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Horm Metab Res 2002; 34(11/12): 678-685
DOI: 10.1055/s-2002-38258
Review
© Georg Thieme Verlag Stuttgart · New York

Leptin and the Adaptations of Lactation in Rodents and Ruminants

R.  G.  Vernon 1 , R.  G. P.  Denis 1, 2 , A.  Sorensen 1 , G.  Williams 2
  • 1 Hannah Research Institute, Ayr, Scotland
  • 2 Diabetes and Endocrinology Research Group, Department of Medicine, University of Liverpool, Liverpool, UK
Further Information

Publication History

Received 1 October 2002

Accepted after revision 25 November 2002

Publication Date:
27 March 2003 (online)

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Abstract

Lactation markedly increases nutrient requirements in both rodents and ruminants. This is met mostly by increased food intake, but there are also adaptations to increase metabolic efficiency. Despite such changes, lactating animals usually experience periods of negative energy balance. This is not due to a physical constraint on food intake, at least in the rat. Leptin, a hormone secreted by adipocytes, plays an important role in the regulation of appetite and energy balance. During lactation, serum leptin concentration is decreased in both rodents and ruminants, and the nocturnal rise in concentration is lost in rats. Hypoleptinaemia in lactation is primarily a result of negative energy balance. There is also increased clearance of serum leptin, and the attenuation of the nocturnal rise in leptin in rats is at least partly due to the suckling stimulus. Hypoleptinaemia is not the major factor driving hyperphagia in lactating rats, but it probably facilitates the increased food intake. Leptin may play a more important role in this respect in lactating ruminants. Leptin is probably involved in other adaptations that increase metabolic efficiency during lactation. The ability of hypothalamic neuropeptides to respond to leptin does not appear to be altered by lactation in either rodents or ruminants. The reason why lactating animals do not respond to hypoleptinaemia with a further increase in appetite, thereby achieving energy balance, appears to be due to a failure to respond to changes in neuropeptides which mediate the effects of leptin.

Key words

Leptin - Lactation - Hyperphagia - Energy Balance - Hypothalamic Neuropeptides

References

  • 1 Barber M C, Clegg R A, Travers M T, Vernon R G. Lipid metabolism in the lactating mammary gland.  Biochim Biophys Acta. 1997;  1347 101-126
    PubMedGoogle Scholar
  • 2 Vernon R G, Pond C M. Adaptations of maternal adipose tissue to lactation.  J Mammary Gland Biol Neoplasia. 1997;  2 231-241
    CrossrefPubMedGoogle Scholar
  • 3 Oftedal O T. The adaptation of milk secretion to the constraints of fasting in bears, seals and baleen whales.  J Dairy Sci. 1992;  76 3234-3246
    PubMedGoogle Scholar
  • 4 Bauman D E, Currie B. Partitioning of nutrients during pregnancy and lactation: a review of mechanisms involving homeostasis and homeorhesis.  J Dairy Sci. 1980;  63 1514-1529
    PubMedGoogle Scholar
  • 5 Wade G N, Schneider J E. Metabolic fuels and reproduction in female mammals.  Neur Behav Rev. 1992;  16 235-275
    CrossrefPubMedGoogle Scholar
  • 6 Chilliard Y. Revue bibliographique: variations quantitatives et métabolisme des lipids dans les tissues adipeux et le foie au cours du cycle gestation-lactation. 1. Chez la ratte.  Reprod Nutr Develop. 1986;  26 1057-1103
    PubMedGoogle Scholar
  • 7 Ota K, Yokoyama A. Body weight and food consumption of lactating rats nursing various sizes of litters.  J Endocrinol. 1992;  38 263-268
    PubMedGoogle Scholar
  • 8 Denis R GP, Williams G, Vernon R G. Regulation of serum leptin and its role in the hyperphagia of lactation in the rat (in press). J Endocrinol 2003
    Google Scholar
  • 9 Ingvartsen K L, Andersen J B. Integration of metabolism and intake regulation: a review focusing on periparturient animals.  J Dairy Sci. 2000;  83 1576-1597
    PubMedGoogle Scholar
  • 10 Williamson D H. Integration of metabolism in tissues of the lactating rat.  FEBS Letts. 1980;  117 K93-K105
    CrossrefPubMedGoogle Scholar
  • 11 Bar-Peled U, Aharoni Y, Robinzon B, Bruckental I, Lehrer R, Maltz E, Knight C, Kali J, Folman Y, Voet H, Gacitua H, Tagari H. The effect of enhanced milk yield of dairy cows by frequent milking or suckling on intake and digestibility of the diet.  J Dairy Sci. 1998;  80 1420-1427
    PubMedGoogle Scholar
  • 12 Kimura T, Maji T, Ashida K. Periodicity of food intake and lipogenesis in rats subjected to two different feeding plans.  J Nutr. 1970;  100 691-697
    PubMedGoogle Scholar
  • 13 Bruckdorfer K R, Kang S S, Khan I H, Bourne A R, Yudkin J. Diurnal changes in the concentrations of plasma lipids, sugars, insulin and corticosterone in rats fed diets containing various carbohydrates.  Horm Metab Res. 1974;  6 99-106
    PubMedGoogle Scholar
  • 14 LeMagnen J. Metabolic and feeding patterns: role of sympathetic and parasympathetic efferent pathways.  J Autonomic Nerv Syst. 1984;  10 325-335
    PubMedGoogle Scholar
  • 15 Döring H, Schwarzer K, Nuesslein-Hildesheim B, Schmidt I. Leptin selectively increases energy expenditure of food-restricted lean mice.  Int J Obesity. 1988;  22 83-88
    PubMedGoogle Scholar
  • 16 Pickavance L, Tadayyon M, Williams G, Vernon R G. Lactation suppresses diurnal rhythm of serum leptin.  Biochem Biophys Res Commun. 1998;  248 196-199
    CrossrefPubMedGoogle Scholar
  • 17 Strubbe J H, Gorissen J. Meal patterning in the lactating rat.  Physiol Behav. 1980;  25 775-777
    CrossrefPubMedGoogle Scholar
  • 18 Munday M R, Williamson D H. Diurnal variations in food intake and in lipogenesis in mammary gland and liver of lactating rats.  Biochem J. 1983;  214 183-187
    PubMedGoogle Scholar
  • 19 Pickavance L, Dryden S, Hopkins D, Bing C, Frankish H, Wang Q, Vernon R G, Williams G. Relationships between hypothalamic neuropeptide Y and food intake in the lactating rat.  Peptides. 1996;  17 577-582
    CrossrefPubMedGoogle Scholar
  • 20 Grigor M R, Thompson M P. Diurnal regulation of milk lipid production and milk secretion in the rat: effect of dietary protein and energy restriction.  J Nutr. 1987;  117 748-753
    PubMedGoogle Scholar
  • 21 Carrick D T, Kuhn N J. Diurnal variation and response to food withdrawal of lactose synthesis in lactating rats.  Biochem J. 1978;  174 319-325
    PubMedGoogle Scholar
  • 22 Sampson D A, Jansen G R. Protein synthesis during lactation: no circadian variation in mammary gland and liver of rats fed diets varying in protein quality and level of intake.  J Nutr. 1984;  114 1470-1478
    PubMedGoogle Scholar
  • 23 Shetty P S. Physiological mechanisms in the adaptive response of metabolic rates to energy restriction.  Nutr Res Rev. 1990;  3 49-74
    PubMedGoogle Scholar
  • 24 Williamson D H, Lund P. Cellular mechanisms for the regulation of adipose tissue lipid metabolism in pregnancy and lactation. In: Allen L, King J, Lönnerdal B (eds) Nutrient regulation during pregnancy, lactation and infant growth. New York; Plenum Press 1994: 39-64
    Google Scholar
  • 25 Grosvenor C E, Mena F. Neuroendocrine control of lactation.  Lactation A comprehensive treatise. In: Larson BL, Smith VR New York; Academic Press 1974 1: 227-276
    Google Scholar
  • 26 Cowie A T, Forsyth I A, Hart I C. Hormonal control of lactation. Berlin, Germany; Springer-Verlag 1980
    Google Scholar
  • 27 Williams G, Bing C, Cai X J, Harrold J A, King P J, Liu X H. The hypothalamus and the control of energy homeostasis: different circuits, different purposes.  Physiol Behav. 2001;  74 683-701
    CrossrefPubMedGoogle Scholar
  • 28 Peaker M, Wilde C J. Feedback control of milk secretion from milk.  J Mammary Gland Biol Neoplasia. 1996;  1 307-315
    PubMedGoogle Scholar
  • 29 Fleming A S. 1976. Control of food intake in the lactating rat: role of suckling and hormones.  Physiol Behav. 1976;  17 841-848
    CrossrefPubMedGoogle Scholar
  • 30 Mann M A, Miele J L, Kinsley C H, Svare B. Postpartum behavior in the mouse: the contribution of suckling stimulation to water intake, food intake and body weight regulation.  Physiol Behav. 1983;  31 633-638
    PubMedGoogle Scholar
  • 31 Woodside B, Abizaid A, Walker C-D. Changes in leptin levels during lactation: implications for lactational hyperphagia and anovulation.  Horm Behav. 2000;  37 353-365
    CrossrefPubMedGoogle Scholar
  • 32 Leon M, Adels L, Coopersmith R, Woodside B. Diurnal cycle of mother-young contact in Norway rats.  Physiol Behav. 1984;  32 999-1003
    CrossrefPubMedGoogle Scholar
  • 33 Zhang Y, Procena R, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432
    CrossrefPubMedGoogle Scholar
  • 34 Friedman J M, Halaas J L. Leptin, and the regulation of body weight in mammals.  Nature. 2000;  395 763-770
    PubMedGoogle Scholar
  • 35 Ahima R S, Flier J S. Adipose tissue as an endocrine organ.  Trends Endocrinol Metab. 2000;  11 327-332
    PubMedGoogle Scholar
  • 36 Havel P J. Role of adipose tissue in body-weight regulation: Mechanisms regulating leptin production and energy balance.  Proc Nutr Soc. 2000;  59 359-371
    CrossrefPubMedGoogle Scholar
  • 37 Spiegelman B M, Flier J S. Obesity and the regulation of energy balance.  Cell. 2001;  104 531-543
    CrossrefPubMedGoogle Scholar
  • 38 Vernon R G, Denis R GP, Sorensen A. Signals of adiposity.  Domest Anim Endocrinol. 2001;  21 197-214
    CrossrefPubMedGoogle Scholar
  • 39 Ahima R S. Leptin and the neuroendocrinology of fasting.  Frontiers Horm Res. 2000;  26 42-56
    PubMedGoogle Scholar
  • 40 Unger R H. Leptin physiology: a second look.  Regulatory Peptides. 2000;  92 87-95
    CrossrefPubMedGoogle Scholar
  • 41 Shulman G I. Cellular mechanisms of insulin resistance.  J Clin Invest. 2000;  106 171-176
    CrossrefPubMedGoogle Scholar
  • 42 McGarry I D. Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.  Diabetes. 2002;  51 7-18
    CrossrefPubMedGoogle Scholar
  • 43 Saladin R, de Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J. Transient increase in obese gene expression after food intake or insulin administration.  Nature. 1995;  377 527-529
    CrossrefPubMedGoogle Scholar
  • 44 Xu B, Kalra P S, Farmerie W G, Kalra S P. Daily changes in hypothalamic gene expression of neuropeptide Y, galanin, proopiomelanocortin and adipocytes leptin gene expression and secretion: effects of food restriction.  Endocrinology. 1999;  140 2868-2875
    CrossrefPubMedGoogle Scholar
  • 45 Nagatani S, Guthikonda P, Foster D L. Appearance of a nocturnal peak of leptin secretion in the pubertal rat.  Horm Behav. 2000;  37 345-352
    CrossrefPubMedGoogle Scholar
  • 46 Nishiyama M, Makino S, Suemaru S, Nanamiya W, Asaba K, Kaneda T, Mimoto T, Nishioka T, Takao T, Hashimoto K. Glucocorticoid effects on the diurnal rhythm of circulating leptin levels.  Horm Res. 2000;  54 69-73
    CrossrefPubMedGoogle Scholar
  • 47 Mastronardi C A, Walczewska A, Yu W H, Karanth S, Parlow A F, McCann S M. The possible role of prolactin in the circadian rhythm of leptin secretion in male rats.  Proc Soc Exp Biol Med. 2000;  224 152-158
    CrossrefPubMedGoogle Scholar
  • 48 Pu S, Dube M G, Kalra P S, Kalra S P. Regulation of leptin secretion: effects of aging on daily patterns of serum leptin and food consumption.  Regul Pept. 2000;  92 107-111
    CrossrefPubMedGoogle Scholar
  • 49 Johnstone L E, Higuchi T. Food intake and leptin during pregnancy and lactation.  Prog Brain Res. 2001;  133 215-227
    PubMedGoogle Scholar
  • 50 Kalsbeek A, Fliers E, Romijn J A, LaFleur S E, Wortel J, Bakker O, Endert E, Buijs R M. The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels.  Endocrinology. 2001;  142 2677-2685
    CrossrefPubMedGoogle Scholar
  • 51 Kawai M, Yamaguchi M, Murakami T, Shima K, Murata Y, Kishi K. The placenta is not the main source of leptin production in pregnant rat: gestational profile of leptin in plasma and adipose tissues.  Biochem Biophys Res Commun. 1997;  240 798-802
    CrossrefPubMedGoogle Scholar
  • 52 Terada Y, Yamakawa K, Sugaya A, Toyoda N. Serum leptin levels do not rise during pregnancy in age-matched rats.  Biochem Biophys Res Commun. 1998;  253 841-844
    CrossrefPubMedGoogle Scholar
  • 53 Woodside B, Abizaid A, Jafferali S. Effect of acute food deprivation on lactational infertility in rats is reduced by leptin administration.  Am J Physiol. 1998;  274 R1653-R1658
    PubMedGoogle Scholar
  • 54 Brogan R S, Mitchell S E, Trayhurn P, Smith M S. 1999. Suppression of leptin during lactation: contribution of the suckling stimulus versus milk production.  Endocrinology. 2001;  140 2621-2627
    PubMedGoogle Scholar
  • 55 Herrera E, Lasunción M A, Huerta L, Martín-Hidalgo A. Plasma leptin levels in rat mother and offspring during pregnancy and lactation.  Biol Neonate. 2000;  78 315-320
    CrossrefPubMedGoogle Scholar
  • 56 Chien E K, Hara M, Rouard M, Yano H, Phillipe M, Polonsky K S, Bell G I. Increases in serum leptin and uterine leptin receptor messenger RNA levels during pregnancy in rats.  Biochem Biophys Res Commun. 1997;  237 476-480
    CrossrefPubMedGoogle Scholar
  • 57 Carmen-Garcia M D, Casanueva F F, Dieguez C, Senaris R M. Gestational profile of leptin messenger ribonucleic acid (mRNA) content in the placenta and adipose tissue in the rat, and regulation of the mRNA levels of the leptin receptor subtypes in the hypothalamus during pregnancy and lactation.  Biol Reprod. 2000;  62 698-703
    PubMedGoogle Scholar
  • 58 Marie M, Findlay P A, Thomas L, Adam C L. Daily patterns of plasma leptin in sheep: effects of photoperiod and food intake.  J Endocrinol. 2001;  170 277-286
    CrossrefPubMedGoogle Scholar
  • 59 Block S S, Butler W R, Ehrhardt R A, Bell A W, van Amburgh M E, Boisclair Y R. Decreased concentration of plasma leptin in periparturient dairy cows is caused by negative energy balance.  J Endo. 2001;  171 339-348
    PubMedGoogle Scholar
  • 60 Sorensen A, Adam C L, Findlay P A, Marie M, Thomas L, Travers M T, Vernon R G. Leptin secretion and hypothalamic neuropeptide and receptor gene expression in sheep.  Am J Physiol. 2002;  282 R1227-R1235
    PubMedGoogle Scholar
  • 61 Bonnet M, Delavaud C, Laud K, Gourdou I, Leroux C, Djiane J, Chilliard Y. Mammary leptin synthesis, milk leptin and their putative physiological roles.  Reprod Nutr Dev. 2002;  42 1-15
    CrossrefPubMedGoogle Scholar
  • 62 López-Soriano J, López-Soriano F J, Carbó N, Argilé J M. Leptin administration to lactating rats is unable to induce changes in lipid metabolism in white adipose tissue or mammary gland.  Eur J Obs Gyn Reprod Biol. 1999;  84 93-97
    PubMedGoogle Scholar
  • 63 Sorensen A, Knight C H. Restoration in mice after litter removal for various lengths of time.  J Reprod Fertil Abstr. 1997;  19 46
    PubMedGoogle Scholar
  • 64 Gualillo O, Lago F, Garcia M, Menendex C, Senaris R, Casanueva F F, Dieguez C. Prolactin stimulates leptin secretion by rat white adipose tissue.  Endocrinology. 1999;  140 5149-5153
    CrossrefPubMedGoogle Scholar
  • 65 Fain J N, Bahouth S W. Hormonal regulation of 18S RNA, leptin mRNA, and leptin release in adipocytes from hypothyroid rats.  Metabolism. 1998;  47 1455-1461
    CrossrefPubMedGoogle Scholar
  • 66 Ahima R S, Saper C F, Flier J S, Elmquist J K. Leptin regulation of neuroendocrine systems.  Frontiers in Neuroendocrinology. 2000;  21 263-307
    CrossrefPubMedGoogle Scholar
  • 67 Baskin D G, Seeley R J, Kuijper J L, Lok S, Weigle D S, Erickson J C, Palmiter R D, Schwartz M W. 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
    PubMedGoogle Scholar
  • 68 Denis R GP, Vernon R G, Williams G. Lactation has differential effects on neuropeptide Y (NPY) and leptin receptor expression in the rat. Proc Brit Neurosci Assoc 2001: 84
    Google Scholar
  • 69 Brogan R S, Grove K L, Smith M S. Differential regulation of leptin receptor but not orexin in the hypothalamus of the lactating rat.  J Neuroendocrinol. 2000;  12 1077-1086
    CrossrefPubMedGoogle Scholar
  • 70 Pelletier G, Tong Y. Lactation but not prolactin increases the levels of pre-proNPY mRNA in the rat arcuate nucleus.  Mol Cell Neurosci. 1992;  3 286-290
    PubMedGoogle Scholar
  • 71 Smith M S. Lactation alters neuropeptide Y and proopiomelanocortin gene expression in the arcuate nucleus of the rat.  Endocrinology. 1993;  133 1258-1265
    CrossrefPubMedGoogle Scholar
  • 72 Malabu U, Kilpatrick A, Ware M, Vernon R G, Williams G. Increased neuropeptide Y concentrations in specific hypothalamic regions of lactating rats: possible relationships to hyperphagia and adaptive changes in energy balance.  Peptides. 1994;  15 83-87
    CrossrefPubMedGoogle Scholar
  • 73 Chen P, Li C, Haskell-Luevano C, Cone R D, Smith M S. Altered gene expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation.  Endocrinology. 1999;  140 2645-2649
    CrossrefPubMedGoogle Scholar
  • 74 Pape J R, Tramu G. Suckling-induced changes in neuropeptide Y and proopiomelanocortin gene expression in the arcuate nucleus of the rat: evaluation of a putative intervention of prolactin.  Neuroendocrinology. 1996;  63 540-549
    PubMedGoogle Scholar
  • 75 Li C, Chen P, Smith M S. The acute suckling stimulus induces expression of neuropeptide Y (NPY) in cells in the dorsomedial hypothalamus and increases NPY expression in the arcuate nucleus.  Endocrinology. 1998;  139 1645-1652
    CrossrefPubMedGoogle Scholar
  • 76 Trayhurn P. Thermogenesis and the energetics of pregnancy and lactation.  Can J Physiol Pharmacol. 1989;  67 370-375
    PubMedGoogle Scholar
  • 77 Vernon R G, Faulkner A, Hay W W, Calvert D T, Flint D J. Insulin resistance of hind-limb tissues in vivo in lactating sheep.  Biochem J. 1990;  290 783-786
    PubMedGoogle Scholar
  • 78 Smith R W, Knight R A, Walsh A. Effect of lactation on the concentrations of protein, lipids and nucleic acids in ovine skeletal muscle.  Res Vet Sci. 1981;  30 253-254
    PubMedGoogle Scholar

Prof. R. G. Vernon

Hannah Research Institute

Ayr KA6 5HL · Scotland ·

Phone: + 44 (1292) 674 022

Fax: + 44 (1292) 674 003

Email: vernonr@hri.sari.ac.uk