Dysfunction of the adhesion G protein-coupled receptor latrophilin 1(ADGRL1/LPHN1)increases the risk of obesity

Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence.Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity.G protein-coupled receptors(GPCRs)are among the main modulators of metabolism and energy balance.They,for instance,regulate appetite and satiety in certain hypothalamic neurons,as well as glucose and lipid metabolism and hormone secretion from adipocytes.Mutations in some GPCRs,such as the melanocortin receptor type 4(MC4R),have been associated with early-onset obesity.Here,we identified the adhesion GPCR latrophilin 1(ADGRL1/LPHN1)as a member of the regulating network governing food intake and the maintenance of energy balance.Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity,accompanied by dysregulation of glucose homeostasis.Consistently,we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity.Therefore,we propose that LPHN1 dysfunction is a risk factor for obesity development.

Stachel-mediated activation of adhesion G protein-coupled receptors:insights from cryo-EM studies

Recently,a set of cryo-electron microscopy(cryo-EM)structures of different adhesion G protein-coupled receptors(aGPCRs)has been published by Xiao et al.1,Ping et al.2,Qu et al.3,and Barros-Álvarez et al.4 shedding light on the activation of the seven-helix transmembrane domain(7TMD)via their tethered peptide agonist.Adhesion GPCRs are an evolutionary old class of receptors that play a key role in several physiological processes including neuron and synapse formation,immune response,and metabolism.They are unique within the superfamily of GPCRs because they combine the structural features of adhesive molecules,mediating cell–cell or cell–matrix interaction,with intracellular G protein-mediated signalling.The long extracellular N terminus of the receptor harbours distinct functional domains including the highly conserved GPCR autoproteolysis-inducing(GAIN)domain with the GPCR proteolysis site(GPS).Many,but not all aGPCRs are autoproteolytically cleaved at the GPS into a N-and a C-terminal fragment(NTF and CTF,respectively),which remain non-covalently attached.