Mice Deficient for an Intestinal G Protein-Coupled Receptor Expression Have Increased Satiety During Rebound Hyperphagia

Abstract Gut-derived hormones have been successfully developed as the therapeutic targets to combat the increasing prevalence of diabetes and obesity. G protein-coupled receptors (GPCRs) in the gastrointestinal (GI) tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We identified that an orphan GPCR, Gpr17, was expressed in the intestinal epithelium and found that loss of intestinal Gpr17 expression increased gut incretin hormone secretion from enteroendocrine cells (EECs). However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their feeding behavior. Here we show that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. Interestingly, intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Moreover, we performed fasting-refeeding challenge with Gpr17-deficient mice fed on high-fat diet (HFD), and our meal pattern analysis revealed that these mice had reduced meal duration of the first meal after refeeding. In conclusion, our genetic knockout studies in rodents showed that ablating intestinal Gpr17 increased satiety during rebound hyperphagia in the fasting-refeeding experimental paradigm. Intestinal Gpr17 could be developed as a therapeutic target to treat obesity by improving energy balance through gut hormone secretion and meal pattern control.

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Faculty Opinions recommendation of Control of feeding behavior in C. elegans by human G protein-coupled receptors permits screening for agonist-expressing bacteria.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1125840.582940 ◽

2008 ◽

Author(s):

Sachdev Sidhu ◽

Raffi Tonikian

Keyword(s):

Feeding Behavior ◽

G Protein ◽

G Protein Coupled Receptors ◽

C Elegans ◽

G Protein Coupled

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Impaired branched chain amino acid metabolism alters feeding behavior and increases orexigenic neuropeptide expression in the hypothalamus

Journal of Endocrinology ◽

10.1530/joe-11-0270 ◽

2011 ◽

Vol 212 (1) ◽

pp. 85-94 ◽

Cited By ~ 14

Author(s):

Megan N Purpera ◽

Li Shen ◽

Marzieh Taghavi ◽

Heike Münzberg ◽

Roy J Martin ◽

...

Keyword(s):

Amino Acid ◽

Food Intake ◽

Feeding Behavior ◽

Control Diet ◽

Peripheral Tissues ◽

Protein Status ◽

Branched Chain Amino Acid ◽

Branched Chain ◽

Branched Chain Aminotransferase ◽

Deficient Mice

Elevation of dietary or brain leucine appears to suppress food intake via a mechanism involving mechanistic target of rapamycin, AMPK, and/or branched chain amino acid (BCAA) metabolism. Mice bearing a deletion of mitochondrial branched chain aminotransferase (BCATm), which is expressed in peripheral tissues (muscle) and brain glia, exhibit marked increases in circulating BCAAs. Here, we test whether this increase alters feeding behavior and brain neuropeptide expression. Circulating and brain levels of BCAAs were increased two- to four-fold in BCATm-deficient mice (KO). KO mice weighed less than controls (25.9 vs 20.4 g,P<0.01), but absolute food intake was relatively unchanged. In contrast to wild-type mice, KO mice preferred a low-BCAA diet to a control diet (P<0.05) but exhibited no change in preference for low- vs high-protein (HP) diets. KO mice also exhibited low leptin levels and increased hypothalamicNpyandAgrpmRNA. Normalization of circulating leptin levels had no effect on either food preference or the increasedNpyandAgrpmRNA expression. If BCAAs act as signals of protein status, one would expect reduced food intake, avoidance of dietary protein, and reduction in neuropeptide expression in BCATm-KO mice. Instead, these mice exhibit an increased expression of orexigenic neuropeptides and an avoidance of BCAAs but not HP. These data thus suggest that either BCAAs do not act as physiological signals of protein status or the loss of BCAA metabolism within brain glia impairs the detection of protein balance.

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G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-127 ◽

2006 ◽

Vol 84 (3-4) ◽

pp. 287-297 ◽

Cited By ~ 124

Author(s):

Fernand Gobeil ◽

Audrey Fortier ◽

Tang Zhu ◽

Michela Bossolasco ◽

Martin Leduc ◽

...

Keyword(s):

G Protein ◽

Cell Nucleus ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Cell Metabolism ◽

Hormone Secretion ◽

G Protein Coupled Receptors ◽

A Cell ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

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Anatomical Profiling of G Protein-Coupled Receptor Expression

Cell ◽

10.1016/j.cell.2008.08.040 ◽

2008 ◽

Vol 135 (3) ◽

pp. 561-571 ◽

Cited By ~ 370

Author(s):

Jean B. Regard ◽

Isaac T. Sato ◽

Shaun R. Coughlin

Keyword(s):

G Protein ◽

Receptor Expression ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Stroke Increases G Protein-Coupled Estrogen Receptor Expression in the Brain of Male but Not Female Mice

Neurosignals ◽

10.1159/000338019 ◽

2013 ◽

Vol 21 (3-4) ◽

pp. 229-239 ◽

Cited By ~ 38

Author(s):

Brad R.S. Broughton ◽

Vanessa H. Brait ◽

Elizabeth Guida ◽

Seyoung Lee ◽

Thiruma V. Arumugam ◽

...

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Receptor Expression ◽

Estrogen Receptor Expression ◽

Female Mice ◽

G Protein Coupled ◽

The Brain

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Detection of G Protein-coupled Receptor Expression in Mouse Vagal Afferent Neurons using Multiplex In Situ Hybridization

Journal of Visualized Experiments ◽

10.3791/62945 ◽

2021 ◽

Author(s):

Johnson Bob-Manuel ◽

Laurent Gautron

Keyword(s):

G Protein ◽

Receptor Expression ◽

Afferent Neurons ◽

G Protein Coupled Receptor ◽

Vagal Afferent ◽

G Protein Coupled

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G protein-coupled receptor expression in Halobacterium salinarum

Focus on Structural Biology - Perspectives on Solid State NMR in Biology ◽

10.1007/978-94-017-2579-8_13 ◽

2001 ◽

pp. 141-159 ◽

Cited By ~ 2

Author(s):

Ann M. Winter-Vann ◽

Lynell Martinez ◽

Cynthia Bartus ◽

Agata Levay ◽

George J. Turner

Keyword(s):

G Protein ◽

Halobacterium Salinarum ◽

Receptor Expression ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1274-1330 ◽

2020 ◽

Author(s):

Hande Mefkure Ozkaya ◽

Muge Sayitoglu ◽

Nil Comunoglu ◽

Eda Sun ◽

Fatma Ela Keskin ◽

...

Keyword(s):

Gene Expression ◽

Estrogen Receptor ◽

Protein Expression ◽

G Protein ◽

Estrogen Receptor Α ◽

Receptor Expression ◽

Positive Correlation ◽

Polymerase Chain ◽

G Protein Coupled ◽

Transforming Gene

Abstract Purpose To evaluate the expression of G-protein coupled estrogen receptor (GPER1), aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) in GH-secreting and non-functioning adenomas (NFA). Methods Thirty patients with acromegaly and 27 patients with NFA were included. Gene expression was determined via quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression was determined via immunohistochemistry. Results There was no difference, in terms of gene expression of aromatase, ERα, PTTG, and FGF2 between the two groups (p>0.05 for all). ERβ gene expression was higher and GPER1 gene expression was lower in GH-secreting adenomas than NFAs (p<0.05 for all). Aromatase and ERβ protein expression was higher in GH-secreting adenomas than NFAs (p=0.01). None of the tumors expressed ERα. GPER1 expression was detected in 62.2% of the GH-secreting adenomas and 45% of NFAs. There was no difference in terms of GPER1, PTTG, FGF2 H scores between the two groups (p>0.05 for all). GPER1 gene expression was positively correlated to ERα, ERβ, PTTG, and FGF2 gene expression (p<0.05 for all). There was a positive correlation between aromatase and GPER1 protein expression (r=0.31; p=0.04). Conclusions GPER1 is expressed at both gene and protein level in a substantial portion of GH-secreting adenomas and NFAs. The finding of a positive correlation between GPER1 and ERα, ERβ, PTTG, and FGF2 gene expression and aromatase and GPER1 protein expression suggests GPER1 along with aromatase and classical ERs might mediate the effects of estrogen through upregulation of PTTG and FGF2.

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G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00406.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. G446-G452 ◽

Cited By ~ 2

Author(s):

Simona E. Carbone ◽

Nicholas A. Veldhuis ◽

Arisbel B. Gondin ◽

Daniel P. Poole

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

G Protein ◽

Molecular Mechanisms ◽

Intestinal Inflammation ◽

Receptor Expression ◽

Enteric Neurons ◽

Future Research ◽

Detailed Knowledge ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

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