Human leptin tissue distribution, but not weight loss-dependent change in expression, is associated with methylation of its promoter

Marchi, M. Claudia; Lisi, Simonetta; Curcio, Michele; Barbuti, Serena; Piaggi, Paolo; Ceccarini, Giovanni; Nannipieri, Monica; Anselmino, Marco; Salvo, Clelia Di; Vitti, Paolo; Pinchera, Aldo; Santini, Ferruccio; Maffei, Margherita

doi:10.4161/epi.6.10.16600

Cited by 52 publications

(46 citation statements)

References 51 publications

(55 reference statements)

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“…We replicated an overall pattern of DNA methylation variation previously identified in this region, with C/EBPαTBS consistently showing the higher percentage of methylation than adjacent CpG sites (Marchi et al, 2011) The pattern is similar to a Canadian study which reports a similar pattern of methylation variation across this region in samples of blood and two fatty tissues, subcutaneous and visceral. The authors report similar overall pattern, but a lower degree of DNA methylation in adipose tissue than blood (Houde et al, 2015).…”

Section: Discussionsupporting

confidence: 76%

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Mosher¹,

Melton²,

Stapleton³

et al. 2016

Human Biology

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DNA methylation is the most widely studied of epigenetic mechanisms, with environmental effects recorded through patterned attachments of methyl groups along the DNA which are capable of modifying gene expression without altering the DNA sequencing. The degree to which these patterns of DNA methylation are heritable, the expected range of normality across populations, and the phenotypic relevance of pattern variation remain unclear. Genes regulating metabolic pathways appear to be vulnerable to ongoing nutritional programming over the life course, as dietary nutrients are significant environmental determinants of DNA methylation, supplying both the methyl groups and energy to generate the methylation process.Here we examine methylation patterns along a region of the metabolic gene leptin (LEP). LEP's putative function includes regulation of energy homeostasis, with its signals affecting energy intake and expenditure, adipogenesis and energy storage, lipid and glucose metabolism, bone metabolism and Pre-print version. Visit http://digitalcommons.wayne.edu/humbiol/ after publication to acquire the final version.reproductive endocrine function. A pattern of differential methylation across CpG sites of the LEP core promoter has been previously identified; however, any consistency of pattern or its phenotypic significance is not fully elucidated among populations. Using DNA extracted from unfractionated white blood cells of peripheral blood samples, our pilot study, divided into two parts, examines the significance of variation in DNA methylation patterns along the leptin core promoter in four populations and uses biomarkers reflecting leptin's functional process in two of those populations to investigate the relevance of the ethnic variation identified in the DNA methylation. Those two populations are the Western Buryats of Siberia and the Mennonites of Central Kansas.LEP's core promoter region contains both the C/EBPα transcription binding site (TBS) which tempers the final step in adipocyte maturity and capacity to synthesize leptin and the TATA motif controlling leptin synthesis. Previous studies report that increased methylation in this region is correlated to decreased gene expression, with others suggesting tissue-specific methylation variation at this region. We hypothesize that evidence of nutritional epigenetic programming would be identified through variation in patterns of DNA methylation and that functional relevance of that variation among populations would be identified through biomarkers which reflect leptin's metabolic signals: serum leptin levels, lipoproteins of the lipid transport system and anthropometric measures.A distinct and consistent overall pattern of differential DNA methylation across seven CpG sites of LEP core promoter is documented in all ethnicities and both sexes in our combined analyses of 313 individuals. This pattern replicates those identified in previous studies, thus suggesting a conserved core promoter region across populations. The second analyses in two of the four ...

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Section: Discussionsupporting

confidence: 76%

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Mosher¹,

Melton²,

Stapleton³

et al. 2016

Human Biology

View full text Add to dashboard Cite

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“…Regarding leptin function and biology, it was established that methylation of a proximal region of LEP promoter constitutes a significant determinant of leptin expression in human adult tissues since that DNA methylation has a role in long-term gene silencing and that demethylation is able to increase and reactive leptin expression [72]. Moreover, several studies have demonstrated that methylation of a CpG island in the leptin promoter plays an important role in leptin expression during pre-adipocyte differentiation [73,74] and may be involved in obesityrelated leptin upregulation [58,75,76].…”

Section: Epigenetic Regulation Of Leptin-related Signalling Pathways:mentioning

confidence: 99%

Leptin resistance in obesity: An epigenetic landscape

et al. 2015

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“…For instance, a recent study by Huang et al described a positive correlation between IGF2-H19 DNA methylation levels and ultrasound-derived measures of subcutaneous fat thickness in young adults [105]. Furthermore, DNA methylation levels at the LEP promoter were shown to be related to its tissue distribution [106]. As mutations in LMNA represent a major determinant of monogenic forms of altered FD, it is of interest that a recent study proposed that lamin A/C-promoter interactions specify chromatin state-dependent transcription outcomes [107].…”

Section: Epigenetics and Other Aspectsmentioning

confidence: 99%

The genetics of fat distribution

et al. 2014

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Fat stored in visceral depots makes obese individuals more prone to complications than subcutaneous fat. There is good evidence that body fat distribution (FD) is controlled by genetic factors. WHR, a surrogate measure of FD, shows significant heritability of up to ∼60%, even after adjusting for BMI. Genetic variants have been linked to various forms of altered FD such as lipodystrophies; however, the polygenic background of visceral obesity has only been sparsely investigated in the past. Recent genome-wide association studies (GWAS) for measures of FD revealed numerous loci harbouring genes potentially regulating FD. In addition, genes with fat depot-specific expression patterns (in particular subcutaneous vs visceral adipose tissue) provide plausible candidate genes involved in the regulation of FD. Many of these genes are differentially expressed in various fat compartments and correlate with obesity-related traits, thus further supporting their role as potential mediators of metabolic alterations associated with a distinct FD. Finally, developmental genes may at a very early stage determine specific FD in later life. Indeed, genes such as TBX15 not only manifest differential expression in various fat depots, but also correlate with obesity and related traits. Moreover, recent GWAS identified several polymorphisms in developmental genes (including TBX15, HOXC13, RSPO3 and CPEB4) strongly associated with FD. More accurate methods, including cardiometabolic imaging, for assessment of FD are needed to promote our understanding in this field, where the main focus is now to unravel the yet unknown biological function of these novel 'fat distribution genes'.

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Human leptin tissue distribution, but not weight loss-dependent change in expression, is associated with methylation of its promoter

Cited by 52 publications

References 51 publications

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Patterns of DNA Methylation across the Leptin Core Promoter in Four Diverse Asian and North American Populations

Leptin resistance in obesity: An epigenetic landscape

The genetics of fat distribution

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