scholarly journals Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Ken-ichiro Nakajima ◽  
Zhenzhong Cui ◽  
Chia Li ◽  
Jaroslawna Meister ◽  
Yinghong Cui ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Potential Role ◽  
G Protein Coupled Receptors ◽  
Signalling Cascades ◽  
Treatment Of Obesity ◽  
G Protein Coupled ◽  
Stimulation Of ◽  
Sustained Increase

Abstract 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.

scholarly journals Potential metabolic and behavioural roles of the putative endocannabinoid receptors GPR18, GPR55 and GPR119 in feeding

2019 ◽  
Vol 17 (10) ◽  
pp. 947-960 ◽  
Author(s):  
Ricardo E. Ramírez-Orozco ◽  
Ricardo García-Ruiz ◽  
Paula Morales ◽  
Carlos M. Villalón ◽  
J. Rafael Villafán-Bernal ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Eating Behaviour ◽  
Endocannabinoid System ◽  
G Protein Coupled Receptors ◽  
Know How ◽  
Feeding Control ◽  
G Protein Coupled

: Endocannabinoids are ancient biomolecules involved in several cellular (e.g., metabolism) and physiological (e.g., eating behaviour) functions. Indeed, eating behaviour alterations in marijuana users have led to investigate the orexigenic/anorexigenic effects of cannabinoids in animal/ human models. This increasing body of research suggests that the endocannabinoid system plays an important role in feeding control. Accordingly, within the endocannabinoid system, cannabinoid receptors, enzymes and genes represent potential therapeutic targets for dealing with multiple metabolic and behavioural dysfunctions (e.g., obesity, anorexia, etc.). Paradoxically, our understanding on the endocannabinoid system as a cellular mediator is yet limited. For example: (i) only two cannabinoid receptors have been classified, but they are not enough to explain the pharmacological profile of several experimental effects induced by cannabinoids; and (ii) several orphan G protein-coupled receptors (GPCRs) interact with cannabinoids and we do not know how to classify them (e.g., GPR18, GPR55 and GPR119; amongst others). : On this basis, the present review attempts to summarize the lines of evidence supporting the potential role of GPR18, GPR55 and GPR119 in metabolism and feeding control that may explain some of the divergent effects and puzzling data related to cannabinoid research. Moreover, their therapeutic potential in feeding behaviour alterations will be considered.

scholarly journals Urocortins in the mammalian endocrine system

2019 ◽  
Vol 61 (1) ◽  
Author(s):  
Caterina Squillacioti ◽  
Alessandra Pelagalli ◽  
Giovanna Liguori ◽  
Nicola Mirabella
Keyword(s):  
Endocrine Cells ◽  
Potential Role ◽  
Endocrine System ◽  
Reproductive Organs ◽  
G Protein Coupled Receptors ◽  
Main Role ◽  
G Protein Coupled

Abstract Urocortins (Ucns), peptides belonging to the corticotropin-releasing hormone (CRH) family, are classified into Ucn1, Ucn2, and Ucn3. They are involved in regulating several body functions by binding to two G protein-coupled receptors: receptor type 1 (CRHR1) and type 2 (CRHR2). In this review, we provide a historical overview of research on Ucns and their receptors in the mammalian endocrine system. Although the literature on the topic is limited, we focused our attention particularly on the main role of Ucns and their receptors in regulating the hypothalamic–pituitary–adrenal and thyroid axes, reproductive organs, pancreas, gastrointestinal tract, and other tissues characterized by “diffuse” endocrine cells in mammals. The prominent function of these peptides in health conditions led us to also hypothesize an action of Ucn agonists/antagonists in stress and in various diseases with its critical consequences on behavior and physiology. The potential role of the urocortinergic system is an intriguing topic that deserves further in-depth investigations to develop novel strategies for preventing stress-related conditions and treating endocrine diseases.

scholarly journals Normal Food Intake and Body Weight in Mice Lacking the G Protein-Coupled Receptor GPR39

Endocrinology ◽  
2007 ◽  
Vol 148 (2) ◽  
pp. 501-506 ◽  
Author(s):  
Frédéric Tremblay ◽  
Mylène Perreault ◽  
Lori D. Klaman ◽  
James F. Tobin ◽  
Erica Smith ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
G Protein ◽  
Ectopic Expression ◽  
Phenotypic Characterization ◽  
Wild Type ◽  
G Protein Coupled Receptor ◽  
Multiple Sources ◽  
G Protein Coupled

It has been recently proposed that obestatin, a peptide encoded by the ghrelin gene, reduces food intake by activating the orphan G protein-coupled receptor GPR39. To gain further insights into the role of GPR39 in body weight homeostasis, we characterized the phenotype of mice with targeted disruption of the GPR39 gene. Body weight, adiposity, and food intake were found to be similar between GPR39+/+ and GPR39−/− mice. Furthermore, fasting glucose and insulin levels were similar between both genotypes. Injection of obestatin peptide (1 μmol/kg, ip) obtained from multiple sources did not consistently inhibit food intake in wild-type mice after an overnight fast, and no difference in food intake was observed between wild-type and GPR39 knockout mice after injection of the peptide. Finally, ectopic expression of GPR39 in HEK293T cells revealed a constitutive activation of the receptor that was unaffected by stimulation with obestatin. Our phenotypic characterization suggests that GPR39 is not a major modulator of food intake in mice, although a more subtle role cannot be excluded. The role of GPR39 in normal physiology requires further study and should be conducted independently of the function of obestatin.

scholarly journals The Roles of GRKs in Hemostasis and Thrombosis

2020 ◽  
Vol 21 (15) ◽  
pp. 5345
Author(s):  
Xi Chen ◽  
Xuefei Zhao ◽  
Matthew Cooper ◽  
Peisong Ma
Keyword(s):  
Platelet Activation ◽  
Potential Role ◽  
Thrombus Formation ◽  
Feedback Regulation ◽  
Cerebrovascular Diseases ◽  
G Protein Coupled Receptors ◽  
Heart Attacks ◽  
Common Causes ◽  
G Protein Coupled

Along with cancer, cardiovascular and cerebrovascular diseases remain by far the most common causes of death. Heart attacks and strokes are diseases in which platelets play a role, through activation on ruptured plaques and subsequent thrombus formation. Most platelet agonists activate platelets via G protein-coupled receptors (GPCRs), which make these receptors ideal targets for many antiplatelet drugs. However, little is known about the mechanisms that provide feedback regulation on GPCRs to limit platelet activation. Emerging evidence from our group and others strongly suggests that GPCR kinases (GRKs) are critical negative regulators during platelet activation and thrombus formation. In this review, we will summarize recent findings on the role of GRKs in platelet biology and how one specific GRK, GRK6, regulates the hemostatic response to vascular injury. Furthermore, we will discuss the potential role of GRKs in thrombotic disorders, such as thrombotic events in COVID-19 patients. Studies on the function of GRKs during platelet activation and thrombus formation have just recently begun, and a better understanding of the role of GRKs in hemostasis and thrombosis will provide a fruitful avenue for understanding the hemostatic response to injury. It may also lead to new therapeutic options for the treatment of thrombotic and cardiovascular disorders.

scholarly journals A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?

2011 ◽  
Vol 164 (3) ◽  
pp. 405-412 ◽  
Author(s):  
N M Albiger ◽  
P Sartorato ◽  
B Mariniello ◽  
M Iacobone ◽  
I Finco ◽  
...  
Keyword(s):  
Primary Aldosteronism ◽  
Potential Role ◽  
Index Case ◽  
G Protein Coupled Receptors ◽  
Aldosterone Secretion ◽  
Normal Tissues ◽  
Gnrh Receptors ◽  
G Protein Coupled ◽  
In Pregnancy

ObjectiveThe mechanisms inducing steroidogenesis in primary aldosteronism (PA) remain poorly defined. It was recently demonstrated that some G-protein-coupled receptors are abnormally expressed in aldosterone-producing adenomas (APA). We evaluated the potential role of LH and GNRH receptors (LHR (or LHCGR) and GNRHR) in regulating aldosterone secretion in a patient with APA arising during pregnancy (index case) and in a subset of other patients with PA.Patients and methodsGNRH test was performed in the index case, 11 other PA, and 5 controls. GNRHR and LHR expressions were examined in 23 APA and 6 normal tissues.ResultsAldosterone response increased significantly (114%) in the index case after GNRH test was performed preoperatively, while it was blunted after adrenalectomy. Aldosterone also increased after human chorionic gonadotropin and triptorelin stimulation. A partial aldosterone response to GNRH was observed in other 7/11 PA, while a significant response was observed in two patients. Controls did not respond to GNRH test.GNRHR was overexpressed and LHR expression was moderate in the APA tissue from the index case. Moreover, LHR was found in normal adrenals and overexpressed in 6/22 APA. GNRHR was overexpressed in 6/22 APA, 2 of them with a 95- and 109-fold higher expression than normal. A correlation between the clinical and molecular findings was observed in five out of seven patients.ConclusionWe describe a case of PA diagnosed during pregnancy, which appeared to correlate with aberrant LHR and GNRHR expression. Our findings suggest that a subset of patients with PA has aberrant LHR and GNRHR expression, which could modulate aldosterone secretion.

Roux-en-Y Gastrointestinal Bypass Promotes Activation of TGR5 and Peptide YY

2020 ◽  
Vol 20 (8) ◽  
pp. 1262-1267
Author(s):  
Haojun Yang ◽  
Hanyang Liu ◽  
YuWen Jiao ◽  
Jun Qian
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Metabolic Diseases ◽  
Peptide Yy ◽  
The Body ◽  
Wild Type ◽  
L Cells ◽  
Body Weights ◽  
Gastrointestinal Bypass ◽  
G Protein Coupled

Background: G protein-coupled bile acid receptor (TGR5) is involved in a number of metabolic diseases. The aim of this study was to identify the role of TGR5 after Roux-en-Y gastric bypass (GBP). Methods: Wild type and TGR5 knockout mice (tgr5-/-) were fed a high-fat diet (HFD) to establish the obesity model. GBP was performed. The changes in body weight and food intake were measured. The levels of TGR5 and peptide YY (PYY) were evaluated by RT-PCR, Western blot, and ELISA. Moreover, the L-cells were separated from wild type and tgr5-/- mice. The levels of PYY in L-cells were evaluated by ELISA. Results: The body weights were significantly decreased after GBP in wild type mice (p<0.05), but not tgr5-/- mice (p>0.05). Food intake was reduced after GBP in wild type mice, but also not significantly affected in tgr5-/- mice (p>0.05). The levels of PYY were significantly increased after GBP compared with the sham group (p<0.05); however, in tgr5-/- mice the expression of PYY was not significantly affected (p>0.05). After INT-777 stimulation in L-cells obtained from murine intestines, the levels of PYY were significantly increased in L-cells tgr5+/+ (p<0.05). Conclusion: Our study suggests that GBP up-regulated the expression of TGR5 in murine intestines, and increased the levels of PYY, which further reduced food intake and decreased the body weight.

scholarly journals GPR40 reduces food intake and body weight through GLP-1

2017 ◽  
Vol 313 (1) ◽  
pp. E37-E47 ◽  
Author(s):  
Judith N. Gorski ◽  
Michele J. Pachanski ◽  
Joel Mane ◽  
Christopher W. Plummer ◽  
Sarah Souza ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Partial Agonist ◽  
Glucose Lowering ◽  
Partial Agonists ◽  
Lower Glucose ◽  
Glucagon Like Peptide 1 ◽  
Glucose Stimulated Insulin Secretion ◽  
G Protein Coupled

G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.

scholarly journals Heterodimerization Between the Lutropin and Follitropin Receptors is Associated With an Attenuation of Hormone-Dependent Signaling

Endocrinology ◽  
2013 ◽  
Vol 154 (10) ◽  
pp. 3925-3930 ◽  
Author(s):  
Xiuyan Feng ◽  
Meilin Zhang ◽  
Rongbin Guan ◽  
Deborah L. Segaloff
Keyword(s):  
Protein Interactions ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
G Protein Coupled Receptors ◽  
Fsh Receptor ◽  
Bioluminescence Resonance Energy Transfer ◽  
Protein Protein Interactions ◽  
Lh Receptor ◽  
G Protein Coupled ◽  
Stimulation Of

The LH receptor (LHR) and FSH receptor (FSHR) are each G protein-coupled receptors that play critical roles in reproductive endocrinology. Each of these receptors has previously been shown to self-associate into homodimers and oligomers shortly after their biosynthesis. As shown herein using bioluminescence resonance energy transfer to detect protein-protein interactions, our data show that the LHR and FSHR, when coexpressed in the same cells, specifically heterodimerize with each other. Further experiments confirm that at least a portion of the cellular LHR/FSHR heterodimers are present on the cell surface and are functional. We then sought to ascertain what effects, if any, heterodimerization between the LHR and FSHR might have on signaling. It was observed that when the LHR was expressed under conditions promoting the heterodimerization with FSHR, LH or human chorionic gonadotropin (hCG) stimulation of Gs was attenuated. Conversely, when the FSHR was expressed under conditions promoting heterodimerization with the LHR, FSH-stimulated Gs activation was attenuated. These results demonstrate that the coexpression of the LHR and FSHR enables heterodimerizaton between the 2 gonadotropin receptors and results in an attenuation of signaling through each receptor.

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