Abstract
Leptin links body energy stores to high energy demanding processes like reproduction and immunity. Based on leptin’s role in autoimmune diseases and cancer, several leptin and leptin receptor (LR) antagonists have been developed, but these intrinsically lead to unwanted weight gain. Here, we report on the uncoupling of leptin’s metabolic and immune functions based on the cross talk with the epidermal growth factor receptor (EGFR). We show that both receptors spontaneously interact and, remarkably, that this complex can partially overrule the lack of LR activation by a leptin antagonistic mutein. Moreover, this leptin mutant induces EGFR phosphorylation comparable to wild-type leptin. Exploiting this non-canonical leptin signalling pathway, we identified a camelid single-domain antibody that selectively inhibits this LR-EGFR cross talk without interfering with homotypic LR signalling. Administration in vivo showed that this single-domain antibody did not interfere with leptin’s metabolic functions, but could reverse the leptin-driven protection against starvation-induced thymic and splenic atrophy. These findings offer new opportunities for the design and clinical application of selective leptin and LR antagonists that avoid unwanted metabolic side effects.
Highlights
The crucial role of leptin in long-term body weight control is well established
We evaluated the role of the immunoglobulin-like domain (IGD) in ligand-independent clustering of the leptin receptor (LR) and epidermal growth factor receptor (EGFR) using co-immunoprecipitation, TR-FRET [52, 53] and the mammalian two-hybrid Kinase substrate sensor (KISS) method [54]
The observation that both LR and LR-FATT are able to pull down the EGFR (Fig. 1a) indicates that the interaction between both receptors is independent of the presence of LR IGD
Summary
The crucial role of leptin in long-term body weight control is well established. This cytokine with hormone-like characteristics is mainly, but not exclusively, produced and secreted by adipocytes, and plasma leptin levels positively correlate with body fat energy stores [1, 2]. Loss-of-function mutations in the leptin-encoding ob gene give rise to a complex syndrome that includes morbid obesity, and abnormalities in lipid and glucose metabolism [3], haematopoiesis [4], innate and adaptive immunity (leading to increased risk of infection in mice and men) [5,6,7,8,9], reproduction [10], development [11], angiogenesis [12], vascular remodelling [13], blood pressure [14], and bone formation [15]. Clinical reports unequivocally link elevated serum leptin levels (caused by obesity) to an increased risk of certain cancers including prostate [28], breast [29, 30], colorectal [31], renal cancers [32] and multiple myeloma [33, 34]
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