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)
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. It is also in this context that we are developing selective antagonists that can uncouple leptin's metabolic and immune regulatory functions.
Related publications:
- Zabeau et al. The Ins and Outs of Leptin Receptor activation. FEBS Lett. (2002)
- Peelman et al. Leptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases. Prog. Lipid Res. (2004)
- Peelman et al. New pharmacological perspectives for the leptin receptor. Trends Pharmacol. Sci. (2006)
- Wauman et al. Insulin receptor substrate 4 couples the leptin receptor to multiple signaling pathways. Mol. Endocrinol. (2008)
- Zabeau et al. Selection of non-competitive leptin antagonists using a random nanobody-based approach. Biochem. J. (2012)
- Moharana et al. Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins. Structure (2014)
- Peelman et al. 20 years of leptin: insights into signaling assemblies of the leptin receptor. J. Endocrinol. (2014)
- Zabeau et al. Leptin's metabolic and immune functions can be uncoupled at the ligand/receptor interaction level. Cell Mol. Life Sci. (2015)
- Wauman et al. The Leptin Receptor Complex: Heavier Than Expected? Front Endocrinol. (2017)
- Wauman et al. The intracellular domain of the leptin receptor prevents mitochondrial depolarization and mitophagy. Biochim. Biophys. Acta. Mol Cell Res. (2018)
- Zabeau et al. A novel leptin receptor antagonist uncouples leptin's metabolic and immune functions. Cell Mol. Life Sci. (2019)
