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

Codoñer-Alejos, Alan; Carrasco-Luna, Joaquín; Codoñer‐Franch, Pilar

doi:10.1159/000506618

Cited by 5 publications

(2 citation statements)

References 18 publications

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“…We previously found that the C/T‐T/T genotypes in the rs11187533 SNP were associated with lower levels of fasting glucose and markers of liver injury, suggesting a protective role of the minor T allele (11). In the present study, we show that the C/T‐T/T genotypes have significantly higher expression of FFAR4 than the C/C genotype, linking the expression values to the rs11187533 SNP genotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies by our group have found significant associations between the FFAR4 rs11187533 single nucleotide polymorphism (SNP) located in intron 2 and several obesity comorbidity parameters (11). Specifically, the mutated C/T‐T/T genotypes were associated with lower values of blood glucose, alanine transaminase (ALT) and gamma‐glutamyl transpeptidase (GGT), which suggests a protective effect of the minor T allele.…”

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confidence: 99%

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Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children

Codoñer-Alejos

Carrasco-Luna

Carrasco-García

et al. 2021

J. pediatr. gastroenterol. nutr.

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Objectives: Free fatty acid receptor 4 (FFAR4) is a G-protein-coupled membrane receptor highly expressed in macrophages that triggers antiinflammatory effects and promotes insulin sensitization. We have previously found significant associations between the FFAR4 rs11187533 single nucleotide polymorphism (SNP) and various obesity comorbidity parameters. We aimed to verify the FFAR4 expression levels in children with obesity and the associated comorbidities. Methods: Thirty-eight children with obesity were studied. Clinical and anthropometric evaluation was performed. A venous sample under fasting conditions was obtained. Biochemical study included parameters of metabolic risk. DNA was extracted and genotyped for the rs11187533 FFAR4 SNP. Real-time PCR technique was performed to investigate the gene expression. Relative FFAR4 mRNA levels were determined according to the 2 ÀDDCt method. Results: Significant differences in FFAR4 expression levels between the CC and CT-TT genotypes of the rs11187533 FFAR4 SNP were observed (P ¼ 0.034). The minor allele T presented higher levels of FFAR4 expression. We found that a loss of FFAR4 expression was associated with extreme obesity (P ¼ 0.032). The lowest FFAR4 expression levels were observed in children who had higher insulin (P ¼ 0.008) and homeostasis model assessment insulin resistance values (P ¼ 0.012) and lower quantitative insulin-sensitivity check index (P ¼ 0.033). Conclusions: The underexpression of FFAR4 was associated with extreme obesity and parameters indicative of obesity comorbidities in children. This under expression could be partially influenced by the presence of the C allele rs11187533 FFAR4 SNP.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children

Codoñer-Alejos

Carrasco-Luna

Carrasco-García

et al. 2021

J. pediatr. gastroenterol. nutr.

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Akkermansia muciniphila supplementation improves glucose tolerance in intestinal Ffar4 knockout mice during the daily light to dark transition

Wang,

Cui,

Zhang

et al. 2023

mSystems

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Disruption of blood glucose utilization may lead to diabetes mellitus, which has complex genetic and environmental aspects, and free fatty acid receptors (FFARs) may bridge the genetic and dietary aspects. FFAR4 has been identified as a new target for diabetes treatment, and it is essential to investigate how FFAR4 affects glucose homeostasis. FFAR4 knockout mice have been shown to cause severely impaired glucose tolerance under high-fat feeding conditions; however, the findings in FFAR4 knockout mice under chow diet conditions seem to be contradictory. Blood glucose utilization in mice under chow diet conditions is thought to show diurnal rhythmicity. In this study, we aim to investigate the role of FFAR4 in glucose utilization rhythm and explore the possible mechanism. Total Ffar4 and gut-specific Ffar4 knockout mice both showed a clear diurnal rhythm in glucose tolerance. However, deletion of total Ffar4 and gut-specific Ffar4 both deteriorate glucose tolerance at the daily light to dark transition (ZT12) in mice. We show that intestinal FFAR4 deficiency leads to significant changes in fecal microbiota at different ZTs. 16S rRNA sequencing results suggested that Akkermansia muciniphila was the main target of intestinal FFAR4 at ZT12. Akkermansia muciniphila supplementation significantly improved the impaired glucose tolerance at ZT12 in mice with gut-specific Ffar4 deletion and was accompanied by recovery of serum hormone level and transcripts of key genes in glucose metabolism. IMPORTANCE Alterations in the intestinal environment are associated with various diseases, and FFAR4 is abundantly enriched in the intestine, where it has been shown to have the ability to regulate intestinal hormone secretion and intestinal microbiota; here, we confirmed previous reports. Meanwhile, we found that intestinal FFAR4 regulates glucagon-like peptide 1 secretion by decreasing Akkermansia muciniphila abundance and show that such change is associated with the level of glucose utilization at ZT12 in mice. Intestinal FFAR4 deficiency leads to severely impaired glucose tolerance at the ZT12 moment in mice, and Akkermansia muciniphila supplementation ameliorates the abnormal glucose utilization at the ZT12 moment caused by FFAR4 deficiency, which is very similar to the dawn phenomenon in diabetic patients. Collectively, our data suggest that intestinal Ffar4 deteriorates glucose tolerance at the daily light to dark transition by affecting Akkermansia muciniphila .

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FFAR4 activation inhibits lung adenocarcinoma via blocking respiratory chain complex assembly associated mitochondrial metabolism

Wang,

Li,

Wang

et al. 2024

Cell Mol Biol Lett

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Despite notable advancements in the investigation and management of lung adenocarcinoma (LUAD), the mortality rate for individuals afflicted with LUAD remains elevated, and attaining an accurate prognosis is challenging. LUAD exhibits intricate genetic and environmental components, and it is plausible that free fatty acid receptors (FFARs) may bridge the genetic and dietary aspects. The objective of this study is to ascertain whether a correlation exists between FFAR4, which functions as the primary receptor for dietary fatty acids, and various characteristics of LUAD, while also delving into the potential underlying mechanism. The findings of this study indicate a decrease in FFAR4 expression in LUAD, with a positive correlation (P < 0.01) between FFAR4 levels and overall patient survival (OS). Receiver operating characteristic (ROC) curve analysis demonstrated a significant diagnostic value [area under the curve (AUC) of 0.933] associated with FFAR4 expression. Functional investigations revealed that the FFAR4-specific agonist (TUG891) effectively suppressed cell proliferation and induced cell cycle arrest. Furthermore, FFAR4 activation resulted in significant metabolic shifts, including a decrease in oxygen consumption rate (OCR) and an increase in extracellular acidification rate (ECAR) in A549 cells. In detail, the activation of FFAR4 has been observed to impact the assembly process of the mitochondrial respiratory chain complex and the malate–aspartate shuttle process, resulting in a decrease in the transition of NAD+ to NADH and the inhibition of LUAD. These discoveries reveal a previously unrecognized function of FFAR4 in the negative regulation of mitochondrial metabolism and the inhibition of LUAD, indicating its potential as a promising therapeutic target for the treatment and diagnosis of LUAD.

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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

Cited by 5 publications

References 18 publications

Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children

Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children

Akkermansia muciniphila supplementation improves glucose tolerance in intestinal Ffar4 knockout mice during the daily light to dark transition

FFAR4 activation inhibits lung adenocarcinoma via blocking respiratory chain complex assembly associated mitochondrial metabolism

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