Functional and genetic epidemiological characterisation of theFFAR4(GPR120) p.R270H variant in the Danish population

Vestmar, M. A.; Andersson, Ehm A.; Christensen, Charlotte; Hauge, M.; Glümer, Charlotte; Linneberg, Allan; Witte, Daniel R.; Jørgensen, Marit Eika; Christensen, Cramer; Brandslund, Ivan; Lauritzen, Torsten; Pedersen, Oluf; Holst, Birgitte; Grarup, Niels; Schwartz, Thue W.; Hansen, Torben

doi:10.1136/jmedgenet-2015-103728

Cited by 21 publications

(16 citation statements)

References 29 publications

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“…Other ethnic groups could present different associations. In fact, the most extensively studied variant of FFAR4 (p.R270H) was not associated with glucose-related traits in an adult Danish population, contrary to classic studies [20].…”

Section: Discussion/conclusioncontrasting

confidence: 71%

The rs11187533 C>T Variant of the FFAR4 Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

2020

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Introduction: Genetic factors can modulate the development of associated comorbidities in obesity. It has been shown that loss-of-function variants of the free fatty acid receptor 4 (FFAR4) gene negatively affect obesity comorbidities such as insulin resistance and fatty liver disease. Objective: To test the relationships of metabolic factors in children with obesity with variants of the FFAR4 gene. Methods: We performed an association study of 3 single nucleotide polymorphisms (SNPs) of FFAR4 (rs10882273 T>C, rs12243124 T>C, and rs11187533 C>T) covering the last intron and last exon of FFAR4 in a cohort of 203 children with obesity. Cardiometabolic factors were determined, including parameters related to insulin resistance, liver injury, and high-sensitivity Creactive protein as an inflammatory marker. Results: Significant genotype -phenotype interactions occurred between the rs11187533 SNP and glucose levels (p = 0.011). Moreover, we identified 2 marginally significant associations between this SNP and the hepatic enzymes alanine aminotransferase (p = 0.022) and gamma-glutamyltransferase (p = 0.015). The homozygous minor allele genotype (TT) was as-sociated with a decrease in glucose levels. Conclusion: The homozygous minor allele genotype of the rs11187533 SNP might be protective against metabolic consequences accompanying obesity and could allow the identification of metabolically healthy obese individuals at early ages.

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Section: Discussion/conclusioncontrasting

confidence: 71%

The rs11187533 C>T Variant of the FFAR4 Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

2020

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“…27,28 We confirmed its FFA1 antagonist activity (pIC 50 = 5.09) but found that the compound also acts as an FFA4 agonist in the β-arrestin-2 recruitment assay although it was devoid of activity in the Ca 2+ assay ( Explorations of the western part of the structure suggested that the benzosultam system was favored. Turning attention back to the eastern site, the eastern phenyl ring of 8 was scanned with the non-polar methyl substituent (26,27,28) and the polar cyano (29)(30)(31) and meta-cyanomethyl (32) substituents, in all cases these resulted in decreased potency with para-substituents being somewhat better tolerated (Table 3). …”

Section: Resultsmentioning

confidence: 99%

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

et al. 2016

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ABSTRACT. The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed non-acidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these non-carboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.

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“…with risk for T2DM was not observed (9). More recently, the p.R270H variant was reported to affect different signaling pathways (i.e., Gq-, Gi-, or -arrestin-mediated pathways), although it was not associated with increased risk of obesity or fasting plasma glucose levels in a Danish adult cohort that was studied (10). One of the goals of the current study was to further investigate the underlying mechanisms by which GPR120 activation modulates insulin sensitivity and glucose homeostasis.…”

mentioning

confidence: 89%

GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy

Satapati

Qian

et al. 2017

Journal of Lipid Research

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GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in / mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism.

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Functional and genetic epidemiological characterisation of theFFAR4(GPR120) p.R270H variant in the Danish population

Abstract: We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

Cited by 21 publications

References 29 publications

The rs11187533 C>T Variant of the <b><i>FFAR4</i></b> Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

The rs11187533 C>T Variant of the <b><i>FFAR4</i></b> Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy

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Functional and genetic epidemiological characterisation of theFFAR4(GPR120) p.R270H variant in the Danish population

Abstract: We demonstrate that p.R270H of FFAR4 impairs Gq and Gi signalling of FFAR4 in vitro; however, this impaired signalling for p.R270H does not translate into associations with human metabolic phenotypes in the investigated populations.

Cited by 21 publications

References 29 publications

The rs11187533 C&#x3e;T Variant of the <b><i>FFAR4</i></b> Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

The rs11187533 C&#x3e;T Variant of the <b><i>FFAR4</i></b> Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

Non-Acidic Free Fatty Acid Receptor 4 Agonists with Antidiabetic Activity

GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy

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The rs11187533 C>T Variant of the <b><i>FFAR4</i></b> Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

The rs11187533 C>T Variant of the <b><i>FFAR4</i></b> Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity