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Selection of non-competitive leptin antagonists using a random nanobody-based approach

Lennart Zabeau (UGent) , Annick Verhee (UGent) , Dominiek Catteeuw (UGent) , Liesbeth Faes, Sylvie Seeuws (UGent) , Tine Decruy (UGent) , Dirk Elewaut (UGent) , Frank Peelman (UGent) and Jan Tavernier (UGent)
(2012) BIOCHEMICAL JOURNAL. 441(1). p.425-434
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Abstract
The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidence suggests that leptin plays a role in human pathologies, such as autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In the present study, we generated and evaluated a panel of neutralizing nanobodies targeting the LR (leptin receptor). A nanobody comprises the variable domain of the naturally occurring single-chain antibodies found in members of the Camelidae family. We identified three classes of neutralizing nanobodies targeting different LR subdomains: i.e. the CRH2 (cytokine receptor homology 2), Ig-like and FNIII (fibronectin type III) domains. Only nanobodies directed against the CRH2 domain inhibited leptin binding. We could show that a nanobody that targets the Ig-like domain potently interfered with leptin-dependent regulation of hypothalamic NPY (neuropeptide Y) expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All of these characteristics resemble the phenotype of leptin and LR-deficient animals. The results of the present study support proposed models of the activated LR complex, and demonstrate that it is possible to block LR signalling without affecting ligand binding. These nanobodies form new tools to study the mechanisms of BBB (blood-brain barrier) leptin transport and the effect of LR inhibition in disease models.
Keywords
DOMAIN, BRAIN, WEIGHT, HYPOTHALAMUS, IDENTIFICATION, ACTIVATION, RECEPTOR, DB/DB MICE, OBESE GENE, BINDING-SITE-III, signalling, receptor activation, nanobody, leptin receptor (LR), body weight

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Please use this url to cite or link to this publication:

Chicago
Zabeau, Lennart, Annick Verhee, Dominiek Catteeuw, Liesbeth Faes, Sylvie Seeuws, Tine Decruy, Dirk Elewaut, Frank Peelman, and Jan Tavernier. 2012. “Selection of Non-competitive Leptin Antagonists Using a Random Nanobody-based Approach.” Biochemical Journal 441 (1): 425–434.
APA
Zabeau, L., Verhee, A., Catteeuw, D., Faes, L., Seeuws, S., Decruy, T., Elewaut, D., et al. (2012). Selection of non-competitive leptin antagonists using a random nanobody-based approach. BIOCHEMICAL JOURNAL, 441(1), 425–434.
Vancouver
1.
Zabeau L, Verhee A, Catteeuw D, Faes L, Seeuws S, Decruy T, et al. Selection of non-competitive leptin antagonists using a random nanobody-based approach. BIOCHEMICAL JOURNAL. 2012;441(1):425–34.
MLA
Zabeau, Lennart, Annick Verhee, Dominiek Catteeuw, et al. “Selection of Non-competitive Leptin Antagonists Using a Random Nanobody-based Approach.” BIOCHEMICAL JOURNAL 441.1 (2012): 425–434. Print.
@article{2055143,
  abstract     = {The adipocyte-derived cytokine leptin acts as a metabolic switch, connecting the body's metabolism to high-energy consuming processes such as reproduction and immune responses. Accumulating evidence suggests that leptin plays a role in human pathologies, such as autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In the present study, we generated and evaluated a panel of neutralizing nanobodies targeting the LR (leptin receptor). A nanobody comprises the variable domain of the naturally occurring single-chain antibodies found in members of the Camelidae family. We identified three classes of neutralizing nanobodies targeting different LR subdomains: i.e. the CRH2 (cytokine receptor homology 2), Ig-like and FNIII (fibronectin type III) domains. Only nanobodies directed against the CRH2 domain inhibited leptin binding. We could show that a nanobody that targets the Ig-like domain potently interfered with leptin-dependent regulation of hypothalamic NPY (neuropeptide Y) expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All of these characteristics resemble the phenotype of leptin and LR-deficient animals. The results of the present study support proposed models of the activated LR complex, and demonstrate that it is possible to block LR signalling without affecting ligand binding. These nanobodies form new tools to study the mechanisms of BBB (blood-brain barrier) leptin transport and the effect of LR inhibition in disease models.},
  author       = {Zabeau, Lennart and Verhee, Annick and Catteeuw, Dominiek and Faes, Liesbeth and Seeuws, Sylvie and Decruy, Tine and Elewaut, Dirk and Peelman, Frank and Tavernier, Jan},
  issn         = {0264-6021},
  journal      = {BIOCHEMICAL JOURNAL},
  keyword      = {DOMAIN,BRAIN,WEIGHT,HYPOTHALAMUS,IDENTIFICATION,ACTIVATION,RECEPTOR,DB/DB MICE,OBESE GENE,BINDING-SITE-III,signalling,receptor activation,nanobody,leptin receptor (LR),body weight},
  language     = {eng},
  number       = {1},
  pages        = {425--434},
  title        = {Selection of non-competitive leptin antagonists using a random nanobody-based approach},
  url          = {http://dx.doi.org/10.1042/BJ20110438},
  volume       = {441},
  year         = {2012},
}

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