Diabetes, Vol 46, Issue 3 513-518, Copyright © 1997 by American Diabetes Association

ARTICLES

Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat

XS Wu-Peng, SC Chua, N Okada, SM Liu, M Nicolson and RL Leibel
Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, New York 10021, USA.

The obese phenotypes of the diabetes (db) mouse and fatty fa) rat are due to functional null mutations of the leptin receptor (Lepr). The recessive mutation in the Koletsky (f) obese rat maps to the same genetic intervals as db and fa and fails to complement the fa mutation. Comparison of the sequence of brain Lepr cDNA from +/+ and f/f animals reveals a T2349A transversion resulting in a Tyr763Stop nonsense mutation in the gene just before the transmembrane domain. Virtual absence of Lepr mRNA in whole brain from f/f animals is consistent with the presence of a null mutation. The predicted reduced cerebrospinal fluid (CSF) transport of leptin in both f/f and fa/fa mutants is reflected in the approximately 10-fold lower ratio of CSF/plasma leptin concentration in the obese versus lean animals. However, equivalent CSF leptin concentration between lean and obese rats (fa/fa, f/f) indicates that leptin can enter the CSF through a non-Lepr-mediated mechanism, which may be saturated at normal physiological plasma leptin concentration.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. J. Kastin and W. Pan Intranasal Leptin: Blood-Brain Barrier Bypass (BBBB) for Obesity? Endocrinology, May 1, 2006; 147(5): 2086 - 2087. [Full Text] [PDF]

				Z. Q. Wang, X. H. Zhang, J. C. Russell, M. Hulver, and W. T. Cefalu Chromium Picolinate Enhances Skeletal Muscle Cellular Insulin Signaling In Vivo in Obese, Insulin-Resistant JCR:LA-cp Rats J. Nutr., February 1, 2006; 136(2): 415 - 420. [Abstract] [Full Text] [PDF]

				X. Deng, M. B. Elam, H. G. Wilcox, L. M. Cagen, E. A. Park, R. Raghow, D. Patel, P. Kumar, A. Sheybani, and J. C. Russell Dietary Olive Oil and Menhaden Oil Mitigate Induction of Lipogenesis in Hyperinsulinemic Corpulent JCR:LA-cp Rats: Microarray Analysis of Lipid-Related Gene Expression Endocrinology, December 1, 2004; 145(12): 5847 - 5861. [Abstract] [Full Text] [PDF]

				S. Bi, B. M. Robinson, and T. H. Moran Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1030 - R1036. [Abstract] [Full Text] [PDF]

				W. A. Banks and C. L. Farrell Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible Am J Physiol Endocrinol Metab, July 1, 2003; 285(1): E10 - E15. [Abstract] [Full Text] [PDF]

				G. J. Morton, K. D. Niswender, C. J. Rhodes, M. G. Myers Jr., J. E. Blevins, D. G. Baskin, and M. W. Schwartz Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats Endocrinology, May 1, 2003; 144(5): 2016 - 2024. [Abstract] [Full Text] [PDF]

				J. H. Kim, P. N. Taylor, D. Young, S. Y. Karst, P. M. Nishina, and J. K. Naggert New Leptin Receptor Mutations in Mice: Leprdb-rtnd, Leprdb-dmpg and Leprdb-rlpy J. Nutr., May 1, 2003; 133(5): 1265 - 1271. [Abstract] [Full Text] [PDF]

				L. L. Atkinson, R. Kozak, S. E. Kelly, A. Onay-Besikci, J. C. Russell, and G. D. Lopaschuk Potential mechanisms and consequences of cardiac triacylglycerol accumulation in insulin-resistant rats Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E923 - E930. [Abstract] [Full Text] [PDF]

				Y. Mitani, A. Mutlu, J. C. Russell, D. N. Brindley, J. DeAlmeida, and M. Rabinovitch Dexfenfluramine protects against pulmonary hypertension in rats J Appl Physiol, November 1, 2002; 93(5): 1770 - 1778. [Abstract] [Full Text] [PDF]

				B.S.J. Yuen, P.C. Owens, J.R. McFarlane, M.E. Symonds, L.J. Edwards, K.G. Kauter, and I.C. McMillen Circulating Leptin Concentrations Are Positively Related to Leptin Messenger RNA Expression in the Adipose Tissue of Fetal Sheep in the Pregnant Ewe Fed at or Below Maintenance Energy Requirements During Late Gestation Biol Reprod, September 1, 2002; 67(3): 911 - 916. [Abstract] [Full Text] [PDF]

				W. T. Cefalu, Z. Q. Wang, X. H. Zhang, L. C. Baldor, and J. C. Russell Oral Chromium Picolinate Improves Carbohydrate and Lipid Metabolism and Enhances Skeletal Muscle Glut-4 Translocation in Obese, Hyperinsulinemic (JCR-LA Corpulent) Rats J. Nutr., June 1, 2002; 132(6): 1107 - 1114. [Abstract] [Full Text] [PDF]

				L. L. Atkinson, S. E. Kelly, J. C. Russell, J. Bar-Tana, and G. D. Lopaschuk MEDICA 16 Inhibits Hepatic Acetyl-CoA Carboxylase and Reduces Plasma Triacylglycerol Levels in Insulin-Resistant JCR: LA-cp Rats Diabetes, May 1, 2002; 51(5): 1548 - 1555. [Abstract] [Full Text] [PDF]

				S. J. Netherton, S. L. Jimmo, D. Palmer, D. G. Tilley, H. A. Dunkerley, D. R. Raymond, J. C. Russell, P. M. Absher, E. H. Sage, R. B. Vernon, et al. Altered Phosphodiesterase 3-Mediated cAMP Hydrolysis Contributes to a Hypermotile Phenotype in Obese JCR:LA-cp Rat Aortic Vascular Smooth Muscle Cells: Implications for Diabetes-Associated Cardiovascular Disease Diabetes, April 1, 2002; 51(4): 1194 - 1200. [Abstract] [Full Text] [PDF]

				M. B. Elam, H. G. Wilcox, L. M. Cagen, X. Deng, R. Raghow, P. Kumar, M. Heimberg, and J. C. Russell Increased hepatic VLDL secretion, lipogenesis, and SREBP-1 expression in the corpulent JCR:LA-cp rat J. Lipid Res., December 1, 2001; 42(12): 2039 - 2048. [Abstract] [Full Text] [PDF]

				S. P. Tofovic, R. K. Dubey, and E. K. Jackson 2-Hydroxyestradiol Attenuates the Development of Obesity, the Metabolic Syndrome, and Vascular and Renal Dysfunction in Obese ZSF1 Rats J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 973 - 977. [Abstract] [Full Text] [PDF]

				M. Li, P. M. Absher, P. Liang, J. C. Russell, B. E. Sobel, and N. K. Fukagawa High Glucose Concentrations Induce Oxidative Damage to Mitochondrial DNA in Explanted Vascular Smooth Muscle Cells Experimental Biology and Medicine, May 1, 2001; 226(5): 450 - 457. [Abstract] [Full Text]

				B. B. Yaspelkis III, J. R. Davis, M. Saberi, T. L. Smith, R. Jazayeri, M. Singh, V. Fernandez, B. Trevino, N. Chinookoswong, J. Wang, et al. Leptin administration improves skeletal muscle insulin responsiveness in diet-induced insulin-resistant rats Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E130 - E142. [Abstract] [Full Text] [PDF]

				B. Winters, Z. Mo, E. Brooks-Asplund, S. Kim, A. Shoukas, D. Li, D. Nyhan, and D. E. Berkowitz Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lepob) mice J Appl Physiol, December 1, 2000; 89(6): 2382 - 2390. [Abstract] [Full Text] [PDF]

				J.-L. Wang, N. Chinookoswong, S. Yin, and Z.-Q. Shi Calorigenic actions of leptin are additive to, but not dependent on, those of thyroid hormones Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1278 - E1285. [Abstract] [Full Text] [PDF]

				G. E. Truett, J. A. Walker, and R. B. S. Harris A developmental switch affecting growth of fatty rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2000; 279(6): R1956 - R1963. [Abstract] [Full Text] [PDF]

				J. C. Russell, D. Ravel, J.-P. Pégorier, P. Delrat, R. Jochemsen, S. F. O'Brien, S. E. Kelly, S. T. Davidge, and D. N. Brindley Beneficial Insulin-Sensitizing and Vascular Effects of S15261 in the Insulin-Resistant JCR:LA-cp Rat J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 753 - 760. [Abstract] [Full Text]

				J. Korner, S. L. Wardlaw, S.-M. Liu, I. M. Conwell, R. L. Leibel, and S. C. Chua Jr. Effects of Leptin Receptor Mutation on Agrp Gene Expression in Fed and Fasted Lean and Obese (LA/N-faf) Rats Endocrinology, July 1, 2000; 141(7): 2465 - 2471. [Abstract] [Full Text] [PDF]

				S. Reichlin, G. Chen, and M. Nicolson Blood to Brain Transfer of Leptin in Normal and Interleukin-1{beta}-Treated Male Rats Endocrinology, June 1, 2000; 141(6): 1951 - 1954. [Abstract] [Full Text] [PDF]

				H. F. Wildman, S. Chua Jr., R. L. Leibel, and G. P. Smith Effects of leptin and cholecystokinin in rats with a null mutation of the leptin receptor Leprfak Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1518 - R1523. [Abstract] [Full Text] [PDF]

				B. V. Zlokovic, S. Jovanovic, W. Miao, S. Samara, S. Verma, and C. L. Farrell Differential Regulation of Leptin Transport by the Choroid Plexus and Blood-Brain Barrier and High Affinity Transport Systems for Entry into Hypothalamus and Across the Blood-Cerebrospinal Fluid Barrier Endocrinology, April 1, 2000; 141(4): 1434 - 1441. [Abstract] [Full Text] [PDF]

				J. A. Brown, S. C. Chua Jr., S. M. Liu, M. T. Andrews, and J. G. Vandenbergh Spontaneous mutation in the db gene results in obesity and diabetes in CD-1 outbred mice Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R320 - R330. [Abstract] [Full Text] [PDF]

				K. Fujioka, J. Patane, J. Lubina, and D. Lau CSF Leptin Levels After Exogenous Administration of Recombinant Methionyl Human Leptin JAMA, October 27, 1999; 282(16): 1517 - 1518. [Full Text] [PDF]

				D. Chen and A. Garg Monogenic disorders of obesity and body fat distribution J. Lipid Res., October 1, 1999; 40(10): 1735 - 1746. [Abstract] [Full Text]

				V. A. Barr, K. Lane, and S. I. Taylor Subcellular Localization and Internalization of the Four Human Leptin Receptor Isoforms J. Biol. Chem., July 23, 1999; 274(30): 21416 - 21424. [Abstract] [Full Text] [PDF]

				S. Reichlin Editorial: Is Leptin a Secretion of the Brain? J. Clin. Endocrinol. Metab., July 1, 1999; 84(7): 2267 - 2269. [Full Text]

				S. Kraeft, K. Schwarzer, S. Eiden, B. Nuesslein-Hildesheim, G. Preibisch, and I. Schmidt Leptin responsiveness and gene dosage for leptin receptor mutation (fa) in newborn rats Am J Physiol Endocrinol Metab, May 1, 1999; 276(5): E836 - E842. [Abstract] [Full Text] [PDF]

				T. Ishizuka, P. Ernsberger, S. Liu, D. Bedol, T. M. Lehman, R. J. Koletsky, and J. E. Friedman Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fak) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB) J. Nutr., December 1, 1998; 128(12): 2299 - 2306. [Abstract] [Full Text]

				J. J. Ramsey, J. W. Kemnitz, R. J. Colman, D. Cunningham, and A. G. Swick Different Central and Peripheral Responses to Leptin in Rhesus Monkeys: Brain Transport May Be Limited J. Clin. Endocrinol. Metab., September 1, 1998; 83(9): 3230 - 3235. [Abstract] [Full Text]

				B. A. da Silva, C. Bjorbak, S. Uotani, and J. S. Flier Functional Properties of Leptin Receptor Isoforms Containing the Gln->Pro Extracellular Domain Mutation of the Fatty Rat Endocrinology, September 1, 1998; 139(9): 3681 - 3690. [Abstract] [Full Text] [PDF]

				C. Bjorbak, J. K. Elmquist, P. Michl, R. S. Ahima, A. van Bueren, A. L. McCall, and J. S. Flier Expression of Leptin Receptor Isoforms in Rat Brain Microvessels Endocrinology, August 1, 1998; 139(8): 3485 - 3491. [Abstract] [Full Text] [PDF]

				J. A. Crouse, G. E. Elliott, T. L. Burgess, L. Chiu, L. Bennett, J. Moore, M. Nicolson, and R. E. Pacifici Altered Cell Surface Expression and Signaling of Leptin Receptors Containing the fatty Mutation J. Biol. Chem., July 17, 1998; 273(29): 18365 - 18373. [Abstract] [Full Text] [PDF]

				R. L. Leibel, W. K. Chung, and S. C. Chua Jr. The Molecular Genetics of Rodent Single Gene Obesities J. Biol. Chem., December 19, 1997; 272(51): 31937 - 31940. [Full Text] [PDF]

				D. W.W. Y. Wang, S. C. Chua Jr., J. P. Morgenstern, R. L. Leibel, H. Baumann, and L. A. Tartaglia Constitutive and impaired signaling of leptin receptors containing the Gln right-arrow Pro extracellular domain fatty mutation PNAS, September 30, 1997; 94(20): 10657 - 10662. [Abstract] [Full Text] [PDF]

				L. Huang, Z. Wang, and C. Li Modulation of Circulating Leptin Levels by Its Soluble Receptor J. Biol. Chem., February 23, 2001; 276(9): 6343 - 6349. [Abstract] [Full Text] [PDF]