Genetic and epigenetic regulation of CRTC1 in human eating behaviour and fat distribution: Methodological and clinical insights and considerations

Obesity constitutes a significant challenge for individual and public health and the prevalence has been dramatically increasing globally. Prevalence rates of overweight and obesity are estimated to be 39% globally [[1]Chooi Y.C. Ding C. Magkos F. The epidemiology of obesity.Metabolism. 2019; 92: 6-10Summary Full Text Full Text PDF PubMed Scopus (1004) Google Scholar]. 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]Ling C. Ronn T. Epigenetics in human obesity and type 2 diabetes.Cell Metab. 2019; 29: 1028-1044Summary Full Text Full Text PDF PubMed Scopus (309) Google Scholar,[3]Rohde K. Keller M. la Cour Poulsen L. et al.(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution.EBioMedicine. 2019; (May 29. [Epub ahead of print])https://doi.org/10.1016/j.ebiom.2019.05.050Summary Full Text Full Text PDF Scopus (12) Google Scholar]. Recent studies in individuals with obesity indicate that various genes implicated in both metabolic regulation and brain function may be involved [[2]Ling C. Ronn T. Epigenetics in human obesity and type 2 diabetes.Cell Metab. 2019; 29: 1028-1044Summary Full Text Full Text PDF PubMed Scopus (309) Google Scholar,[3]Rohde K. Keller M. la Cour Poulsen L. et al.(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution.EBioMedicine. 2019; (May 29. [Epub ahead of print])https://doi.org/10.1016/j.ebiom.2019.05.050Summary Full Text Full Text PDF Scopus (12) Google Scholar]. 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]Altarejos J.Y. Goebel N. Conkright M.D. et al.The Creb1 coactivator Crtc1 is required for energy balance and fertility.Nat Med. 2008; 14: 1112-1117Crossref PubMed Scopus (156) Google Scholar] – is an interesting candidate for improving the understanding of molecular mechanisms of obesity. Following up on animal studies and the reported associations between genotypic CRTC1 variation and BMI and fat mass in humans (e.g. [[4]Altarejos J.Y. Goebel N. Conkright M.D. et al.The Creb1 coactivator Crtc1 is required for energy balance and fertility.Nat Med. 2008; 14: 1112-1117Crossref PubMed Scopus (156) Google Scholar,[5]Choong E. Quteineh L. Cardinaux J.R. et al.Influence of CRTC1 polymorphisms on body mass index and fat mass in psychiatric patients and the general adult population.JAMA Psychiat. 2013; 70: 1011-1019Crossref PubMed Scopus (40) Google Scholar]), the aim of the study by Rohde et al. [[3]Rohde K. Keller M. la Cour Poulsen L. et al.(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution.EBioMedicine. 2019; (May 29. [Epub ahead of print])https://doi.org/10.1016/j.ebiom.2019.05.050Summary Full Text Full Text PDF Scopus (12) Google Scholar] in EBioMedicine was to investigate genetic and epigenetic (DNA methylation) regulation of the CRTC1 gene in relation to eating behaviours and physiological parameters relevant to obesity. Research questions were studied in two independent community samples and in individuals with obesity. Interestingly, DNA methylation was assessed in whole blood and in two types of adipose tissue (omental/visceral and subcutaneous). The study yielded various methodological and clinical insights: One of the novel findings was that DNA methylation levels of a CpG within the CRTC1 rs7256986 polymorphism and in a neighbouring CpG were allele/genotype-dependent, suggesting a methylation quantitative trait locus (meQTL). This result complements previous studies that have identified various other SNPs involved in metabolic traits that may play a causal role in the regulation of DNA methylation in adipose tissue [[6]Volkov P. Olsson A.H. Gillberg L. et al.A genome-wide mQTL analysis in human adipose tissue identifies genetic variants associated with DNA methylation, gene expression and metabolic traits.PLoS One. 2016; 11e0157776Crossref PubMed Scopus (62) Google Scholar]. Identifying a meQTL in blood and adipose tissue in relation to eating behaviours and obesity is of interest since it could provide mechanistic insight into how SNPs influence the (clinical) phenotype. It may also constitute one of the possible mechanisms explaining how DNA methylation patterns could be transferred to subsequent generations. Whereas the MeQTL was present in both blood and in the two types of adipose tissues, DNA methylation and gene expression levels in the three tissues were somewhat differentially associated with the various outcome measures. The reason for this cross-tissue divergence is unclear, but may further underscore the importance of collecting multiple samples when studying peripheral tissue DNA methylation in association with behavioural and physiological outcome [[7]Di Sante J. Ismaylova E. Nemoda Z. et al.Peripheral DNA methylation of HPA axis-related genes in humans: cross-tissue convergence, two-year stability and behavioural and neural correlates.Psychoneuroendocrinology. 2018; 97: 196-205Crossref PubMed Scopus (15) Google Scholar]. Interestingly, animal studies have shown that (unlike other CREB co-activators such as Crtc2) Crtc1 is primarily expressed in the brain [[4]Altarejos J.Y. Goebel N. Conkright M.D. et al.The Creb1 coactivator Crtc1 is required for energy balance and fertility.Nat Med. 2008; 14: 1112-1117Crossref PubMed Scopus (156) Google Scholar,[8]Rossetti C. Sciarra D. Petit J.M. et al.Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression.Transl Psychiatry. 2017; 7: 1269Google Scholar]. The various associations reported by Rohde et al. [[3]Rohde K. Keller M. la Cour Poulsen L. et al.(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution.EBioMedicine. 2019; (May 29. [Epub ahead of print])https://doi.org/10.1016/j.ebiom.2019.05.050Summary Full Text Full Text PDF Scopus (12) Google Scholar] with blood and adipose tissue-based (epi)genetic measures of CRTC1 are in line with the obese phenotype observed in Crtc1 knockout mice [[4]Altarejos J.Y. Goebel N. Conkright M.D. et al.The Creb1 coactivator Crtc1 is required for energy balance and fertility.Nat Med. 2008; 14: 1112-1117Crossref PubMed Scopus (156) Google Scholar,[8]Rossetti C. Sciarra D. Petit J.M. et al.Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression.Transl Psychiatry. 2017; 7: 1269Google Scholar]. 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. It may still be too early to know whether findings could be applied in clinical practice. Effect sizes and sample sizes were generally small and many of the reported associations did not withstand multiple comparison correction. On the other hand, small effect sizes in this domain of research are common given that eating behaviour / obesity are highly complex behaviours / disorders with multiple genetic and environmental determinants [[1]Chooi Y.C. Ding C. Magkos F. The epidemiology of obesity.Metabolism. 2019; 92: 6-10Summary Full Text Full Text PDF PubMed Scopus (1004) Google Scholar,[2]Ling C. Ronn T. Epigenetics in human obesity and type 2 diabetes.Cell Metab. 2019; 29: 1028-1044Summary Full Text Full Text PDF PubMed Scopus (309) Google Scholar]. Studies with larger sample sizes and including measures such as early-life adversity, mental health and socioeconomic status may further help to adjust for confounding factors in the reported (epi)genetic associations. Furthermore, we know very little about how stable peripheral methylation samples (including but not limited to CRTC1 methylation) are over time and methylation stability could be different depending on tissue. Longitudinal studies assessing DNA methylation at various points in time may provide insight into the dynamic nature of CRTC1 methylation and into whether peripheral CRTC1 methylation patterns are prone to changes in environmental conditions such as diet. Lastly, animal models suggested that Crtc1 may play a role in the bidirectional relation between obesity and depression [[8]Rossetti C. Sciarra D. Petit J.M. et al.Gender-specific alteration of energy balance and circadian locomotor activity in the Crtc1 knockout mouse model of depression.Transl Psychiatry. 2017; 7: 1269Google Scholar]. An interesting question for future research is to what extent CTRC1 dysregulation is associated with psychiatric disorders such as Anorexia Nervosa (AN) where weight dysregulation, restraint eating and altered energy metabolism are key symptoms. Although AN and obesity are considered at the opposite ends of the spectrum of weight regulation, both disorders have been shown to share genetic and epigenetic correlations with metabolic phenotypes [[2]Ling C. Ronn T. Epigenetics in human obesity and type 2 diabetes.Cell Metab. 2019; 29: 1028-1044Summary Full Text Full Text PDF PubMed Scopus (309) Google Scholar,[9]Duncan L. Yilmaz Z. Gaspar H. et al.Significant locus and metabolic genetic correlations revealed in genome-wide association study of Anorexia Nervosa.Am J Psychiatry. 2017; 174: 850-858Crossref PubMed Scopus (266) Google Scholar,[10]Steiger H. Booij L. Kahan E. et al.A longitudinal, epigenome-wide study of DNA methylation in anorexia nervosa: results in actively ill, partially weight-restored, long-term remitted and non-eating-disordered women.J Psychiatry Neurosci. 2019; 44: 205-213Google Scholar]. Yet, it is not known whether CRTC1 plays a role in AN. In sum, the study by Rohde et al. [[3]Rohde K. Keller M. la Cour Poulsen L. et al.(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution.EBioMedicine. 2019; (May 29. [Epub ahead of print])https://doi.org/10.1016/j.ebiom.2019.05.050Summary Full Text Full Text PDF Scopus (12) Google Scholar] provides some interesting insights into the (epi)genetic regulation of CRTC1 in humans and its possible relevance for (mal)adaptive eating and energy metabolism. Results could help to guide the design of future (epi)genetic studies on the role of CRTC1 in disorders where altered metabolic function may play a role. The author has no conflict of interest. (Epi)genetic regulation of CRTC1 in human eating behaviour and fat distributionOur data support the known role of CRCT1 regulating energy metabolism in brain. Here, we highlight relevance of CRTC1 regulation in blood and adipose tissue. Full-Text PDF Open Access

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