, M, Champigny, O, Lonnqvist, F, Ailhaud, G, Dani, C & Ricquier, D (1997) Leptin gene is expressed in rat brown adipose tissue at birth. FASEB Journal 11, 382–387.CrossRefGoogle ScholarPubMed
De Vos, P, Saladin, R, Auwerx, J & Staels, B (1995) Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. Journal of Biological Chemistry 270, 15958–15961.CrossRefGoogle Scholar
Enerback, S, Jacobsson, A, Simpson, E.M, Guerra, C, Yamashita, H, Harper, M & Kozack, LP (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but are not obese. Nature 387, 90–94.CrossRefGoogle Scholar
Fei, H, Okano, H, Li, C, Lee, G, Zhoa, C, Darnell, R & Friedman, JM (1997) Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proceedings of the National Academy of Sciences USA 94, 7001–7005.Google Scholar
Fleury, C, Neverova, M, Collins, S, Raimbault, S, Champigny, O, Levi-Meyrueis, C, Bouillaud, F, Seldin, MF, Surwit, RS, Riquier, D & Warden, CH (1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinaemia. Nature Genetics 15, 269–272.Google Scholar
Flier, JS, Harris, M & Hollenberg, AN (2000) Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring. Journal of Clinical Investigation 105, 859–861.CrossRefGoogle ScholarPubMed
Friedman, JM & Halaas, JL (1998) Leptin and the regulation of body weight in mammals. Nature 395, 736–770.Google Scholar
Geary, M, Herschkovitz, R, Pringle, PJ, Rodeck, CH & Hindmarsh, PC (1999) Ontogeny of serum leptin concentrations in the human. Clinical Endocrinology 51, 189–192.CrossRefGoogle ScholarPubMed
Gregoire, FM, Smas, CM & Sul, HS (1998) Understanding adipocyte differentiation. Physiological Reviews 78, 783–809.CrossRefGoogle ScholarPubMed
Hassink, SG, de Lancey, E, Sheslow, DV, Smith-Kirwin, SM, O'Conner, DM, Considine, RV, Opentanova, I, Dostal, K, Spear, L, Leef, K, Ash, M, Spitzer, AR & Funanage, VL (1997) Placental leptin: an important new growth factor in intrauterine and neonatal development. Pediatrics 100, 124–129.CrossRefGoogle ScholarPubMed
Haynes, WG, Sivitz, WI, Morgan, DA, Walsh, SA & Mark, AL (1997) Sympathetic and cardiorenal actions of leptin. Hypertension 30, 619–623.CrossRefGoogle ScholarPubMed
Hoggard, N, Hunter, L, Duncan, JS, Williams, LM, Trayhurn, P & Mercer, JG (1997 a) Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proceedings of the National Academy of Sciences USA 94, 11073–11078.Google Scholar
Hoggard, N, Hunter, L, Lea, RG, Trayhurn, P & Mercer, JG (2000) Ontogeny of the expression of leptin and its receptor in the murine fetus and placenta. British Journal of Nutrition 83, 317–326.CrossRefGoogle ScholarPubMed
Hoggard, N, Mercer, JG, Rayner, DV, Moar, K, Trayhurn, P & Williams, LM (1997 b) Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR and in situ hybridisation. Biochemical and Biophysical Research Communications 232, 383–387.Google Scholar
Hytinantti, T, Koistinen, HA, Koivisto, VA, Karonen, S & Andersson, S (1999) Changes in leptin concentration during the early postnatal period: adjustment to extrauterine life? Pediatric Research 45, 197–201.Google Scholar
Imagawa, K, Matsumoto, Y, Numata, Y, Morita, A, Kikouka, S, Tamaki, M, Higashikubo, C, Tsuji, T, Sasakura, K, Teraoka, H, Masuzaki, H, Hosoda, K, Ogawa, Y & Nakao, K (1998) Development of a sensitive ELISA for human leptin, using monoclonal antibodies. Clinical Chemistry 44, 2165–2171.Google Scholar
Lean, MEJ, James, WPT, Jennings, G & Trayhurn, P (1986 a) Brown adipose tissue in patients with phaeochromocytoma. International Journal of Obesity 10, 219–227.Google ScholarPubMed
Lean, MEJ, James, WPT, Jennings, G & Trayhurn, P (1986 b) Brown adipose tissue uncoupling protein content in human infants, children and adults. Clinical Science 71, 291–297.CrossRefGoogle ScholarPubMed
Lee, G, Proenca, R, Montez, JM, Carroll, KM, Darvishzadeh, JG, Lee, JI & Friedman, JM (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635.CrossRefGoogle ScholarPubMed
Lonnqvist, F, Nordfors, L, Jansson, M, Thorne, A, Schalling, M & Arner, P (1997) Leptin secretion from adipose tissue in women. Journal of Clinical Investigation 99, 2398–2404.CrossRefGoogle ScholarPubMed
Lowell, BB, S-Susulic, V, Hamann, A, Lawitts, JA, Himms-Hagen, J, Boyer, BB, Kozak, LP & Flier, JS (1993) Development of obesity in transgenenic mice after genetic ablation of brown adipose tissue. Nature 366, 740–742.CrossRefGoogle Scholar
McCreath, KJ, Howcroft, J, Campbell, KHS, Colman, A, Schnieke, AE & Kind, AJ (2000) Production of gene-targeted sheep by nuclear transfer from cultured somatic cells. Nature 405, 1066–1069.CrossRefGoogle ScholarPubMed
Madej, T, Boguski, MS & Bryant, SH (1995) Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Letters 373, 13–18.Google Scholar
Marchini, G, Fried, G, Ostlund, E & Hagenas, L (1998) Plasma leptin in infants: relations to birth weight and weight loss. Pediatrics 101, 429–432.CrossRefGoogle ScholarPubMed
Matsuda, J, Yokota, I, Iida, M, Murakami, T, Yamada, M, Saijo, T, Naito, E, Ito, M, Shima, K & Kuroda, Y (1999) Dynamic changes in serum leptin concentrations during the fetal and neonatal periods. Pediatric Research 45, 71–75.CrossRefGoogle ScholarPubMed
Mercer, JG, Hoggard, N, Williams, LM, Lawrence, CB, Hannah, LT & Trayhurn, P (1996) Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Letters 387, 113–116.Google Scholar
Messinis, IE & Milingos, SD (1999) Leptin in human reproduction. Human Reproduction Update 5, 52–63.Google Scholar
Mostyn, A, Dastoor, EJ, Stephenson, T, Webb, R & Symonds, ME (2000 a) Effect of acute leptin administration on thermoregulation in day old lambs during non-rapid eye movement sleep. Proceedings of the Nutrition Society 59, 13A.Google Scholar
Mostyn, A, Forhead, A, Keisler, DH, Stephenson, T, Fowden, AL & Symonds, ME (2001) Influence of cortisol on uncoupling protein-1 (UCP1) and leptin mRNA expression in perirenal adipose tissue in the late gestation sheep fetus. Proceedings of The Nutrition Society 60 (In the Press).Google Scholar
Mostyn, A, Keisler, DH, Symonds, ME, Dastoor, EJ, Webb, R & Stephenson, T (1999) The effect of acute leptin treatment of neonatal lambs on plasma leptin concentrations and thermoregulation. Journal of Endocrinology 163, Suppl., P75.Google Scholar
Mostyn, A, Pearce, S, Keisler, DH, Stephenson, T, Webb, R & Symonds, ME (2000 b) Effect of chronic leptin administration to neonatal lambs on uncoupling protein-1 abundance in brown adipose tissue. Journal of Physiology 528P, 32P.Google Scholar
Mostyn, A, Rayner, DV & Trayhurn, P (1998) Effects of adrenaline, noradrenaline and isoprenaline on circulating leptin levels in mice. Proceedings of the Nutrition Society 58, 69A.Google Scholar
Nedergaard, J & Cannon, B (1992) The uncoupling protein thermogenin and mitochondrial thermogenesis. In New Comprehensive Biochemistry, pp. 385–419 [Ernster, L, editor\. Amsterdam, The Netherlands: Elsevier Science Publishers.Google Scholar
Pelleymounter, MA, Cullen, MJ, Baker, MB, Hecht, R, Winters, D, Boone, T & Collins, F (1995) Effects of obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543.CrossRefGoogle ScholarPubMed
Ricquier, D, Nechad, M & Mory, G (1982) Ultrastructural and biochemical characterization of human brown adipose tissue in pheochromocytoma. Journal of Clinical Endocrinology and Metabolism 54, 803–807.Google Scholar
Rippe, C, Berger, K, Boiers, C, Ricquier, D & Erlanson-Albertson, C (2000) Effect of high-fat diet, surrounding temperature, and enterostatin on uncoupling protein gene expression. American Journal of Physiology 279, E293–E300.Google ScholarPubMed
Scarpace, PJ, Matheny, M, Pollock, BH & Tumer, N (1997) Leptin increases uncoupling protein expression and energy expenditure. American Journal of Physiology 273, E226–E230.Google ScholarPubMed
Scarpace, PJ, Nicolson, M & Matheny, M (1998) UCP2, UCP3 and leptin gene expression: modulation by food restriction and leptin. Journal of Endocrinology 159, 349–357.CrossRefGoogle ScholarPubMed
Schubring, C, Siebler, T, Kratsch, J, Englaro, P, Blum, WF, Triep, K & Kiess, W (1999) Leptin serum concentrations in healthy neonates within the first week of life: relation to insulin and growth hormone levels, skinfold thickness, body mass index and weight. Clinical Endocrinology 51, 199–204.CrossRefGoogle ScholarPubMed
Shekhawat, PS, Garland, JS, Shivpuri, C, Mick, G, Sasidharan, P, Pelz, CJ & McCormick, KL (1998) Neonatal cord blood leptin: it's relationship to birth weight, body mass index, maternal diabetes, and steroids. Pediatric Research 43, 338–343.Google Scholar
Steppan, CM & Swick, AG (1999) A role for leptin in brain development. Biochemical and Biophysical Research Communications 256, 600–602.CrossRefGoogle ScholarPubMed
Symonds, ME (1995) Pregnancy, parturition and neonatal development: interactions between nutrition and thyroid hormones. Proceedings of the Nutrition Society 54, 329–342.CrossRefGoogle ScholarPubMed
Symonds, ME, Andrews, DC & Johnson, P (1989 a) The control of thermoregulation in the developing lamb during slow wave sleep. Journal of Developmental Physiology 11, 289–298.Google ScholarPubMed
Symonds, ME, Andrews, DC & Johnson, P (1989 b) The endocrine and metabolic response to feeding in the developing lamb. Journal of Endocrinology 123, 295–302.Google Scholar
Symonds, ME, Bird, JA, Clarke, L, Gate, J & Lomax, MA (1995) Nutrition, temperature and homeostasis during perinatal development. Experimental Physiology 80, 907–940.Google Scholar
Tarquini, B, Tarquini, R, Perfetto, F, Cornelissen, G & Halberg, F (1999) Genetic and environmental influences on human cord blood leptin concentration. Pediatrics 103, 998–1006.CrossRefGoogle ScholarPubMed
Tartaglia, LA, Dembski, M, Weng, X, Deng, N, Culpepper, J, Devos, R, Richards, GJ, Campfield, LA, Clark, FT, Deeds, J, Muir, C, Sanker, S, Moriarty, A, Moore, K, Smutko, JS, Mays, GG, Woolf, EA, Monroe, CA & Tepper, RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271.CrossRefGoogle ScholarPubMed
Udagawa, J, Hatta, T, Naora, H & Otani, H (2000) Expression of the long form of leptin receptor (Ob-Rb) mRNA in the brain of mouse embryos and newborn mice. Brain Research 868, 251–258.CrossRefGoogle Scholar
Vidal-Puig, A, Solanes, G, Grujic, D, Flier, JS & Lowell, BB (1997) UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochemical and Biophysical Research Communications 235, 79–82.CrossRefGoogle ScholarPubMed
Vidal-Puig, AJ, Grujic, D, Zhang, C, Hagen, T, Boss, O, Ido, Y, Szczepanik, A, Wade, J, Mootha, V, Cortright, R, Muoio, DM & Lowell, BB (2000) Energy metabolism in uncoupling protein 3 knockout mice. Journal of Biological Chemistry 275, 16258–16266.CrossRefGoogle ScholarPubMed
Wilson, V, Dandrea, J, Stephenson, T, Webb, R & Symonds, ME (2000) The influence of maternal nutrient restriction between early to mid gestation on placental weight and leptin abundance in sheep. Proceedings of the Nutrition Society 59, 9A.Google Scholar
Wu, Z, Puigserver, P & Spiegelman, BM (1999) Transcriptional activation of adipogenesis. Current Opinion in Cell Biology 11, 689–694.Google Scholar
Yuan, C, Attele, AS, Zhang, L, Lynch, JP, Xie, J & Shi, ZQ (2000) Leptin reduces body weight gain in neonatal rats. Pediatric Research 48, 380–383.Google Scholar
Yuen, BSJ, McMillen, IC, Symonds, ME & Owens, PC (1999) Abundance of leptin mRNA in fetal adipose tissue is related to fetal body weight. Journal of Endocrinology 163, R11–R14.Google Scholar
Yura, S, Sagawa, N, Mise, H, Mori, T, Masuzaki, H, Ogawa, Y & Nakao, K (1998) A positive umbilical venous-arterial difference of leptin levels and its rapid decline after birth. American Journal of Obstetrics and Gynecology 178, 926–930.CrossRefGoogle ScholarPubMed
Zhang, Y, Olbort, M, Schwarzer, K, Nuesslein-Hildesheim, B, Nicolson, M, Murphy, E, Kowalski, TJ, Schmidt, I & Leibel, RL (1997) The leptin receptor mediates apparent autocrine regulation of leptin gene expression. Biochemical and Biophysical Research Communications 240, 492–495.CrossRefGoogle ScholarPubMed
Zhang, Y, Proenca, R, Maffei, M, Barone, M, Leopold, L & Friedman, JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–431.Google Scholar