Orphan G protein-coupled receptors and obesity

Xu, Yaxi; Jackson, Valerie R.; Civelli, Olivier

doi:10.1016/j.ejphar.2004.07.029

Cited by 38 publications

(27 citation statements)

References 115 publications

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“…A number of targets play an important role in the regulation of food intake and dysregulation of these targets can lead to a variety of metabolic disorders and play a role in obesity (22). We can start from the Target view (https://pharos.nih.gov/idg/targets) and use the Disease filter to search for targets associated with ‘Obesity’.…”

Section: Resultsmentioning

confidence: 99%

Pharos: Collating protein information to shed light on the druggable genome

et al. 2016

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The ‘druggable genome’ encompasses several protein families, but only a subset of targets within them have attracted significant research attention and thus have information about them publicly available. The Illuminating the Druggable Genome (IDG) program was initiated in 2014, has the goal of developing experimental techniques and a Knowledge Management Center (KMC) that would collect and organize information about protein targets from four families, representing the most common druggable targets with an emphasis on understudied proteins. Here, we describe two resources developed by the KMC: the Target Central Resource Database (TCRD) which collates many heterogeneous gene/protein datasets and Pharos (https://pharos.nih.gov), a multimodal web interface that presents the data from TCRD. We briefly describe the types and sources of data considered by the KMC and then highlight features of the Pharos interface designed to enable intuitive access to the IDG knowledgebase. The aim of Pharos is to encourage ‘serendipitous browsing’, whereby related, relevant information is made easily discoverable. We conclude by describing two use cases that highlight the utility of Pharos and TCRD.

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Section: Resultsmentioning

confidence: 99%

Pharos: Collating protein information to shed light on the druggable genome

et al. 2016

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“…We selected a range of ARC genes including many GPCR, neuropeptides, signaling molecules, and transcription factors (reviewed in [6;30;31] and employed TLDA technology to screen for potential candidate genes using two doses of BPA. Of the 40 genes selected, six genes were affected by developmental BPA exposures.…”

Section: Discussionmentioning

confidence: 99%

“…These genes include receptors for hormones and neurotransmitters, signalling molecules, transcription factors, and neuropeptides (reviewed in [6;30;31]. Peripheral hormonal receptors, including members of G-protein coupled receptor (GPCR) and cytokine receptor families, are vital for the hypothalamic sensing of the body’s energy status, which is then communicated to other hypothalamic neurons to control reproduction, especially during puberty.…”

Section: Introductionmentioning

confidence: 99%

Regulation of arcuate genes by developmental exposures to endocrine-disrupting compounds in female rats

Roepke

Yang

Yasrebi

et al. 2016

Reproductive Toxicology

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Developmental exposure to endocrine-disrupting compounds (EDCs) alters reproduction and energy homeostasis, both of which are regulated by the arcuate nucleus (ARC). Little is known about the effects of EDC on ARC gene expression. In Experiment #1, pregnant dams were treated with either two doses of bisphenol A (BPA) or oil from embryonic day (E)18-21. Neonates were injected from postnatal day (PND)0-7. Vaginal opening, body weights, and ARC gene expression were measured. Chrm3 (muscarinic receptor 3) and Adipor1 (adiponectin receptor 1) were decreased by BPA. Bdnf (brain-derived neurotropic factor), Igf1 (insulin-like growth factor 1), Htr2c (5-hydroxytryptamine receptor), and Cck2r (cholescystokinin 2 receptor) were impacted. In Experiment #2, females were exposed to BPA, diethylstilbestrol (DES), di(2-ethylhexyl)phthalate, or methoxychlor (MXC) during E11-PND7. MXC and DES advanced the age of vaginal opening and ARC gene expression was impacted. These data indicate that EDCs alter ARC genes involved in reproduction and energy homeostasis in females.

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“…The neuro-endocrine system plays a pivotal role in regulation of energy homeostasis, in which G protein-coupled receptor (GPCR) pathways are increasingly discovered to be an important modulator [6]–[8]. GPR26 is a central orphan GPCR whose biological function remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Targeted Inactivation of GPR26 Leads to Hyperphagia and Adiposity by Activating AMPK in the Hypothalamus

2012

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G-protein coupled receptor 26 (GPR26) is a brain-specific orphan GPCR with high expression in the brain region that controls satiety. Depletion of GPR26 has been shown to increase fat storage in C. elegans, whereas GPR26 deficiency in the hypothalamus is associated with high genetic susceptibility to the onset of obesity in mice. However, the metabolic function of GPR26 in mammals remains elusive. Herein, we investigated a role of GPR26 in regulating energy homeostasis by generating mice with targeted deletion of the GPR26 gene. We show that GPR26 deficiency causes hyperphagia and hypometabolism, leading to early onset of diet-induced obesity. Accordingly, GPR26 deficiency also caused metabolic complications commonly associated with obesity, including glucose intolerance, hyperinsulinemia, and dyslipidemia. Moreover, consistent with hyperphagia in GPR26 null mice, GPR26 deficiency significantly increased hypothalamic activity of AMPK, a key signaling event that stimulates appetite. In further support of a regulatory role of GPR26 in satiety, GPR26 knockout mice also demonstrate hypersensitivity to treatment of rimonabant, an endocannabinoid receptor-1 antagonist commonly used to treat obesity by suppressing appetite in humans. Together, these findings identified a key role of GPR26 as a central regulator of energy homeostasis though modulation of hypothalamic AMPK activation.

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Orphan G protein-coupled receptors and obesity

Cited by 38 publications

References 115 publications

Pharos: Collating protein information to shed light on the druggable genome

Pharos: Collating protein information to shed light on the druggable genome

Regulation of arcuate genes by developmental exposures to endocrine-disrupting compounds in female rats

Targeted Inactivation of GPR26 Leads to Hyperphagia and Adiposity by Activating AMPK in the Hypothalamus

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