Selection of non-competitive leptin antagonists using a random nanobody-based approach.
Summary of "Selection of non-competitive leptin antagonists using a random nanobody-based approach."
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 like autoimmune diseases and cancer, thus providing a rationale for the development of leptin antagonists. In this study, we generated and evaluated a panel of neutralizing nanobodies targeting the leptin receptor (LR). 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, Ig-like and FNIII 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 neuropeptide Y expression. As a consequence, daily intraperitoneal injection increased body weight, body fat content, food intake, liver size and serum insulin levels. All these characteristics resemble the phenotype of leptin and LR deficient animals. Our data 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 blood-brain-barrier leptin transport and the effect of LR inhibition in disease models.
Affiliation
Journal Details
This article was published in the following journal.
Name: The Biochemical journal
ISSN: 1470-8728
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21851341
- DOI: http://dx.doi.org/10.1042/BJ20110438
Medical and Biotech [MESH] Definitions
Receptors, Leptin
Cell surface receptors for obesity factor (LEPTIN), a hormone secreted by the WHITE ADIPOCYTES. Upon leptin-receptor interaction, the signal is mediated through the JAK2/STAT3 pathway to regulate food intake, energy balance and fat storage.
Leptin
A 16-kDa peptide hormone secreted from WHITE ADIPOCYTES. Leptin serves as a feedback signal from fat cells to the CENTRAL NERVOUS SYSTEM in regulation of food intake, energy balance, and fat storage.
Mating Preference, Animal
The selection or choice of sexual partner in animals. Often this reproductive preference is based on traits in the potential mate, such as coloration, size, or behavioral boldness. If the chosen ones are genetically different from the rejected ones, then NATURAL SELECTION is occurring.
Selection, Genetic
Differential and non-random reproduction of different genotypes, operating to alter the gene frequencies within a population.
Calcium Channels, L-type
Long-lasting voltage-gated CALCIUM CHANNELS found in both excitable and nonexcitable tissue. They are responsible for normal myocardial and vascular smooth muscle contractility. Five subunits (alpha-1, alpha-2, beta, gamma, and delta) make up the L-type channel. The alpha-1 subunit is the binding site for calcium-based antagonists. Dihydropyridine-based calcium antagonists are used as markers for these binding sites.
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