leptin_receptor_activation

Leptin receptor activation

From insights in the activation of the leptin receptor to the design of leptin antagonists.

Leptin is primarily produced by adipocytes, and functions in a negative feedback loop acting on neuronal cells in the hypothalamus. Inactivating mutations in the leptin or leptin receptor (LR) genes lead to a complex syndrome with a marked obese phenotype in both mice and man. Several peripheral functions have also been ascribed to leptin and evidence for a pathogenic role in cardiovascular and several autoimmune diseases as well as in tumour progression is accumulating, thus providing a rationale for the development of leptin antagonists.

We study the events leading to ligand-induced leptin receptor activation and the signalling pathways emanating from the activated receptor complex.

Molecular modelling combined with detailed mutagenesis analysis has led us to propose a detailed model for leptin/LR complex formation. We have identified three receptor interaction sites on leptin and introduction of mutations in site III has generated a leptin mutein with antagonistic properties in vitro and in vivo. More recently, several neutralising nanobodies targeting the leptin receptor have been obtained. Nanobodies comprise the antigen-binding domain of naturally occurring single-chain antibodies and do not generally cross the blood-brain barrier. Beside studying leptin's role in disease models, these different leptin antagonists may be useful tools to dissect the central versus peripheral effects of leptin.

Model for a hexameric leptin-leptin receptor complex (image courtesy of F. Peelman)
Model for a hexameric leptin-leptin receptor complex (image courtesy of F. Peelman)

The cytosolic domain of the leptin receptor contains three conserved tyrosine residues. We are charting the various signalling pathways that couple to each of these recruitment sites using biochemical approaches and using the in-cell MAPPIT technique. Both downstream signalling and feedback inhibitory pathways, e.g. by SOCS proteins, are being studied. Findings from such studies may be relevant to leptin resistance, a condition that underlies human obesity.

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