Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.
Background:The relevance of the widely expressed GPCR P2Y 14 is only partially understood. Results: Analysis of P2Y 14 -KO mice revealed decreased gastrointestinal emptying, reduced glucose tolerance, and insulin release. Conclusion: P2Y 14 function is required for proper intestine emptying and adequate glucose response. Significance: P2Y 14 plays a role in smooth muscle function and maintaining energy homeostasis by influencing insulin release.
Seven-transmembrane
receptors signal via G-protein- and β-arrestin-dependent
pathways. We describe a peripheral CB
1
R antagonist (MRI-1891)
highly biased toward inhibiting CB
1
R-induced β-arrestin-2
(βArr2) recruitment over G-protein activation. In obese wild-type
and βArr2-knockout (KO) mice, MRI-1891 treatment reduces food
intake and body weight without eliciting anxiety even at a high dose
causing partial brain CB
1
R occupancy. By contrast, the
unbiased global CB
1
R antagonist rimonabant elicits anxiety
in both strains, indicating no βArr2 involvement. Interestingly,
obesity-induced muscle insulin resistance is improved by MRI-1891
in wild-type but not in βArr2-KO mice. In C2C12 myoblasts, CB
1
R activation suppresses insulin-induced akt-2 phosphorylation,
preventable by MRI-1891, βArr2 knockdown or overexpression of
CB
1
R-interacting protein. MRI-1891, but not rimonabant,
interacts with nonpolar residues on the N-terminal loop, including
F108, and on transmembrane helix-1, including S123, a combination
that facilitates βArr2 bias. Thus, CB
1
R promotes
muscle insulin resistance via βArr2 signaling, selectively mitigated
by a biased CB
1
R antagonist at reduced risk of central
nervous system (CNS) side effects.
Skeletal muscle (SKM) insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Because G-protein–coupled receptors (GPCRs) represent excellent drug targets, we hypothesized that activation of specific functional classes of SKM GPCRs might lead to improved glucose homeostasis in type 2 diabetes. At present, little is known about the in vivo metabolic roles of the various distinct GPCR signaling pathways operative in SKM. In this study, we tested the hypothesis that selective activation of SKM Gq signaling can improve SKM glucose uptake and whole-body glucose homeostasis under physiological and pathophysiological conditions. Studies with transgenic mice expressing a Gq-linked designer GPCR selectively in SKM cells demonstrated that receptor-mediated activation of SKM Gq signaling greatly promoted glucose uptake into SKM and significantly improved glucose homeostasis in obese, glucose-intolerant mice. These beneficial metabolic effects required the activity of SKM AMPK. In contrast, obese mutant mice that lacked both Gαq and Gα11 selectively in SKM showed severe deficits in glucose homeostasis. Moreover, GPCR-mediated activation of Gq signaling also stimulated glucose uptake in primary human SKM cells. Taken together, these findings strongly suggest that agents capable of enhancing SKM Gq signaling may prove useful as novel antidiabetic drugs.
Most in vivo effects of 3-iodothyronamine (3-T1AM) have been thus far thought to be mediated by binding at the trace amine-associated receptor 1 (TAAR1). Inconsistently, the 3-T1AM-induced hypothermic effect still persists in Taar1 knockout mice, which suggests additional receptor targets. In support of this general assumption, it has previously been reported that 3-T1AM also binds to the a-2A-adrenergic receptor (ADRA2A), which modulates insulin secretion. However, the mechanism of this effect remains unclear. We tested two different scenarios that may explain the effect: the sole action of 3-T1AM at ADRA2A and a combined action of 3-T1AM at ADRA2A and TAAR1, which is also expressed in pancreatic islets. We first investigated a potential general signaling modification using the label-free EPIC technology and then specified changes in signaling by cAMP inhibition and MAPKs (ERK1/2) determination. We found that 3-T1AM induced G i/o activation at ADRA2A and reduced the norepinephrine (NorEpi)-induced MAPK activation. Interestingly, in ADRA2A/TAAR1 hetero-oligomers, application of NorEpi resulted in uncoupling of the G i/o signaling pathway, but it did not affect MAPK activation. However, 3-T1AM application in mice over a period of 6 days at a daily dose of 5 mg/kg had no significant effects on glucose homeostasis. In summary, we report an agonistic effect of 3-T1AM on the ADRA2A-mediated G i/o pathway but an antagonistic effect on MAPK induced by NorEpi. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate G i/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.Key Words " G protein-coupled receptor " adrenergic receptor
Designer receptors exclusively activated by a designer drug (DREADDs) are clozapine-N-oxide-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, clozapine-N-oxide-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger -arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein-mediated versus -arrestin-mediated signaling in different cell types or physiological processes, the availability of G proteinand -arrestin-biased DREADDs would be highly desirable. In this study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M 3 muscarinic receptor that can activate G q/11 with high efficacy but lacks the ability to interact with -arrestins. We also demonstrate that this novel DREADD is active in vivo and that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (G q/11 )-dependent versus -arrestin-dependent signaling in hepatocytes. Thus, this novel G q/11 -biased DREADD represents a powerful new tool to study the physiological relevance of G q/11 -dependent signaling in distinct tissues and cell types, in the absence of -arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of side effects.
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