This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamashita, H. Articles by Friedman, J. E. Search for Related Content PubMed PubMed Citation Articles by Yamashita, H. Articles by Friedman, J. E.

Leptin Administration Prevents Spontaneous Gestational Diabetes in Heterozygous Lepr^db/+ Mice: Effects on Placental Leptin and Fetal Growth¹

Departments of Nutrition and Reproductive Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935; and Rowett Research Institute (N.H.), Buckburn, Aberdeen, Scotland, United Kingdom AB21 9SB

Address all correspondence and requests for reprints to: Jacob E. Friedman, Ph.D., University of Colorado Health Sciences Center, Section of Neonatology-B195, 4200 East Ninth Avenue, Denver, Colorado 80262. E-mail: jed.friedman{at}uchsc.edu

Gestational diabetes mellitus (GDM) results from an interaction between susceptibility genes and the diabetogenic effects of pregnancy. During pregnancy, mice heterozygous for the lepin receptor (db/+) gain more weight, are glucose intolerant, and produce macrosomic fetuses compared with wild-type (+/+) mothers, suggesting that an alteration in leptin action may play a role in GDM and fetal overgrowth. To investigate whether leptin administration or pair-feeding can reduce adiposity and thereby prevent GDM and neonatal overgrowth, we examined energy balance, glucose and insulin tolerance, and fetal growth in pregnant db/+ and +/+ mice treated with recombinant human leptin-IgG during late pregnancy. Leptin reduced food intake and adiposity in pregnant db/+ mice to levels similar to pregnant +/+ mice and significantly reduced maternal weight gain. Maternal glucose levels were markedly lower during glucose and insulin challenge tests in leptin-treated db/+ mice relative to db/+ and pair-fed controls. Despite reduced energy intake and improved glucose tolerance, leptin administration did not reduce fetal overgrowth in offspring from db/+ mothers. Fetal and placental leptin levels were 1.3- to 1.5-fold higher in offspring from db/+ mothers and remained unchanged with leptin administration, whereas leptin treatment in +/+ mothers or pair-feeding decreased placental leptin concentration and reduced fetal birth weight. Our results provide evidence that leptin administration during late gestation can reduce adiposity and improve glucose tolerance in the db/+ mouse model of spontaneous GDM. However, fetal and placenta leptin levels are higher in db/+ mothers and are subject to reduced negative feedback in response to leptin treatment. These data suggest that alterations in placenta leptin may contribute to the regulation of fetal growth independently of maternal glucose levels.

This article has been cited by other articles:

				A. J. Forhead, C. A. Lamb, K. L. Franko, D. M. O'Connor, F. B. P. Wooding, R. L. Cripps, S. Ozanne, D. Blache, Q. W. Shen, M. Du, et al. Role of leptin in the regulation of growth and carbohydrate metabolism in the ovine fetus during late gestation J. Physiol., May 1, 2008; 586(9): 2393 - 2403. [Abstract] [Full Text] [PDF]

				S. Lambin, R. van Bree, S. Caluwaerts, L. Vercruysse, I. Vergote, and J. Verhaeghe Adipose tissue in offspring of Leprdb/+ mice: early-life environment vs. genotype Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E262 - E271. [Abstract] [Full Text] [PDF]

				A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M. O. Carruba, et al. Leptin Increases Axonal Growth Cone Size in Developing Mouse Cortical Neurons by Convergent Signals Inactivating Glycogen Synthase Kinase-3beta J. Biol. Chem., May 5, 2006; 281(18): 12950 - 12958. [Abstract] [Full Text] [PDF]

				J. Udagawa, R. Hashimoto, H. Suzuki, T. Hatta, Y. Sotomaru, K. Hioki, Y. Kagohashi, T. Nomura, Y. Minami, and H. Otani The Role of Leptin in the Development of the Cerebral Cortex in Mouse Embryos Endocrinology, February 1, 2006; 147(2): 647 - 658. [Abstract] [Full Text] [PDF]

				S. R. Ravelich, A. N. Shelling, A. Ramachandran, S. Reddy, J. A. Keelan, D. N. Wells, A. J. Peterson, R. S.F. Lee, and B. H. Breier Altered Placental Lactogen and Leptin Expression in Placentomes from Bovine Nuclear Transfer Pregnancies Biol Reprod, December 1, 2004; 71(6): 1862 - 1869. [Abstract] [Full Text] [PDF]

				S. C. Chua Jr., S. M. Liu, Q. Li, A. Sun, W. F. DeNino, S. B. Heymsfield, and X. E. Guo Transgenic complementation of leptin receptor deficiency. II. Increased leptin receptor transgene dose effects on obesity/diabetes and fertility/lactation in lepr-db/db mice Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E384 - E392. [Abstract] [Full Text]

				J. T. Smith and B. J. Waddell Leptin Distribution and Metabolism in the Pregnant Rat: Transplacental Leptin Passage Increases in Late Gestation but Is Reduced by Excess Glucocorticoids Endocrinology, July 1, 2003; 144(7): 3024 - 3030. [Abstract] [Full Text] [PDF]

				J. T. Smith and B. J. Waddell Leptin Receptor Expression in the Rat Placenta: Changes in Ob-Ra, Ob-Rb, and Ob-Re with Gestational Age and Suppression by Glucocorticoids Biol Reprod, October 1, 2002; 67(4): 1204 - 1210. [Abstract] [Full Text] [PDF]

				Y. Sun, S. Liu, S. Ferguson, L. Wang, P. Klepcyk, J. S. Yun, and J. E. Friedman Phosphoenolpyruvate Carboxykinase Overexpression Selectively Attenuates Insulin Signaling and Hepatic Insulin Sensitivity in Transgenic Mice J. Biol. Chem., June 21, 2002; 277(26): 23301 - 23307. [Abstract] [Full Text] [PDF]

				R. M. Seeber, J. T. Smith, and B. J. Waddell Plasma Leptin-Binding Activity and Hypothalamic Leptin Receptor Expression During Pregnancy and Lactation in the Rat Biol Reprod, June 1, 2002; 66(6): 1762 - 1767. [Abstract] [Full Text] [PDF]

				A. J. Forhead, L. Thomas, J. Crabtree, N. Hoggard, D. S. Gardner, D. A. Giussani, and A. L. Fowden Plasma Leptin Concentration in Fetal Sheep during Late Gestation: Ontogeny and Effect of Glucocorticoids Endocrinology, April 1, 2002; 143(4): 1166 - 1173. [Abstract] [Full Text] [PDF]

				J. Shao, H. Yamashita, L. Qiao, B. Draznin, and J. E. Friedman Phosphatidylinositol 3-Kinase Redistribution Is Associated With Skeletal Muscle Insulin Resistance in Gestational Diabetes Mellitus Diabetes, January 1, 2002; 51(1): 19 - 29. [Abstract] [Full Text] [PDF]