(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution

Rohde, Kerstin; Keller, Maria; Poulsen, Lars la Cour; Rønningen, Torunn; Stümvoll, Michael; Tönjes, Anke; Kovacs, Peter; Horstmann, Annette; Villringer, Arno; Blüher, Matthias; Böttcher, Yvonne

doi:10.1016/j.ebiom.2019.05.050

Cited by 13 publications

(14 citation statements)

References 32 publications

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“…ITPR3 is known as well for process of sensory perception of taste. CRTC1 gene in human has highest transcript expression in brain compared to other tissues and is known for affecting eating behavior [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Investigation of ancestral alleles in the Bovinae subfamily

et al. 2021

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Background In evolutionary theory, divergence and speciation can arise from long periods of reproductive isolation, genetic mutation, selection and environmental adaptation. After divergence, alleles can either persist in their initial state (ancestral allele - AA), co-exist or be replaced by a mutated state (derived alleles -DA). In this study, we aligned whole genome sequences of individuals from the Bovinae subfamily to the cattle reference genome (ARS.UCD-1.2) for defining ancestral alleles necessary for selection signatures study. Results Accommodating independent divergent of each lineage from the initial ancestral state, AA were defined based on fixed alleles on at least two groups of yak, bison and gayal-gaur-banteng resulting in ~ 32.4 million variants. Using non-overlapping scanning windows of 10 Kb, we counted the AA observed within taurine and zebu cattle. We focused on the extreme points, regions with top 0. 1% (high count) and regions without any occurrence of AA (null count). High count regions preserved gene functions from ancestral states that are still beneficial in the current condition, while null counts regions were linked to mutated ones. For both cattle, high count regions were associated with basal lipid metabolism, essential for survival of various environmental pressures. Mutated regions were associated to productive traits in taurine, i.e. higher metabolism, cell development and behaviors and in immune response domain for zebu. Conclusions Our findings suggest that retaining and losing AA in some regions are varied and made it species-specific with possibility of overlapping as it depends on the selective pressure they had to experience.

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Section: Resultsmentioning

confidence: 99%

Investigation of ancestral alleles in the Bovinae subfamily

et al. 2021

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“…In the present study, we used the Leipzig Obesity cohort, which has been previously described in detail 2 18–20. Briefly, the cohort contains lean, overweight and obese subjects from whom intraindividually paired samples of SAT and OVAT were taken during bariatric surgery or other procedures such as cholecystectomy.…”

Section: Methodsmentioning

confidence: 99%

Role of the DNA repair genesH2AXandHMGB1in human fat distribution and lipid profiles

Rohde

Rønningen

Poulsen

et al. 2020

BMJ Open Diab Res Care

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Significance of this studyWhat is already known about this subject? ► DNA damage in adipocytes occurs early in obesity and is related to increased inflammation ► HMGB1 level are elevated during adipogenesis which acts as alarm signal of inflammation. In contrast, nuclear HMGB1 is thought to be involved in DNA repair mechanisms like H2AX, which is a key driver for DNA repair. The formation of yH2AX foci serves as earliest signal of occured DNA damage and initiates downstream signalling. ► While both, HGMB1 and H2AX protein level are well established markers of inflammtion and DNA repair, regulatory mechanisms of their gene expression level have scarcely been analysed so far, especially in the context of adipose tissue distribution.What are the new findings?► DNA damage contributes to adipose tissue inflammation and is related to metabolic diseases. We here sought to understand the fat depot-specific regulation of the DNA repair genes H2AX and HMGB1. ► We show differential gene expression pattern of H2AX and HMGB1 in subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) which is linked to DNA methylation and/or H2AX 3'untranslated region (3'UTR) variant rs7350. Further, we observed associations with lipid metabolites and with the OVAT/SAT ratio.How might these results change the focus of research or clinical practice?► Our data shed light on the impact of adipose tissue depot-specific regulation of DNA repair genes linking DNA methylation to lipid metabolism and fat distribution. Our data might help to understand the individual risk for developing comorbidities of obesity. AbStrActIntroduction Regional fat distribution strongly relates to metabolic comorbidities. We identified the DNA repair genes H2AX and HMGB1 to be differentially expressed between human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) depots. As increased DNA damage is linked to metabolic disease, we here sought to analyze whether depot-specific H2AX and HMGB1 expression is related to anthropometric and metabolic profiles of obesity. We further tested for different H2AX mRNA regulatory mechanisms by analyzing promoter DNA methylation and genotyped rs7350 in the H2AX locus.Research design and methods Gene expression (OVAT n=48; SAT n=55) and DNA promoter methylation data (OVAT and SAT n=77) were extracted from an existing dataset as described elsewhere. Genotype data for the 3'untranslated region (3'UTR) H2AX variant rs7350 were generated by using the TaqMan genotyping system in 243 subjects of the same cohort. Statistical analyses were done using SPSS statistics software 24 and GraphPad Prism 6.Results We identified H2AX being higher (p=0.002) and HMGB1 being less expressed (p=0.0001) in OVAT compared with SAT. Further, we observed positive interdepot correlations of OVAT and SAT for both HMGB1 (p=1×10 -6 ) and H2AX mRNA levels (p=0.024). Depotspecific associations were observed for both genes' methylation levels with either high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerid...

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“…It is now being increasingly recognized that obesity results from a complex interplay between genetics and environmental factors and that epigenetic processes may constitute a physiological mechanism by which these genetic and environmental factors interact [2,3]. Recent studies in individuals with obesity indicate that various genes implicated in both metabolic regulation and brain function may be involved [2,3]. As such, the CREB regulated transcription coactivator 1 (CRTC1) – an important mediator in the hypothalamus of the effects of hormones and nutrient signals on energy balance [4] – is an interesting candidate for improving the understanding of molecular mechanisms of obesity.…”

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confidence: 99%

“…Interestingly, animal studies have shown that (unlike other CREB co-activators such as Crtc2) Crtc1 is primarily expressed in the brain [4,8]. The various associations reported by Rohde et al [3] with blood and adipose tissue-based (epi)genetic measures of CRTC1 are in line with the obese phenotype observed in Crtc1 knockout mice [4,8]. Yet, as DNA methylation cannot be assessed directly in the living human brain, an important avenue for future work is the use of animal models of obesity to validate current methylation findings in brain tissue.…”

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confidence: 99%