Fasting and time of day independently modulate circadian rhythm relevant gene expression in adipose and skin tissue

Alexessander Couto Alves, Craig A Glastonbury, Julia S El-Sayed Moustafa, Kerrin S Small, Alexessander Couto Alves, Craig A Glastonbury, Julia S El-Sayed Moustafa, Kerrin S Small

Abstract

Background: Intermittent fasting and time-restricted diets are associated with lower risk biomarkers for cardio-metabolic disease. The shared mechanisms underpinning the similar physiological response to these events is not established, but circadian rhythm could be involved. Here we investigated the transcriptional response to fasting in a large cross-sectional study of adipose and skin tissue from healthy volunteers (N = 625) controlling for confounders of circadian rhythm: time of day and season.

Results: We identified 367 genes in adipose and 79 in skin whose expression levels were associated (FDR < 5%) with hours of fasting conditionally independent of time of day and season, with 19 genes common to both tissues. Among these genes, we replicated 38 in human, 157 in non-human studies, and 178 are novel associations. Fasting-responsive genes were enriched for regulation of and response to circadian rhythm. We identified 99 genes in adipose and 54 genes in skin whose expression was associated to time of day; these genes were also enriched for circadian rhythm processes. In genes associated to both exposures the effect of time of day was stronger and in an opposite direction to that of hours fasted. We also investigated the relationship between fasting and genetic regulation of gene expression, including GxE eQTL analysis to identify personal responses to fasting.

Conclusion: This study robustly implicates circadian rhythm genes in the response to hours fasting independently of time of day, seasonality, age and BMI. We identified tissue-shared and tissue-specific differences in the transcriptional response to fasting in a large sample of healthy volunteers.

Keywords: Adipose; Circadian rhythm; Fasting; Gene expression; Gene x environment; Skin; eQTL.

Conflict of interest statement

Ethics approval and consent to participate

This project was approved by the ethics committee at St Thomas’ Hospital London, where all the biopsies were carried out. Volunteers gave informed consent and signed an approved consent form prior to the biopsy procedure. Volunteers were supplied with an appropriate detailed information sheet regarding the research project and biopsy procedure by post prior to attending for the biopsy.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Overall distribution of a hours fasting, b hours fasting stratified by AM/PM, and c biopsy time of day in the 625 individuals participating in this study
Fig. 2
Fig. 2
Histogram of the P values for the association between expression levels of all expressed genes in adipose and skin tissue with time of the day (TOD) and hours fasting (HF): a TOD in skin, b TOD in adipose, c HF in skin, d HF in adipose
Fig. 3
Fig. 3
Tissue-specificity of gene expression response to hours of fasting and time of day. Venn diagram of genes associated to hours fasting (top) and time of day (bottom) in adipose tissue (red) and skin (yellow) tissue. Genes associated to an exposure in both tissues are listed in the tables on the right. Tissue-shared genes are annotated to indicate genes that are members of the circadian clock or known to be regulated by circadian clock genes
Fig. 4
Fig. 4
Expression levels of most genes involved in the circadian clock are associated with fasting in adipose tissue. Diagram shows the Ingenuity canonical pathway of the circadian clock annotated to highlight genes showing fasting-associated changes in fat gene expression in this study. Proteins (homo or heterodimer) with all coding genes associated to fasting are annotated in red, proteins with at least one gene associated with fasting are annotated with a pink border
Fig. 5
Fig. 5
SNP x Hours of Fasting interactions on gene expression. The vertical axis represents expression of the given gene and the horizontal axis hours of fasting. Each point represents one individual. Each plot is split into three panels with individuals plotted in the panel corresponding to their genotype at the given SNP. Solid line represents the linear regression of expression on hours fasting, discontinuous line represents a smooth loess local regression

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