Central Leptin Stimulates Ingestive Behavior and Urine Flow in the Near Term Ovine Fetus

Leptin inhibits ingestive behavior and induces diuresis and natriuresis. To examine whether leptin influences fetal physiologic functions, we investigated the effect of central leptin on ovine fetal swallowing activity and urine flow. Six pregnant ewes with singleton fetuses (130 ± 2 d gestation) were prepared with maternal and fetal arterial and venous catheters, fetal lateral intra-ventricle cannula, fetal bladder and amniotic fluid catheters. Electromyogram wires were placed in the fetal thyrohyoid muscle and upper and lower nuchal esophagus and electrodes were implanted on the parietal dura. Five days after surgery, recombinant human leptin was infused into the lateral ventricle and the fetus monitored for 8 h. Central leptin increased fetal swallowing activity during low-voltage electrocortical activity from basal values (0.96 ± 0.08 swallows/min) at 2 h (1.41 ± 0.24 swallows/min), 4 h (2.81 ± 0.57 swallows/min), 6 h (2.53 ± 0.59 swallows/min) and 8 h (2.08 ± 0.39 swallows/min, p < 0.05). In comparison to basal values, low voltage electrocortical activity decreased (57 ± 5 % to 42 ± 4 %) and high voltage electrocortical increased (43 ± 5 % to 61 ± 4 %). In response to leptin, fetal urine flow initially decreased from basal values at 2 h (0.12 ± 0.03 to 0.08 ± 0.02 ml/kg/min, p < 0.05) then subsequently increased at 4 h and 6 h (0.20 ± 0.04; 0.21 ± 0.04 ml/kg/min, respectively, p < 0.05). Central leptin significantly increases near term ovine fetal swallowing activity and urine output, suggesting that leptin contributes to in utero development of ingestive behavior.

Key words:

OB Protein - Renal - Fetal Sheep - Swallowing - Thirst - Behavioral State

References

• 1 Epstein A. The ontogeny of neurochemical systems for control of feeding and drinking.  Proc Soc Exp Biol Med. 1984;  175 127-134
• 2 Hall W G, Cramer C P, Blass E M. Ontogeny of suckling in rats: Transitions toward adult ingestion.  J Comp Physl Psych. 1977;  91 1141-1151
• 3 Phillips D I, Barker D J, Osmond C. Infant feeding, fetal growth and adult thyroid function.  Acta Endocrinol (Copenh.). 1993;  129 134-138
• 4 Campfield L A, Smith F J, Bum P. The OB protein (leptin) pathway - a link between adipose tissue mass and central neural networks.  Horm Metab Res. 1996;  28 619-632
• 5 Dyer C J, Simmons J M, Matteri R L, Keisler D H. Leptin receptor mRNA is expressed in ewe anterior pituitary and adipose tissues and is differentially expressed in hypothalamic regions of well-fed and feed-restricted ewes.  Domes Anim Endo. 1997;  14 119-128
• 6 Schwartz M, Seeley R, Campfield A, Burn P, Baskin D. Identification of targets of leptin action in rat hypothalamus.  J Clin Invest. 1996;  98 1101-1106
• 7 Cusin I F, Rohner-Jeanrenaud A, Stricker-Krongrad , Jeanrenaud B. The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats.  Diabetes. 1986;  45 1446-1450
• 8 Henry B A, Goding J W, Alexander W S, Tilbrook A J, Canny B J, Dunshea F, Rao A, Mansell A, Clarke I J. Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function.  Endo . 1999;  140 1175-1182
• 9 Seeley R J, Van Dijk G, Campfield L A, Smity F J, Burn P, Neliigan J A, Bell S M, Baskin D G, Woods S C, Schwartz M W. Intraventricular leptin reduces food intake and body weight of lean rats but not obese zucker rats.  Horm Metab Res. 1996;  28 664-668
• 10 Weigle D, Bukowski T, Foster D, Holderman S, Kramer J, Lasser G, Lofton-Day C, Prunkard D, Raymond C, Kuijper J. Recombinant ob protein reduces feeding and body weight in the ob/ob mouse.  J Clin Invest. 1995;  96 2065-2070
• 11 Schwartz M, Baskin D, Burkowski T, Kuijper J, Foster D, Lasser G, Prunkard D, Porte D, Woods S, Seeley R, Weigle D. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice.  Diabetes. 1996;  45 532-535
• 12 Smith F J, Campfield L A, Moschera J A, Bailon P S, Burn P. Brain administration of OB protein (leptin) inhibits neuropeptide-Y-induced feeding in ob/ob mice.  Regl Pept. 1998;  75 433-439
• 13 Steinman J, Gunion M, Morley J. Forebrain and hindbrain involvement of neuropeptide Y in ingestive behaviors of rats.  Pharm Bioch Behav. 1994;  47 207-214
• 14 Uehara Y, Shimizu H, Ohtani K, Sato N, Mori M. Hypothalamic corticotropin-releasing hormone is a mediator of the anorexigenic effect of leptin.  Diabetes. 1998;  47 890-893
• 15 Bell S M, Reynolds J G, Thiele T E, Figlewicz D P, Woods S C. Effects of third intracerebroventricular injections of corticotropin-releasing factor (CRF) on ethanol drinking and food intake.  Psychopharmacology (Berl). 1998;  139 128-135
• 16 Haynes W G, Morgan D A, Walsh S A, Mark A L, Sivitz W I. Receptor-mediated regional sympathetic nerve activation by leptin.  J Clin Inv. 1997;  100 270-278
• 17 Jackson E, Li P. Human leptin has natriuretic activity in the rat.  Am J Physiol. 1997;  272 F333-F338
• 18 Spinedi E, Gaillard R C. A regulatory loop between the hypothalo-pituitary-adrenal (HPA) axis and circulating leptin: a physiological role of ACTH.  Endo. 1998;  139 4016-4020
• 19 Yu W H, Kimura M, Walczewska A, Karanth S, McCann M. Role of leptin in hypothalamic-pituitary function.  Proc Natl Acad Sci. 1997;  94 1023-1028
• 20 Schubring C, Kiess W, Englaro P, Rascher W, Dotsch J, Hanitsch S, Attanasio A, Blum W F. Levels of leptin in maternal serum, amniotic fluid, and arterial and venous cord blood: relation to neonatal and placental weight.  J Clin Endo Metab. 1997;  82 1480-1483
• 21 Matsuda J, Yokota I, lida M, Murakami T, Naito E, Ito M, Shima K, Kuroda Y. Serum leptin concentration in cord blood: Relationship to birth weight and gender.  J Clin Endo Metab. 1997;  82 1642-1644
• 22 Schwartz M W, Seeley R J. The new biology of body weight regulation.  J Am Diet Assoc. 1997;  97 54-58
• 23 Takahashi M, Funahashi T, Shimomura I, Miyaoka K, Matsuzawa Y. Plasma leptin levels and body fat distribution.  Horm Metab Res. 1996;  28 751-752
• 24 Barker D J, Martyn C N. The maternal and fetal origins of cardiovascular disease.  J Epidemiol Community Health. 1992;  46 8-11
• 25 Pitkin R, Reynolds W A. Fetal ingestion and metabolism of amniotic fluid protein.  Am J Obstet Gynecol. 1975;  123 356-365
• 26 Ross M G, Sherman D J, Ervin M G, Day L, Humme J. Stimuli for fetal swallowing: systemic factors.  Am J Obstet Gynecol. 1989;  161 1559-1565
• 27 Skowsky W R, Rosenbloom A, Fisher D A. Radioimmunoassay of arginine vasopressin: development and application.  J Clin Endo Metab. 1974;  38 278-287
• 28 Ross M G, Kullama L K, Ogundipe O A, Chan K, Ervin M G. Central angiotensin II stimulation of ovine fetal swallowing.  J Appl Physiol. 1994;  76 1340-1345
• 29 Roberts T J, Nijland M JM, Balderrama A C, Ross M G. Intracerebroventricular injection of leptin stimulates ingestive behavior in the near term ovine fetus.  Am J Physiol Endocrinol Metab. 2000;  279 (3) E494-500
• 30 Sherman D, Ross M, Day L, Ervin G. Fetal swallowing: correlation of electromyography and esophageal fluid flow.  Am J Physiol. 1990;  258 R1386-R1395
• 31 Sivitz I, Walsh A, Morgan D A, Thomas M J, Haynes W G. Effects of leptin on insulin sensitivity in normal rats.  Endo. 1997;  138 3395-3401
• 32 Wang Q, Bing C, Al-Barazanji K, Mossakowaska D, Wang X, McBay D, Neville W, Taddayon M, Pickavance L, Dryden S, Thomas M, McHale M, Gloyer I, Wilson S, Buckingham R, Arch J, Trayhurn P, Williams G. Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat.  Diabetes. 1997;  46 335-341
• 33 Williams L, Adam C, Mercer J, Moar D, Slater L, Hunter P, Findlay P, Hoggard N. Leptin receptor and neuropeptide Y gene expression in the sheep brain.  J Neuroendo. 1999;  11 165-169
• 34 Mercer J, Hoggard N, Williams L, Lawrence C, Hannah L, Trayhurn P. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in the mouse hypothalamus and adjacent brain regions by in-situ hybridization.  Febs Letts. 1996;  387 113-116
• 35 Guan X, Hess J, Houg Y, Hey P, van der Ploeg L. Differential expression of mRNA for leptin receptor isoforms in the rat brain.  Mol Cell Endo. 1997;  133 1-7
• 36 Henry B, Goding J, Alexander W, Tilbrook A, Canny B, Dunshea F, Rao A, Mansell A, Clarke I. Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function.  Endo. 1999;  1240 1165-1182
• 37 Capuano C A, Leibowitz S F, Barr G A. Effect of paraventricular injection of neuropeptide Y on milk and water intake of preweanling rats.  Neuropeptides. 1993;  24 177-182
• 38 Hoggard N, Hunter L, Duncan J, Williams L, Trayuhurn P, Mercer J. Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta.  Proc Natl Acad Sci. 1997;  94 11 073-11 078
• 39 Yuen B, McMillen I, Symonds M, Owens P. Abundance of leptin mRNA in fetal adipose tissue is related to fetal body weight.  J Endo. 1999;  163 R1-R4
• 40 Nijland M J, Chao C R, Ross M G. Anticholinergic suppression of ovine fetal swallowing activity.  Am J Obstet Gynecol. 1997;  177 1105-1112
• 41 Dunbar L C, Hu Y, Lu H. Intracerebroventricular leptin increases lumbar and renal sympathetic nerve activity and blood pressure in normal rats.  Diabetes. 1997;  46 2040-2043
• 42 Haynes W G, Sivitz W I, Morgan D A, Walsh S A, Mark A L. Sympathetic and cardiorenal actions of leptin.  Hypertension. 1997;  30 619-623
• 43 Lu H, Duanmu Z, Houck C, Jen K J, Buison A, Dunbar J C. Obesity due to high fat diet decreases the sympathetic nervous and cardiovascular responses to intracerebroventricular leptin in rats.  Brain Res Bull. 1998;  47 331-335
• 44 Costa A, Poma A, Martignoni E, Nappi G, Ur E, Grossman A. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants.  Neuroreport. 1997;  24 1131-1134
• 45 Dodic M, Wintour W M. Effects of prolonged (48 h) infusion of cortisol on blood pressure, renal function and fetal fluids in the immature ovine foetus.  Clin Exp Pharmacol Physiol. 1994;  12 971-980
• 46 Erikkson E, Swenne I. Diabetes in pregnancy: fetal macrosomia, hyperinsulinemia, and islet hyperplasia in the offspring of rats subjected to temporary protein-energy malnutrition early in life.  Pediatr Res. 1993;  34 791-795
• 47 Utriainen T, Malmstrom R, Makimattila S, Yki-Jarvinen H. Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects.  Diabetes. 1996;  45 1364-1366
• 48 Considine R V, Caro J R. Leptin: Genes, concepts and clinical perspective.  .  Horm Res. 1996;  46 249-256