A novel leptin receptor antagonist uncouples leptin’s metabolic and immune functions

• DOI: 10.1007/s00018-019-03004-9
• Publication Date: 2019-01-18T05:27:28Z
• Authors: Lennart Zabeau; Joris Wauman; Julie Dam; Sandra Van Lint; Elianne Burg; Jennifer De Geest; Elke Rogge; Anisia Silva; Ralf Jockers; Jan Tavernier
• Keywords: Leptin receptor

Leptin links body energy stores to high demanding processes like reproduction and immunity. Based on leptin's role in autoimmune diseases cancer, several leptin receptor (LR) antagonists have been developed, but these intrinsically lead unwanted weight gain. Here, we report the uncoupling of metabolic immune functions based cross talk with epidermal growth factor (EGFR). We show that both receptors spontaneously interact and, remarkably, this complex can partially overrule lack LR activation by a antagonistic mutein. Moreover, mutant induces EGFR phosphorylation comparable wild-type leptin. Exploiting non-canonical signalling pathway, identified camelid single-domain antibody selectively inhibits LR-EGFR without interfering homotypic signalling. Administration vivo showed did not interfere functions, could reverse leptin-driven protection against starvation-induced thymic splenic atrophy. These findings offer new opportunities for design clinical application selective avoid side effects.