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Gene Review

Lepr  -  leptin receptor

Mus musculus

Synonyms: B219, Db, LEP-R, LEPROT, Leprb, ...
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Disease relevance of Lepr

  • In summary, we discovered three new mutations of Lepr, providing new mouse models for obesity and diabetes [1].
  • CRE-mediated excision of Lepr coding exon 17 from Lepr with a frameshift in subsequent exons results in a syndrome of obesity, diabetes, and infertility in LeprDelta17/Delta17 mice, which is indistinguishable from Lepr(neo/neo) and Lepr(db/db) mice [2].
  • Six nucleotide polymorphisms were observed in the coding region of Lepr. In KK/Ta x (BALB/c x KK/Ta) F1 backcross mice, the Lepr variant of KK/Ta mice failed to alter any of the variables of obesity except for body weight at 20 weeks of age [3].
  • Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate [4].
  • Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not [5].

Psychiatry related information on Lepr

  • Consistent with the increased lean body mass of s/s animals, locomotor activity and acute cold tolerance (partly a measure of shivering thermogenesis) in s/s mice were modestly but significantly improved compared with db/db mice, although they were decreased compared with wild-type mice [6].
  • Induction of leptin receptor expression in the liver by leptin and food deprivation [7].

High impact information on Lepr

  • As predicted, acute treatment of Lepr(db/db) mice with a PPARdelta agonist depletes lipid accumulation [8].
  • Importantly, these animals are completely resistant to both high-fat diet-induced and genetically predisposed (Lepr(db/db)) obesity [8].
  • Breeding the Plin -/- alleles into Leprdb/db mice reverses the obesity by ncreasing the metabolic rate of the mice [9].
  • To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic [10].
  • We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice [11].

Chemical compound and disease context of Lepr

  • Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period [12].
  • The transgene also corrects the infertility of db/db females and confers the ability to lactate sufficiently to nurse normal-sized litters [13].
  • In contrast, CNTFAx15 treatment of db/db mice caused significantly greater weight loss and marked improvements in diabetic parameters (e.g., levels of glucose, insulin, triglyceride, cholesterol, and nonesterified free fatty acids) than could be accounted for by reduced caloric intake alone [14].
  • Estrogenic restoration of functional pancreatic islet cytoarchitecture in diabetes (db/db) mutant C57BL/KsJ mice: relationship to estradiol localization, systemic glycemia, and persistent hyperinsulinemia [15].
  • In this study we demonstrate that histamine deficiency elevates serum leptin level and decreases full-length leptin receptor isoform with a slight increase of the short one and results in mild late onset obesity [16].

Biological context of Lepr

  • We conclude that suppression of Lepr gene expression by PGK-neo is phenotypically equivalent to deletion of the Lepr signaling motifs, and therefore the Lepr(neo/neo) mouse may be used to investigate conditional gene repair of Lepr signaling deficiency [2].
  • Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus [17].
  • This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus [18].
  • LRb regulates energy homeostasis and neuroendocrine function; the absence of LRb in db/db mice results in obesity, impaired growth, infertility and diabetes [19].
  • Here we show that, like db/db mice, lepr(S1138) homozygotes (s/s) are hyperphagic and obese [19].

Anatomical context of Lepr


Associations of Lepr with chemical compounds

  • Altering dietary protein type and quantity reduces urinary albumin excretion without affecting plasma glucose concentrations in +Lepr db/+Lepr db (db/db) mice [23].
  • Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice [24].
  • These effects were not due to the high levels of glucocorticoids present in db/db mice as administration of corticosterone to WT mice failed to reproduce this phenomenon [25].
  • However, this same treatment did not affect hypothalamic histamine turnover in db/db mice [26].
  • Finally, treatment of diabetic db/db mice with rosiglitazone inhibited expression of 11beta-HSD-1 in adipose tissue [27].

Physical interactions of Lepr

  • Consistently, antibodies directed against the extracellular domain of OB-R coprecipitated Jak2 [28].
  • Gonadectomized mutants were analyzed to correlate how strain- and gender-dependent variation in ST activities interacted with db to achieve diabetogenesis [29].

Enzymatic interactions of Lepr


Regulatory relationships of Lepr


Other interactions of Lepr


Analytical, diagnostic and therapeutic context of Lepr


  1. New leptin receptor mutations in mice: Lepr(db-rtnd), Lepr(db-dmpg) and Lepr(db-rlpy). Kim, J.H., Taylor, P.N., Young, D., Karst, S.Y., Nishina, P.M., Naggert, J.K. J. Nutr. (2003) [Pubmed]
  2. An allelic series for the leptin receptor gene generated by CRE and FLP recombinase. McMinn, J.E., Liu, S.M., Dragatsis, I., Dietrich, P., Ludwig, T., Eiden, S., Chua, S.C. Mamm. Genome (2004) [Pubmed]
  3. Minor gene effect of leptin receptor variant on the body weight in KK/Ta mice. Gohda, T., Tanimoto, M., Kaneko, S., Shibata, T., Funabiki, K., Horikoshi, S., Tomino, Y. Diabetes, obesity & metabolism. (2006) [Pubmed]
  4. Role of leptin and melanocortin signaling in uremia-associated cachexia. Cheung, W., Yu, P.X., Little, B.M., Cone, R.D., Marks, D.L., Mak, R.H. J. Clin. Invest. (2005) [Pubmed]
  5. Selective deletion of leptin receptor in neurons leads to obesity. Cohen, P., Zhao, C., Cai, X., Montez, J.M., Rohani, S.C., Feinstein, P., Mombaerts, P., Friedman, J.M. J. Clin. Invest. (2001) [Pubmed]
  6. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Bates, S.H., Dundon, T.A., Seifert, M., Carlson, M., Maratos-Flier, E., Myers, M.G. Diabetes (2004) [Pubmed]
  7. Induction of leptin receptor expression in the liver by leptin and food deprivation. Cohen, P., Yang, G., Yu, X., Soukas, A.A., Wolfish, C.S., Friedman, J.M., Li, C. J. Biol. Chem. (2005) [Pubmed]
  8. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Wang, Y.X., Lee, C.H., Tiep, S., Yu, R.T., Ham, J., Kang, H., Evans, R.M. Cell (2003) [Pubmed]
  9. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Martinez-Botas, J., Anderson, J.B., Tessier, D., Lapillonne, A., Chang, B.H., Quast, M.J., Gorenstein, D., Chen, K.H., Chan, L. Nat. Genet. (2000) [Pubmed]
  10. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Ducy, P., Amling, M., Takeda, S., Priemel, M., Schilling, A.F., Beil, F.T., Shen, J., Vinson, C., Rueger, J.M., Karsenty, G. Cell (2000) [Pubmed]
  11. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Chen, H., Charlat, O., Tartaglia, L.A., Woolf, E.A., Weng, X., Ellis, S.J., Lakey, N.D., Culpepper, J., Moore, K.J., Breitbart, R.E., Duyk, G.M., Tepper, R.I., Morgenstern, J.P. Cell (1996) [Pubmed]
  12. Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo. Kim, J.G., Baggio, L.L., Bridon, D.P., Castaigne, J.P., Robitaille, M.F., Jetté, L., Benquet, C., Drucker, D.J. Diabetes (2003) [Pubmed]
  13. Transgenic complementation of leptin receptor deficiency. II. Increased leptin receptor transgene dose effects on obesity/diabetes and fertility/lactation in lepr-db/db mice. Chua, S.C., Liu, S.M., Li, Q., Sun, A., DeNino, W.F., Heymsfield, S.B., Guo, X.E. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  14. Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. Sleeman, M.W., Garcia, K., Liu, R., Murray, J.D., Malinova, L., Moncrieffe, M., Yancopoulos, G.D., Wiegand, S.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  15. Estrogenic restoration of functional pancreatic islet cytoarchitecture in diabetes (db/db) mutant C57BL/KsJ mice: relationship to estradiol localization, systemic glycemia, and persistent hyperinsulinemia. Garris, D.R., Garris, B.L. Cell Tissue Res. (2005) [Pubmed]
  16. High leptin level is accompanied with decreased long leptin receptor transcript in histamine deficient transgenic mice. Hegyi, K., Fülöp, K.A., Kovács, K.J., Falus, A., Tóth, S. Immunol. Lett. (2004) [Pubmed]
  17. Identification and expression cloning of a leptin receptor, OB-R. Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G.J., Campfield, L.A., Clark, F.T., Deeds, J., Muir, C., Sanker, S., Moriarty, A., Moore, K.J., Smutko, J.S., Mays, G.G., Wool, E.A., Monroe, C.A., Tepper, R.I. Cell (1995) [Pubmed]
  18. Abnormal splicing of the leptin receptor in diabetic mice. Lee, G.H., Proenca, R., Montez, J.M., Carroll, K.M., Darvishzadeh, J.G., Lee, J.I., Friedman, J.M. Nature (1996) [Pubmed]
  19. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Bates, S.H., Stearns, W.H., Dundon, T.A., Schubert, M., Tso, A.W., Wang, Y., Banks, A.S., Lavery, H.J., Haq, A.K., Maratos-Flier, E., Neel, B.G., Schwartz, M.W., Myers, M.G. Nature (2003) [Pubmed]
  20. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Vaisse, C., Halaas, J.L., Horvath, C.M., Darnell, J.E., Stoffel, M., Friedman, J.M. Nat. Genet. (1996) [Pubmed]
  21. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Gao, Q., Mezei, G., Nie, Y., Rao, Y., Choi, C.S., Bechmann, I., Leranth, C., Toran-Allerand, D., Priest, C.A., Roberts, J.L., Gao, X.B., Mobbs, C., Shulman, G.I., Diano, S., Horvath, T.L. Nat. Med. (2007) [Pubmed]
  22. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Kieffer, T.J., Heller, R.S., Leech, C.A., Holz, G.G., Habener, J.F. Diabetes (1997) [Pubmed]
  23. Altering dietary protein type and quantity reduces urinary albumin excretion without affecting plasma glucose concentrations in +Lepr db/+Lepr db (db/db) mice. Teixeira, S.R., Tappenden, K.A., Erdman, J.W. J. Nutr. (2003) [Pubmed]
  24. TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes. Nakagawa, Y., Shimano, H., Yoshikawa, T., Ide, T., Tamura, M., Furusawa, M., Yamamoto, T., Inoue, N., Matsuzaka, T., Takahashi, A., Hasty, A.H., Suzuki, H., Sone, H., Toyoshima, H., Yahagi, N., Yamada, N. Nat. Med. (2006) [Pubmed]
  25. Leptin receptor expression on T lymphocytes modulates chronic intestinal inflammation in mice. Siegmund, B., Sennello, J.A., Jones-Carson, J., Gamboni-Robertson, F., Lehr, H.A., Batra, A., Fedke, I., Zeitz, M., Fantuzzi, G. Gut (2004) [Pubmed]
  26. Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain. Itateyama, E., Chiba, S., Sakata, T., Yoshimatsu, H. Exp. Biol. Med. (Maywood) (2003) [Pubmed]
  27. Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta -hydroxysteroid dehydrogenase type 1 expression and activity. Berger, J., Tanen, M., Elbrecht, A., Hermanowski-Vosatka, A., Moller, D.E., Wright, S.D., Thieringer, R. J. Biol. Chem. (2001) [Pubmed]
  28. The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. Ghilardi, N., Skoda, R.C. Mol. Endocrinol. (1997) [Pubmed]
  29. The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia. Leiter, E.H., Chapman, H.D., Coleman, D.L. Endocrinology (1989) [Pubmed]
  30. Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways. O'Rourke, L., Yeaman, S.J., Shepherd, P.R. Diabetes (2001) [Pubmed]
  31. PTP1B regulates leptin signal transduction in vivo. Zabolotny, J.M., Bence-Hanulec, K.K., Stricker-Krongrad, A., Haj, F., Wang, Y., Minokoshi, Y., Kim, Y.B., Elmquist, J.K., Tartaglia, L.A., Kahn, B.B., Neel, B.G. Dev. Cell (2002) [Pubmed]
  32. In vivo administration of leptin activates signal transduction directly in insulin-sensitive tissues: overlapping but distinct pathways from insulin. Kim, Y.B., Uotani, S., Pierroz, D.D., Flier, J.S., Kahn, B.B. Endocrinology (2000) [Pubmed]
  33. Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling. M??nzberg, H., Jobst, E.E., Bates, S.H., Jones, J., Villanueva, E., Leshan, R., Bj??rnholm, M., Elmquist, J., Sleeman, M., Cowley, M.A., Myers, M.G. J. Neurosci. (2007) [Pubmed]
  34. Identification of SOCS-3 as a potential mediator of central leptin resistance. Bjørbaek, C., Elmquist, J.K., Frantz, J.D., Shoelson, S.E., Flier, J.S. Mol. Cell (1998) [Pubmed]
  35. Localization of leptin receptor mRNA expression in mouse brain. Huang, X.F., Koutcherov, I., Lin, S., Wang, H.Q., Storlien, L. Neuroreport (1996) [Pubmed]
  36. Regulation of leptin receptor and NPY gene expression in hypothalamus of leptin-treated obese (ob/ob) and cold-exposed lean mice. Mercer, J.G., Moar, K.M., Rayner, D.V., Trayhurn, P., Hoggard, N. FEBS Lett. (1997) [Pubmed]
  37. Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus. Korner, J., Savontaus, E., Chua, S.C., Leibel, R.L., Wardlaw, S.L. J. Neuroendocrinol. (2001) [Pubmed]
  38. Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain. Lin, S., Storlien, L.H., Huang, X.F. Brain Res. (2000) [Pubmed]
  39. Leptin receptor-mediated regulation of cholinergic neurotransmitter phenotype in cells of central nervous system origin. Di Marco, A., Demartis, A., Gloaguen, I., Lazzaro, D., Delmastro, P., Ciliberto, G., Laufer, R. Eur. J. Biochem. (2000) [Pubmed]
  40. Both leptin and leptin-receptor are essential for apolipoprotein M expression in vivo. Xu, N., Nilsson-Ehle, P., Hurtig, M., Ahrén, B. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  41. Hyperleptinemia, leptin resistance, and polymorphic leptin receptor in the New Zealand obese mouse. Igel, M., Becker, W., Herberg, L., Joost, H.G. Endocrinology (1997) [Pubmed]
  42. Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus--relationship with NPY neurones. Håkansson, M.L., Hulting, A.L., Meister, B. Neuroreport (1996) [Pubmed]
  43. Molecular cloning and properties of the chicken leptin-receptor (CLEPR) gene. Horev, G., Einat, P., Aharoni, T., Eshdat, Y., Friedman-Einat, M. Mol. Cell. Endocrinol. (2000) [Pubmed]
  44. Leptin affects oligodendroglial development in the mouse embryonic cerebral cortex. Udagawa, J., Nimura, M., Otani, H. Neuro Endocrinol. Lett. (2006) [Pubmed]
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