The rs1421085 variant within FTO promotes brown fat thermogenesis

Zhang, Zhiyin; Chen, Na; Yin, Nan; Liu, Ruixin; He, Yang; Li, Danjie; Tong, Muye; Gao, Anming; Lu, Peng; Zhao, Y.; Li, Huabing; Zhang, Junfang; Zhang, Dan; Gu, Wei; Hong, Jing; Wang, Weiqing; Qi, Lü; Ning, Guang; Wang, Jiqiu

doi:10.1038/s42255-023-00847-2

Cited by 16 publications

(10 citation statements)

References 90 publications

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“…Obesity research suggests that the FTO gene region alters the function of nearby genes (IRX3 and IRX5), which impact the involvement of fat cells in thermogenesis (Laber et al, 2021;Zhang et al, 2023). The psychiatric literature suggests that this region also affects neuronal activity, namely dopamine receptor type 2 and 3 function (Hess et al, 2013;Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…While BMI and alcohol-related GWAS have identified intronic FTO variants (Kranzler et al, 2019; Loos & Yeo, 2014; Zhou et al, 2023), this conjunctional analysis highlights this locus as the region that is most significantly associated with both phenotypes. Obesity research suggests that the FTO gene region alters the function of nearby genes ( IRX3 and IRX5 ), which impact the involvement of fat cells in thermogenesis (Laber et al, 2021; Zhang et al, 2023). The psychiatric literature suggests that this region also affects neuronal activity, namely dopamine receptor type 2 and 3 function (Hess et al, 2013; Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Malone,

Davis,

Piserchia

et al. 2024

Preprint

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Background: The prevalence of co-occurring heavy alcohol consumption and obesity is increasing in the United States. Despite neurobiological overlap in the regulation of alcohol consumption and eating behavior, alcohol- and body mass index (BMI)-related phenotypes show no or minimal genetic correlation. We hypothesized that the lack of genetic correlation is due to mixed effect directions of variants shared by AUD and BMI. Methods: We applied MiXeR, to investigate shared genetic architecture between AUD and BMI in individuals of European ancestry. We used conjunctional false discovery rate (conjFDR) analysis to detect loci associated with both phenotypes and their directional effect, Functional Mapping and Annotation (FUMA) to identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) samples to examine gene expression enrichment across tissue types, and BrainXcan to evaluate the shared associations of AUD and BMI with brain image-derived phenotypes. Results: MiXeR analysis indicated polygenic overlap of 80.9% between AUD and BMI, despite a genetic correlation (rg) of -.03. ConjFDR analysis yielded 56 lead SNPs with the same effect direction and 76 with the opposite direction. Of the 132 shared lead SNPs, 53 were novel for both AUD and BMI. GTEx analyses identified significant overexpression in the frontal cortex (BA9), hypothalamus, cortex, anterior cingulate cortex (BA24), hippocampus, and amygdala. Amygdala and caudate nucleus gray matter volumes were significantly associated with both AUD and BMI in BrainXcan analyses. Conclusions: More than half of variants significantly associated with AUD and BMI had opposite directions of effect for the traits, supporting our hypothesis that this is the basis for their lack of genetic correlation. Follow-up analyses identified brain regions implicated in executive functioning, reward, homeostasis, and food intake regulation. Together, these findings clarify the extensive polygenic overlap between AUD and BMI and elucidate several overlapping neurobiological mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Malone,

Davis,

Piserchia

et al. 2024

Preprint

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“…39 Other model work has suggested that altered thermogenic capacity and resistance to adiposity induced by a high fat diet might explain the genetic associations. 40 Of relevance for this review, these insights highlight how common genetic variant signals are potentially complex in interpretation but have advanced possible pathways relating to variation in levels of adiposity.…”

Section: Genetic Contributions To Obesity: Anchoring Inferencementioning

confidence: 99%

New insights into understanding obesity: from measures to mechanisms

Timpson,

Wade,

Smith

et al. 2024

bmjmed

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Associations between obesity and health are unequivocal and coupled with a substantial body of evidence suggesting that associations are likely causal. These associations and the supporting causal evidence are useful, but hide both the inadequacies of the measures used to qualify obesity and the mechanisms that are responsible for the observable relationships. A challenge therefore remains to determine both the intermediate factors associated with obesity and the mechanisms responsible for connecting excess adiposity (the defining feature of obesity) and health. A growing collection of detailed measures including examples in genomics, proteomics, metabolomics, and the microbiome are now available, allowing a broad approach to characterising obesity and analysing the associations between excess adiposity and health—but to what extent do these associations also provide insight into mechanism? In this specialist review, the problems facing the analysis of obesity (and related measures) both as a disease and as a risk factor for many downstream health outcomes are explored. This review looks to shift focus away from mechanisms of obesity and towards a useful interpretation of mechanisms associated with obesity in the context of promising developments in causal epidemiology.

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“…Bei einer Ausschaltung von Irx3 nahmen transgene Mäuse unter einer fettreichen Diät kein Gewicht zu [58]. Eine aktuelle Studie konnte diese Effekte auf Irx3 und Irx5 in drei Mausmodellen jedoch nicht einheitlich bestätigen [60]. Diese Studie zeigte, dass die FTO-Variante rs1421085 direkt die Expression von FTO erhöht und Mäuse, die das C-Allel der Variante trugen, weniger Gewicht bei einer fettreichen Diät zunahmen also wildtypische Mäuse [60].…”

Section: Die Polygene Adipositasunclassified

“…Eine aktuelle Studie konnte diese Effekte auf Irx3 und Irx5 in drei Mausmodellen jedoch nicht einheitlich bestätigen [60]. Diese Studie zeigte, dass die FTO-Variante rs1421085 direkt die Expression von FTO erhöht und Mäuse, die das C-Allel der Variante trugen, weniger Gewicht bei einer fettreichen Diät zunahmen also wildtypische Mäuse [60]. Dieser Effekt war jedoch Temperatur-abhängig und bei einer thermoneutralen Temperatur nur abgeschwächt nachweisbar [60].…”

Section: Die Polygene Adipositasunclassified

Genetische Ursachen der Adipositas und ihre therapeutischen Implikationen

Rajcsanyi,

Schmidt,

Düerkop

et al. 2023

Adipositas - Ursachen, Folgeerkrankungen, Therapie

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ZusammenfassungAdipositas ist eine komplexe Störung, die von Umweltfaktoren und genetischen Varianten beeinflusst wird. Basierend auf den genetischen Grundlagen wird zwischen zwei Formen der Adipositas unterschieden. Die monogene (und syndromale) Adipositas ist selten und wird von Mutationen in jeweils einem Gen bedingt. Zur Manifestation einer extremen Adipositas mit Hyperphagie kommt es bereits in den ersten Lebensjahren. Abhängig vom betroffenen Gen können zudem weitere phänotypische Ausprägungen hinzukommen. Die polygene Adipositas dagegen ist weitaus häufiger. Ursächlich für diese Form ist eine Vielzahl von genetischen Varianten, die jeweils einen geringen, aber additiven Effekt auf das Körpergewicht haben. Frühzeitige genetische Diagnostik kann die vorliegende Form der Adipositas identifizieren und die Wahl einer geeigneten Therapieoption, ob Lebensstilintervention, bariatrische Chirurgie oder pharmakologische Behandlung, unterstützen. Wir stellen aktuelle Erkenntnisse der Forschung über die genetischen Ursachen der Adipositas dar. Zudem werden therapeutische und diagnostische Optionen, die teils auf genetischen Befunden basieren, beleuchtet.

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The rs1421085 variant within FTO promotes brown fat thermogenesis

Cited by 16 publications

References 90 publications

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations

New insights into understanding obesity: from measures to mechanisms

Genetische Ursachen der Adipositas und ihre therapeutischen Implikationen

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