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Recombinant leptin mutants and leptin binding proteins aimed to block leptin action in vivo

  • A. Gertler (a1), Y. Sandowski (a1) and N. Raver (a1)


Obese protein (OB) also known as leptin serves as a protein signal secreted from adipose tissue and acts on a central nervous system that regulate ingestive behavior and energy balance (Campfield, 2000). The sequence of various leptins from 10 mammalian species was compiled and the 3D structure of human leptin mutant W100E was elucidated (Zhang et al., 1997). We have prepared recombinant leptins of sheep, chicken, cow and pig. Mammalian and chicken leptins are respectively 146 and 145 amino acid containing proteins found in circulation. Leptin in blood is found in both free and bound form; the main binding protein is the extracellular domain (ECD) of leptin receptor (Liu et al., 1997). One of the established functions of leptin, is its attenuating effect on the expression of NPY and other neuropeptides in hypothalamus that subsequently leads to decreased food intake (Campfield, 2000). Therefore it seems logical that blocking leptin receptors that are responsible for transferring it through the blood-brain barrier or for its action in hypothalamus will lead to increase in food intake. Leptin receptor belongs to cytokine receptor superfamily. Its ECD consists of ∷ 800 amino acids but it was suggested that only the cytokine homology subdomain II (CHD) consisting of ∷ 200 amino acids is responsible for binding (Fong et al., 1997). The objective of the present work is to prepare recombinant proteins aimed to block leptin action. We suggest two approaches (a) preparation of leptin antagonists capable of binding but not homodimerizing leptin receptors and (b) subcloning and preparing CHD II of leptin receptor responsible for binding of the hormone.



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Campfield, L.A. 2000. Central mechanisms responsible for the actions of OB protein (leptin) on food intake, metabolism and body energy storage. Frontiers of Hormone Research 26: 2612.
Fong, T.M., Huang, R.R., Tota, M.R., Mao, C., Smith, T., Varnerin, J., Karpitskiy, V.V., Krause, J.E. and Van der Ploeg, L.H. 1998. Localization of leptin binding domain in the leptin receptor. Molecular Pharmacology 53: 53234.
Liu, C., Liu, X.J., Barry, G., Ling, N., Maki, R.A. and De Souza, E.B. 1997. Expression and characterization of a putative high affinity human soluble leptin receptor. Endocrinology 138: 1383548.
Zhang, F., Basinski, M.B., Beals, J.M., Briggs, S.L., Churgay, L.M., Clawson, D.K., DiMarchi, R.D., Furman, T.C., Hale, J.E., Hsiung, H.M., Schoner, B.E., Smith, D.P., Zhang, X,Y., Wery, J-P. and Schweitz, R.W. 1997. Crystal structure of the obese protein leptin-E100. Nature (London) 387: 387206.

Recombinant leptin mutants and leptin binding proteins aimed to block leptin action in vivo

  • A. Gertler (a1), Y. Sandowski (a1) and N. Raver (a1)


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