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Updated: May 30, 2026
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Selection of Transporter-Targeted Inhibitory Nanobodies by Solid-Supported-Membrane (SSM)-Based Electrophysiology
Published on: May 3, 2021
Selection of non-competitive leptin antagonists using a random nanobody-based approach
Lennart Zabeau1, Annick Verhee, Dominiek Catteeuw
1Flanders Institute for Biotechnology, Department of Medical Protein Research, Ghent University, Faculty of Medicine and Health Sciences, A. Baertsoenkaai 3, 9000 Ghent, Belgium.
The Biochemical Journal
|August 20, 2011
Summary
Researchers developed nanobodies that block leptin receptor signaling without preventing leptin binding. These tools can study leptin transport and its role in diseases, offering new therapeutic avenues.
Area of Science:
- Immunology
- Endocrinology
- Neuroscience
Background:
- Leptin, an adipocyte-derived cytokine, regulates metabolism and links it to energy-consuming processes like reproduction and immunity.
- Leptin's involvement in pathologies such as autoimmune diseases and cancer necessitates the development of leptin antagonists.
- Leptin receptor (LR) signaling is crucial for various physiological functions, making it a target for therapeutic intervention.
Purpose of the Study:
- To generate and characterize neutralizing nanobodies targeting the leptin receptor (LR).
- To investigate whether LR signaling can be blocked independently of leptin binding.
- To explore the potential of these nanobodies as tools for studying leptin transport and LR inhibition in disease models.
Main Methods:
- Generation and evaluation of a panel of nanobodies targeting different LR subdomains (CRH2, Ig-like, FNIII).
- Assessing the effect of nanobodies on leptin binding to the LR.
- Analyzing the impact of specific nanobodies on leptin-dependent hypothalamic NPY expression and physiological parameters in vivo.
Main Results:
- Identified three classes of neutralizing nanobodies targeting distinct LR subdomains.
- Nanobodies targeting the CRH2 domain inhibited leptin binding, while those targeting the Ig-like domain blocked leptin signaling without affecting binding.
- A nanobody targeting the Ig-like domain disrupted leptin-dependent NPY regulation, leading to increased body weight, fat content, food intake, liver size, and serum insulin levels, mimicking leptin deficiency.
Conclusions:
- Demonstrated the feasibility of blocking LR signaling independently of ligand binding using specific nanobodies.
- These novel nanobodies serve as valuable tools for investigating blood-brain barrier leptin transport and the role of LR inhibition in disease pathogenesis.
- The findings support current models of activated LR complex and offer new avenues for therapeutic strategies targeting leptin signaling pathways.
