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.

The adhesion GPCR and PCP component flamingo (FMI-1) alters body size and regulates the composition of the extracellular matrix.

The extracellular matrix (ECM) is a network of macromolecules that presents a vital scaffold for cells and enables multiple ways of cellular communication. Thus, it is essential for many physiological processes such as development, tissue morphogenesis, homeostasis, the shape and partially the size of the body and its organs. To ensure these, the composition of the ECM is tissue-specific and highly dynamic. ECM homeostasis is therefore tightly controlled by several mechanisms. Here, we show that FMI-1, the homolog of the Adhesion GPCR Flamingo/CELSR/ADGRC in the nematode Caenorhabditis elegans, modulates the composition of the ECM by controlling the production both of ECM molecules such as collagens and also of ECM modifying enzymes. Thereby, FMI-1 affects the morphology and functionality of the nematode´s cuticle, which is mainly composed of ECM, and also modulates the body size. Mechanistic analyses highlight the fact that FMI-1 exerts its function from neurons non-cell autonomously (trans) solely via its extracellular N terminus. Our data support a model, by which the activity of the receptor, which has a well-described role in the planar cell polarity (PCP) pathway, involves the PCP molecule VANG-1, but seems to be independent of the DBL-1/BMP pathway.

Photoluminescence properties of tetrahedral zinc(ii) complexes supported by calix[4]arene-based salicylaldiminato ligands.

The synthesis and photophysical properties of four new hybrid salicylaldiminato-calix[4]arene ligands and their corresponding zinc(ii) complexes are described. The Schiff bases were obtained from condensation reactions between cone-25,27-di(aminoethoxy)-26,28-dihydroxy-calix[4]arene and salicylaldehyde (H2L1) or o-vanillin (H2L2) and 1,3-alt-25,27-di(aminoethoxy)-26,28-di(n-propyloxy)-calix[4]arene and 3,5-di-tert-butyl-salicylaldehyde (H2L3) or o-vanillin (H2L4). Complexation reactions were investigated by ESI-MS, IR, NMR, UV-vis absorption and steady-state and time resolved fluorescence spectroscopy, and X-ray crystallography. All ligands support 1 : 1 complexes (ZnL1-ZnL4), with equilibrium constants derived from absorption spectrophotometry in the range log K11 = 5.5-8.2 (MeCN or MeOH/CH2Cl2, I = 0.01 M). The zinc complexes show blue fluorescence, both in solution as well as in the solid state, with λem, Φf, and τ ranging from 472-504 nm, 0.11-0.60, and 2-9 ns, respectively. The nature of the substituents on the salicylaldiminato fragments was found to be the main parameter that influences the photophysical properties of the zinc complexes. Insights into the electronic nature of the UV-vis transitions were obtained with time dependent density functional theory (TD-DFT) calculations.

Zn2+ -Ion Sensing by Fluorescent Schiff Base Calix[4]arene Macrocycles.

A macrocyclic ligand (H2 L) containing two o,o'-bis(iminomethyl)phenol and two calix[4]arene head units has been synthesized and its coordination chemistry towards divalent Ni and Zn investigated. The new macrocycle forms complexes of composition [ML] (M=Zn, M=Ni) and [ZnL(py)2 ], which were characterized by elemental analysis; IR, UV/Vis, and NMR spectroscopy; electrospray ionization mass spectrometry (ESI-MS); and X-ray crystallography (for [ZnL(py)2 ] and [NiL]). H2 L allows the sensitive optical detection of Zn2+ among a series of biologically relevant metal ions by a dual fluorescence enhancement/quenching effect in solution. The fluorescence intensity of the macrocycle increases by a factor of ten in the presence of Zn2+ with a detection limit in the lower nanomolar region.