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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
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
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
journal title
BIOCHEMICAL JOURNAL
Biochem. J.
volume
441
issue
1
pages
425 - 434
Web of Science type
Article
Web of Science id
000298940900041
JCR category
BIOCHEMISTRY & MOLECULAR BIOLOGY
JCR impact factor
4.654 (2012)
JCR rank
61/288 (2012)
JCR quartile
1 (2012)
ISSN
0264-6021
DOI
10.1042/BJ20110438
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2055143
handle
http://hdl.handle.net/1854/LU-2055143
date created
2012-03-01 11:44:16
date last changed
2012-04-05 10:09:31
@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},
}

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.