Integrated Multiomic Analysis Reveals the High-Fat Diet Induced Activation of the MAPK Signaling and Inflammation Associated Metabolic Cascades via Histone Modification in Adipose Tissues

Abstract

BackgroundThe number of diet induced obese population is increasing every year, and the incidence of type 2 diabetes is also on the rise. Histone methylation and acetylation have been shown to be associated with lipogenesis and obesity by manipulating gene expression via the formation of repression or activation domains on chromosomes.ObjectiveIn this study, we aimed to explore gene activation or repression and related biological processes by histone modification across the whole genome on a high-fat diet (HFD) condition. We also aimed to elucidate the correlation of these genes that modulated by histone modification with energy metabolism and inflammation under both short-term and long-term HFD conditions.MethodWe performed ChIP-seq analysis of H3K9me2 and H3K9me3 in brown and white adipose tissues (WATs; subcutaneous adipose tissue) from mice fed with a standard chow diet (SCD) or HFD and a composite analysis of the histone modification of H3K9me2, H3K9me3, H3K4me1 and H3K27ac throughout the whole genome. We also employed and integrated two bulk RNA-seq and a single-nuclei RNA sequencing dataset and performed western blotting (WB) to confirm the gene expression levels in adipose tissue of the SCD and HFD groups.ResultsThe ChIP-seq and transcriptome analysis of mouse adipose tissues demonstrated that a series of genes were activated by the histone modification of H3K9me2, H3K9me3, H3K4me1, and H3K27ac in response to HFD condition. These genes were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in lipogenesis, energy metabolism and inflammation. Several genes in the activated mitogen-activated protein kinase (MAPK) pathway might be related to both inflammation and energy metabolism in mice, rats and humans fed with HFD for a short or long term, as showed by bulk RNA-seq and single nuclei RNA-seq datasets. Western blot analyses further confirmed the increased expression of MET, VEGFA and the enhanced phosphorylation ratio of p44/42 MAPK upon HFD treatment.ConclusionThis study expanded our understanding of the influence of eating behavior on obesity and could assist the identification of putative therapeutic targets for the prevention and treatment of metabolic disorders in the future.

Signaling pathways in obesity: mechanisms and therapeutic interventions

“… 62 In adipose tissues from HFD-fed mice, integrated multiomic analysis shows that the inflammatory genes are enriched in MAPK pathways in macrophages. 68 Licochalcone F, a synthetic retrochalcone, was found to inhibit tumor necrosis factor (TNF)α-induced expression of inflammatory factors and further alleviated glucose tolerance, reduced adipocyte size, and decreased macrophage infiltration in WAT, by interacting with MAPK signaling pathway. 69 …”

Regulation of Adipose Thermogenesis and its Critical Role in Glucose and Lipid Metabolism

“…Nowadays, there are several scientific research methods and several technologies are being developed. Some emerging research methods can be introduced into the study of adipose tissue, such as the three-dimensional genome of adipocytes and single-cell multi-omics sequencing, to discover more functional genes that play a role in the function of adipose tissue [123][124][125]. In addition, in recent years, tRNA-derived RNA fragments and piRNAs in ncRNAs have also attracted the attention of researchers [126,127], and their roles in adipose tissue are still worthy of our attention and exploration.…”

Recent progress in epigenetics of obesity

“…Post-translational modifications of DNAm and histone synergistically build complex epigenetic signals and alter transcriptional networks in patients with cardiometabolic disorders [ 82 ]. In a previous study, Wang et al [ 83 ] explored the effects of genome-wide histone modifications on genetic and biological processes during a high-fat diet and elucidated the relevance of gene modifications to energy metabolism and inflammation under different conditions. ChIP-seq and transcriptome in mouse adipose tissue revealed that numerous genes involved in adipogenesis, energy metabolism and inflammatory pathways were modified by H3K9me2, H3K9me3, H3K4me1 and H3K27ac histones during a high-fat diet.…”