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Gene Review

Lep  -  leptin

Mus musculus

Synonyms: Leptin, Ob, Obesity factor, ob, obese
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Disease relevance of Lep

  • Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice [1].
  • In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure [2].
  • Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels [2].
  • The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity [3].
  • In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects [4].
  • Together with the finding of enhanced proliferation of T(reg) cells observed in leptin- and ObR-deficient mice, these results suggest a potential for therapeutic interventions in immune and autoimmune diseases [5].
  • While heterozygous Lep mutations initially exacerbate obesity, in situations of severe obesity, reduced leptin levels may act oppositely and have beneficial effects on energy homeostasis [6].
  • Second, we observe that ob/ob mice treated with low-dose leptin peripherally but not centrally exhibit increased thymocyte cellularity in the absence of any weight loss or significant reduction in systemic corticosterone levels [7].
  • Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain [8].
  • Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA [9].

Psychiatry related information on Lep


High impact information on Lep


Chemical compound and disease context of Lep

  • Finally, lean animals, but not ob/ob littermates, had significant fibrosis as assessed by picrosirius red staining and abundant alpha-smooth muscle actin staining [17].
  • Compared with age-matched ob/ob mice, 2KO mice had delayed postprandial triglyceride and fatty acid clearance; associated with decreased body weight (4-17 weeks age: male: -13.7%, female: -20.6%, p < 0.0001) and HOMA (homeostasis model assessment) index (-37.7%), suggesting increased insulin sensitivity [18].
  • Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons [19].
  • The protective potential of ASP deficiency against obesity and involvement of the leptin pathway were examined in ob/ob C3(-/-) double knockout mice (2KO) [18].
  • Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate [19].

Biological context of Lep


Anatomical context of Lep

  • Leptin is the 167 amino-acid protein product of the Lep (obese) gene that is released predominantly from adipose tissue and circulates at levels related to the amount of fat [22].
  • The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus [21].
  • But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone [3].
  • Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus [3].
  • We conclude that leptin is involved in the protective mechanisms that allow an organism to cope with the potentially autoaggressive effects of its immune system [23].

Associations of Lep with chemical compounds


Physical interactions of Lep


Enzymatic interactions of Lep

  • We found that J774.2 macrophages express the functional long form of the leptin receptor (ObRb) and that this becomes tyrosine-phosphorylated after stimulation with low doses of leptin [35].
  • Immunoblot experiments showed that tyrosine phosphorylation of Stat3 increased in total cellular extracts and that the phosphorylated protein translocated into the nucleus upon leptin treatment [36].
  • The stimulation by leptin was not accompanied by recruitment of any tyrosine phosphorylated proteins to PI3K-C2alpha and no shift in electrophoretic mobility was noted [37].
  • We conclude that, although the metabolic adaptations to fasting and CR include changes in plasma leptin concentration and phosphorylated acetyl-CoA carboxylase, these effects occur without changes in AMPK activity [38].

Co-localisations of Lep


Regulatory relationships of Lep


Other interactions of Lep

  • These data suggest that alpha-MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling [47].
  • Obese Mc4r-/-mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non-obese Mc4r-/- mice do [47].
  • Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes [21].
  • These results suggest that NPY is a central effector of leptin deficiency [4].
  • An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice [40].

Analytical, diagnostic and therapeutic context of Lep


  1. Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. Sekiya, M., Osuga, J., Okazaki, H., Yahagi, N., Harada, K., Shen, W.J., Tamura, Y., Tomita, S., Iizuka, Y., Ohashi, K., Okazaki, M., Sata, M., Nagai, R., Fujita, T., Shimano, H., Kraemer, F.B., Yamada, N., Ishibashi, S. J. Biol. Chem. (2004) [Pubmed]
  2. Adiponectin acts in the brain to decrease body weight. Qi, Y., Takahashi, N., Hileman, S.M., Patel, H.R., Berg, A.H., Pajvani, U.B., Scherer, P.E., Ahima, R.S. Nat. Med. (2004) [Pubmed]
  3. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdán, M.G., Diano, S., Horvath, T.L., Cone, R.D., Low, M.J. Nature (2001) [Pubmed]
  4. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Erickson, J.C., Hollopeter, G., Palmiter, R.D. Science (1996) [Pubmed]
  5. A key role of leptin in the control of regulatory T cell proliferation. De Rosa, V., Procaccini, C., Calì, G., Pirozzi, G., Fontana, S., Zappacosta, S., La Cava, A., Matarese, G. Immunity (2007) [Pubmed]
  6. Counterintuitive effects of double-heterozygous null melanocortin-4 receptor and leptin genes on diet-induced obesity and insulin resistance in C57BL/6J mice. Trevaskis, J.L., Meyer, E.A., Galgani, J.E., Butler, A.A. Endocrinology (2008) [Pubmed]
  7. Leptin acts in the periphery to protect thymocytes from glucocorticoid-mediated apoptosis in the absence of weight loss. Trotter-Mayo, R.N., Roberts, M.R. Endocrinology (2008) [Pubmed]
  8. Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents. Lim, G., Wang, S., Zhang, Y., Tian, Y., Mao, J. J. Clin. Invest. (2009) [Pubmed]
  9. Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Griffin, T.M., Huebner, J.L., Kraus, V.B., Guilak, F. Arthritis Rheum. (2009) [Pubmed]
  10. Hypothalamic neuronal histamine as a target of leptin in feeding behavior. Yoshimatsu, H., Itateyama, E., Kondou, S., Tajima, D., Himeno, K., Hidaka, S., Kurokawa, M., Sakata, T. Diabetes (1999) [Pubmed]
  11. Neuropeptide Y and corticotropin-releasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding. Jang, M., Romsos, D.R. J. Nutr. (1998) [Pubmed]
  12. Impact of interrupted leptin pathways on ventilatory control. Polotsky, V.Y., Smaldone, M.C., Scharf, M.T., Li, J., Tankersley, C.G., Smith, P.L., Schwartz, A.R., O'Donnell, C.P. J. Appl. Physiol. (2004) [Pubmed]
  13. Metabolic signals modulate hypothalamic-pituitary-adrenal axis activation during maternal separation of the neonatal mouse. Schmidt, M.V., Levine, S., Alam, S., Harbich, D., Sterlemann, V., Ganea, K., de Kloet, E.R., Holsboer, F., M??ller, M.B. J. Neuroendocrinol. (2006) [Pubmed]
  14. Temperature dependence of O2 consumption; opposite effects of leptin and etomoxir on respiratory quotient in mice. Högberg, H., Engblom, L., Ekdahl, A., Lidell, V., Walum, E., Alberts, P. Obesity (Silver Spring, Md.) (2006) [Pubmed]
  15. Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Clee, S.M., Yandell, B.S., Schueler, K.M., Rabaglia, M.E., Richards, O.C., Raines, S.M., Kabara, E.A., Klass, D.M., Mui, E.T., Stapleton, D.S., Gray-Keller, M.P., Young, M.B., Stoehr, J.P., Lan, H., Boronenkov, I., Raess, P.W., Flowers, M.T., Attie, A.D. Nat. Genet. (2006) [Pubmed]
  16. The molecular clock mediates leptin-regulated bone formation. Fu, L., Patel, M.S., Bradley, A., Wagner, E.F., Karsenty, G. Cell (2005) [Pubmed]
  17. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Saxena, N.K., Ikeda, K., Rockey, D.C., Friedman, S.L., Anania, F.A. Hepatology (2002) [Pubmed]
  18. Acylation-stimulating protein (ASP) deficiency induces obesity resistance and increased energy expenditure in ob/ob mice. Xia, Z., Sniderman, A.D., Cianflone, K. J. Biol. Chem. (2002) [Pubmed]
  19. Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting. Makimura, H., Mizuno, T.M., Yang, X.J., Silverstein, J., Beasley, J., Mobbs, C.V. Diabetes (2001) [Pubmed]
  20. Obesity in BSB mice is correlated with expression of genes for iron homeostasis and leptin. Farahani, P., Chiu, S., Bowlus, C.L., Boffelli, D., Lee, E., Fisler, J.S., Krauss, R.M., Warden, C.H. Obes. Res. (2004) [Pubmed]
  21. 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]
  22. ACTH and alpha-MSH inhibit leptin expression and secretion in 3T3-L1 adipocytes: model for a central-peripheral melanocortin-leptin pathway. Norman, D., Isidori, A.M., Frajese, V., Caprio, M., Chew, S.L., Grossman, A.B., Clark, A.J., Michael Besser, G., Fabbri, A. Mol. Cell. Endocrinol. (2003) [Pubmed]
  23. Leptin is an endogenous protective protein against the toxicity exerted by tumor necrosis factor. Takahashi, N., Waelput, W., Guisez, Y. J. Exp. Med. (1999) [Pubmed]
  24. 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]
  25. Leptin-regulated endocannabinoids are involved in maintaining food intake. Di Marzo, V., Goparaju, S.K., Wang, L., Liu, J., Bátkai, S., Járai, Z., Fezza, F., Miura, G.I., Palmiter, R.D., Sugiura, T., Kunos, G. Nature (2001) [Pubmed]
  26. 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]
  27. Leptin regulation of the mesoaccumbens dopamine pathway. Fulton, S., Pissios, P., Manchon, R.P., Stiles, L., Frank, L., Pothos, E.N., Maratos-Flier, E., Flier, J.S. Neuron (2006) [Pubmed]
  28. High circulating leptin receptors with normal leptin sensitivity in liver-specific insulin receptor knock-out (LIRKO) mice. Cohen, S.E., Kokkotou, E., Biddinger, S.B., Kondo, T., Gebhardt, R., Kratzsch, J., Mantzoros, C.S., Kahn, C.R. J. Biol. Chem. (2007) [Pubmed]
  29. Leptin stimulates both JAK2-dependent and JAK2-independent signaling pathways. Jiang, L., Li, Z., Rui, L. J. Biol. Chem. (2008) [Pubmed]
  30. 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]
  31. Endothelin-1 stimulates leptin production in adipocytes. Xiong, Y., Tanaka, H., Richardson, J.A., Williams, S.C., Slaughter, C.A., Nakamura, M., Chen, J.L., Yanagisawa, M. J. Biol. Chem. (2001) [Pubmed]
  32. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Kellerer, M., Koch, M., Metzinger, E., Mushack, J., Capp, E., Häring, H.U. Diabetologia (1997) [Pubmed]
  33. Activation of urocortin transport into brain by leptin. Kastin, A.J., Akerstrom, V., Pan, W. Peptides (2000) [Pubmed]
  34. Dexamethasone rapidly increases hypothalamic neuropeptide Y secretion in adrenalectomized ob/ob mice. Chen, H.L., Romsos, D.R. Am. J. Physiol. (1996) [Pubmed]
  35. 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]
  36. Leptin activates Stat3, Stat1 and AP-1 in mouse adipose tissue. Bendinelli, P., Maroni, P., Pecori Giraldi, F., Piccoletti, R. Mol. Cell. Endocrinol. (2000) [Pubmed]
  37. TNF-alpha and leptin activate the alpha-isoform of class II phosphoinositide 3-kinase. Ktori, C., Shepherd, P.R., O'Rourke, L. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  38. Metabolic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Gonzalez, A.A., Kumar, R., Mulligan, J.D., Davis, A.J., Weindruch, R., Saupe, K.W. Am. J. Physiol. Endocrinol. Metab. (2004) [Pubmed]
  39. Hypothalamic resistin immunoreactivity is reduced by obesity in the mouse: co-localization with alpha-melanostimulating hormone. Wilkinson, M., Wilkinson, D., Wiesner, G., Morash, B., Ur, E. Neuroendocrinology (2005) [Pubmed]
  40. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Ollmann, M.M., Wilson, B.D., Yang, Y.K., Kerns, J.A., Chen, Y., Gantz, I., Barsh, G.S. Science (1997) [Pubmed]
  41. Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice. Asakawa, A., Inui, A., Ueno, N., Makino, S., Fujino, M.A., Kasuga, M. Gastroenterology (1999) [Pubmed]
  42. Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity. Lambert, P.D., Anderson, K.D., Sleeman, M.W., Wong, V., Tan, J., Hijarunguru, A., Corcoran, T.L., Murray, J.D., Thabet, K.E., Yancopoulos, G.D., Wiegand, S.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  43. Leptin suppresses stearoyl-CoA desaturase 1 by mechanisms independent of insulin and sterol regulatory element-binding protein-1c. Biddinger, S.B., Miyazaki, M., Boucher, J., Ntambi, J.M., Kahn, C.R. Diabetes (2006) [Pubmed]
  44. Leptin induces CD40 expression through the activation of Akt in murine dendritic cells. Lam, Q.L., Zheng, B.J., Jin, D.Y., Cao, X., Lu, L. J. Biol. Chem. (2007) [Pubmed]
  45. Leptin increases adult hippocampal neurogenesis in vivo and in vitro. Garza, J.C., Guo, M., Zhang, W., Lu, X.Y. J. Biol. Chem. (2008) [Pubmed]
  46. Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats. Huo, L., Gamber, K.M., Grill, H.J., Bjørbaek, C. Endocrinology (2008) [Pubmed]
  47. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Marsh, D.J., Hollopeter, G., Huszar, D., Laufer, R., Yagaloff, K.A., Fisher, S.L., Burn, P., Palmiter, R.D. Nat. Genet. (1999) [Pubmed]
  48. 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]
  49. Identification of targets of leptin action in rat hypothalamus. Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P., Baskin, D.G. J. Clin. Invest. (1996) [Pubmed]
  50. Leptin mediates Clostridium difficile toxin A-induced enteritis in mice. Mykoniatis, A., Anton, P.M., Wlk, M., Wang, C.C., Ungsunan, L., Blüher, S., Venihaki, M., Simeonidis, S., Zacks, J., Zhao, D., Sougioultzis, S., Karalis, K., Mantzoros, C., Pothoulakis, C. Gastroenterology (2003) [Pubmed]
  51. Leptin stimulates fetal and adult erythroid and myeloid development. Mikhail, A.A., Beck, E.X., Shafer, A., Barut, B., Gbur, J.S., Zupancic, T.J., Schweitzer, A.C., Cioffi, J.A., Lacaud, G., Ouyang, B., Keller, G., Snodgrass, H.R. Blood (1997) [Pubmed]
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