GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.

Growth differentiation factor 15 (GDF15), a distant member of the transforming growth factor (TGF)-ß family, is a secreted protein that circulates as a 25-kDa dimer. In humans, elevated GDF15 correlates with weight loss, and the administration of GDF15 to mice with obesity reduces body weight, at least in part, by decreasing food intake. The mechanisms through which GDF15 reduces body weight remain poorly understood, because the cognate receptor for GDF15 is unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), a distant relative of receptors for a distinct class of the TGF-ß superfamily ligands. Gfral is expressed in neurons of the area postrema and nucleus of the solitary tract in mice and humans, and genetic deletion of the receptor abrogates the ability of GDF15 to decrease food intake and body weight in mice. In addition, diet-induced obesity and insulin resistance are exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a new regulator of body weight and as the bona fide receptor mediating the metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as a potential pharmacotherapy for the treatment of obesity.

Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs.

A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Ethanol potentiates the TRPV1-mediated cough in the guinea pig.

Ethanol is a chemical irritant able to induce a large variety of effects in the airways. It has been reported that ethanol sensitizes the transient receptor potential vanilloid-1 (TRPV1) to various stimuli and inhalation of ethanol enhances the cough mediated by TRPV1 activation (capsaicin) in patients suffering of airway sensory hyperreactivity. Here, we set out to investigate whether ethanol sensitizes the cough induced by TRPV1 activation in a guinea pig model and the possible mechanism of such exacerbating effect. Aerosolized resiniferatoxin (RTX, 0.5 microM) and hypertonic saline (7%) produced a cough response dependent and independent of TRPV1 activation, respectively. Ethanol (3%, 10 min) inhalation, that per se did not cause any tussive response, significantly increased the number of coughs evoked by RTX inhalation without affecting hypertonic saline (7%) induced cough. Potentiation by ethanol of the tussive response to RTX was prevented by the PKC inhibitor, GF109203X (GFX). In conclusion, ethanol selectively exaggerates, via a PKC-dependent pathway, the cough response evoked by TRPV1 stimulation. The present results may contribute to explain respiratory distresses sometimes associated to alcohol consumption, including cough and asthma.