Characterization of metabolic phenotypes of mice lacking GPR61, an orphan G-protein coupled receptor

Nambu, Hirohide; Fukushima, Masafumi; Hikichi, Hirohiko; Inoue, Takao; Nagano, Norihiro; Terada, Yoshio; Nambu, Tadahiro; Itô, Junko; Ogawa, Yoshihiro; Ozaki, Satoshi; Ohta, Hisashi

doi:10.1016/j.lfs.2011.09.002

Cited by 27 publications

(19 citation statements)

References 40 publications

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“…The top giDMR, which is also identified in the primary linear model analyses (discovery P =3.78 × 10 −6 and replication P =0.01), is in the promoter of the GPR61 (G-protein coupled receptor 61) gene. Knockout studies of GPR61 in mice exhibit hyperphagia-induced obesity and higher plasma insulin levels 32 . The sixth ranked giDMR is in the PRKCB (protein kinase C, β) gene region, and another top giDMR is in the PRKCB TSS, and both are hypo-methylated in T2D cases.…”

Section: Resultsmentioning

confidence: 99%

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

et al. 2014

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DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.

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Section: Resultsmentioning

confidence: 99%

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

et al. 2014

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“…They are abundantly expressed in the brain and in some other tissues including pancreatic beta-cells 8 – 11 . GPR61-deficient mice are obese and hyperphagic 12 . The phenotype of GPR62 and GPR135 knockout mice was not reported yet.…”

Section: Introductionmentioning

confidence: 99%

Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT2 receptor reciprocally modulate their signaling functions

Oishi

Karamitri

Gerbier

et al. 2017

Sci Rep

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Understanding the function of orphan G protein-coupled receptors (GPCRs), whose cognate ligand is unknown, is of major importance as GPCRs are privileged drug targets for many diseases. Recent phylogenetic studies classified three orphan receptors, GPR61, GPR62 and GPR135 among the melatonin receptor subfamily, but their capacity to bind melatonin and their biochemical functions are not well characterized yet. We show here that GPR61, GPR62 and GPR135 do not bind [3H]-melatonin nor 2-[125I]iodomelatonin and do not respond to melatonin in several signaling assays. In contrast, the three receptors show extensive spontaneous ligand-independent activities on the cAMP, inositol phosphate and ß-arrestin pathways with distinct pathway-specific profiles. Spontaneous ß-arrestin recruitment internalizes all three GPRs in the endosomal compartment. Co-expression of the melatonin binding MT2 receptor with GPR61, GPR62 or GPR135 has several consequences such as (i) the formation of receptor heteromers, (ii) the inhibition of melatonin-induced ß-arrestin2 recruitment to MT2 and (iii) the decrease of elevated cAMP levels upon melatonin stimulation in cells expressing spontaneously active GPR61 and GPR62. Collectively, these data show that GPR61, GPR62 and GPR135 are unable to bind melatonin, but show a reciprocal regulatory interaction with MT2 receptors.

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“…Although the precise function of GPR61 is unknown, GPR61-deficient mice exhibited obesity associated with hyperphagia (Nambu et al 2011); moreover, GPR61 has been implicated in type 2 diabetes (Yuan et al 2014). Our findings suggest that GPR61 in non-gonadotrophs may play an important role in regulating food intake and body weight, which is a possibility that bears further consideration in future investigations.…”

Section: Discussionmentioning

confidence: 99%

“…However, gonadotroph lipid rafts containing GnRHR are also likely to contain other types of receptor that have yet to be identified. G protein-coupled receptor 61 (GPR61) is an orphan receptor that is widely expressed in the brain, including in the hypothalamus and pituitary (Lee et al 2001;Nambu et al 2011), although its function and ligand(s) are unknown. GPR61 associates with Gs protein (Takeda et al 2003;Toyooka et al 2009) and stimulates extracellular signal-regulated kinase (ERK) signaling in neurons (Hossain et al 2016).…”

mentioning

confidence: 99%

Heifers express G-protein coupled receptor 61 in anterior pituitary gonadotrophs in stage-dependent manner

Pandey

Kereilwe

Borromeo

et al. 2017

Animal Reproduction Science

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Characterization of metabolic phenotypes of mice lacking GPR61, an orphan G-protein coupled receptor

Cited by 27 publications

References 40 publications

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins

Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT2 receptor reciprocally modulate their signaling functions

Heifers express G-protein coupled receptor 61 in anterior pituitary gonadotrophs in stage-dependent manner

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