GPRC5B Activates Obesity-Associated Inflammatory Signaling in Adipocytes

Kim, Yeon Jeong; Sano, Tomoaki; Nabetani, Takuji; Asano, Yoshitaka; Hirabayashi, Yoshio

doi:10.1126/scisignal.2003149

Cited by 52 publications

(48 citation statements)

References 32 publications

(53 reference statements)

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“…We [16] ), and obesity risk in the knockout mouse (GPRC5B [17] ). In total, 25 genes with 30 single nucleotide polymorphisms (SNPs) were selected (full list in suppl.…”

Section: Introductionmentioning

confidence: 99%

Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

Aller¹,

Mariman²,

Bouwman³

et al. 2017

Lifestyle Genomics

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Background:Weight loss success is determined by genetic factors, which may differ according to treatment strategy. Methods: From a multidisciplinary obesity treatment program involving dietary advice, psychological counseling, and increased physical activity, 587 subjects (68% female; 46.1 ± 12.4 years; BMI 39.9 ± 6.3) were recruited. At baseline, a blood sample was drawn for DNA isolation. Genotypes were determined for 30 polymorphisms in 25 candidate genes. The association between genotypes and weight loss was assessed after 3 months (short-term) and after 12 months of treatment (long-term). Weight loss was categorized as ≥ 5% or <5% of initial weight. Results: The G/G genotype of PLIN1 (rs2289487) and PLIN1 (rs2304795), the T/T genotype of PLIN1 (rs1052700), and the C/C genotype of MMP2 predicted ≥ 5% weight loss in the first 3 months. The C/G-G/G genotype of PPARγ (rs1801282) and the T/C genotype of TIMP4 (rs3755724) predicted ≥ 5% weight loss after 12 months. Subjects with the combination of PPARγ (rs1801282) C/G-G/G and TIMP4 (rs3755724) T/C lost even more weight. Conclusion: Polymorphisms in genes related to regulation of fat storage and structural adaptation of the adipocytes are predictors for weight loss success with different genes being relevant for short-term and long-term weight loss success.

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“…We [16] ), and obesity risk in the knockout mouse (GPRC5B [17] ). In total, 25 genes with 30 single nucleotide polymorphisms (SNPs) were selected (full list in suppl.…”

Section: Introductionmentioning

confidence: 99%

Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

Aller¹,

Mariman²,

Bouwman³

et al. 2017

Lifestyle Genomics

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“…This suggests that GPCR family proteins may also mediate intercellular communications when transported to target cells via extracellular vesicles. Although the biological roles of such non-cell-autonomous responses remain largely unexplored, our recent study has revealed that extracellular vesicle-mediated transport of the orphan G-protein-coupled receptor GPRC5B critically regulates three-dimensional tubule formation (18), assigning a new role for GPRC5B in addition to its previously reported cell-autonomous roles in mouse neocortex neurogenesis (19) and obesity-associated inflammatory signaling (20).…”

mentioning

confidence: 99%

Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex

Kwon

Nacke

et al. 2016

Journal of Biological Chemistry

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Edited by Thomas SöllnerExosomes, 40 -150-nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. Although exosomes are known to originate from maturation of endosomes into multivesicular endosomes (also known as multivesicular bodies) with subsequent fusion of the multivesicular endosomes with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes. The L-type lectin LMAN2 (also known as VIP36) appears to be specifically required for the accumulation of GPRC5B in the Golgi complex and restriction of GPRC5B transport along the exosomal pathway. This may occur due to interference with the adaptor protein GGA1-mediated trans Golgi network-to-endosome transport of GPRC5B. The adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum. Our data thus reveal a Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively.

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“…GPRC5B, also known as retinoic acid-inducible gene 2 (Raig2), is a member of the Raig subfamily of type 3 (family C) GPCRs [10]. This orphan receptor is highly expressed in human and mouse islets [11], brain [12] and white adipose tissue [13]. Observations that it is up-regulated in islets from donors with type 2 diabetes (T2D) [11] and that its deletion in mice causes glucose intolerance [13] suggest that it may be involved in the pathogenesis of diabetes, but the molecular mechanisms underlying this remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Identifying Signalling Pathways Regulated by GPRC5B in β-Cells by CRISPR-Cas9-Mediated Genome Editing

Atanes¹,

Ruz‐Maldonado

Hawkes

et al. 2018

Cell Physiol Biochem

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Background/Aims: CRISPR-Cas9, a RNA-guided targeted genome editing tool, has revolutionized genetic engineering by offering the ability to precisely modify DNA. GPRC5B is an orphan receptor belonging to the group C family of G protein-coupled receptors (GPCRs). In this study, we analysed the functional roles of the Gprc5b receptor in MIN6 β-cells using CRISPR-Cas9 and transient over-expression of Gprc5b. Methods: The optimal transfection reagent for use in MIN6 β-cells was determined by analysing efficiency of GFP plasmid delivery by cell sorting. A MIN6 β-cell line in which Gprc5b expression was knocked down (Gprc5b KD) was generated using CRISPR-Cas9 technology. Gprc5b receptor mRNA expression, proliferation, apoptosis, Cignal 45-Pathway Reporter Array signalling and western blot assays were carried out using Gpcr5b KD MIN6 β-cells that had been transiently transfected with different concentrations of mouse Gprc5b plasmid to over-express Gprc5b. Results: JetPRIME® was the best candidate for MIN6 β-cell transfection, providing approximately 30% transfection efficiency. CRISPR-Cas9 technology targeting Gprc5b led to stable knock-down of this receptor in MIN6 β-cells and its re-expression induced proliferation and potentiated cytokine- and palmitate-induced apoptosis. The Cignal 45 Reporter analysis indicated Gprc5b-dependent regulation of apoptotic and proliferative pathways, and western blotting confirmed activation of signalling via TGF-β and IFNγ. Conclusion: This study provides evidence of CRISPR-Cas9 technology being used to down-regulate Gprc5b expression in MIN6 β-cells. This strategy allowed us to identify signalling pathways linking GPRC5B receptor expression to β-cell proliferation and apoptosis.

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GPRC5B Activates Obesity-Associated Inflammatory Signaling in Adipocytes

Cited by 52 publications

References 32 publications

Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

Genetic Predictors of ≥5% Weight Loss by Multidisciplinary Advice to Severely Obese Subjects

Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex

Identifying Signalling Pathways Regulated by GPRC5B in β-Cells by CRISPR-Cas9-Mediated Genome Editing

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