Transcriptome Analyses of Adipose Tissue Samples Identify EGFL6 as a Candidate Gene Involved in Obesity-Related Adipose Tissue Dysfunction in Children

Abstract

Obesity develops early in childhood and is accompanied by early signs of adipose tissue (AT) dysfunction and metabolic disease in children. In order to analyse the molecular processes during obesity-related AT accumulation in children, we investigated genome-wide expression profiles in AT samples, isolated adipocytes, and stromal vascular fraction (SVF) cells and assessed their relation to obesity as well as biological and functional AT parameters. We detected alterations in gene expression associated with obesity and related parameters, i.e., BMI SDS, adipocyte size, macrophage infiltration, adiponectin, and/or leptin. While differential gene expression in AT and adipocytes shared an enrichment in metabolic pathways and pathways related to extracellular structural organisation, SVF cells showed an overrepresentation in inflammatory pathways. In adipocytes, we found the strongest positive association for epidermal growth factor-like protein 6 (EGFL6) with adipocyte hypertrophy. EGFL6 was also upregulated during in vitro adipocyte differentiation. In children, EGFL6 expression was positively correlated to parameters of AT dysfunction and metabolic disease such as macrophage infiltration into AT, hs-CRP, leptin levels, and HOMA-IR. In conclusion, we provide evidence for early alterations in AT gene expression related to AT dysfunction in children and identified EGFL6 as potentially being involved in processes underlying the pathogenesis of metabolic disease.

COBL, MKX and MYOC Are Potential Regulators of Brown Adipose Tissue Development Associated with Obesity-Related Metabolic Dysfunction in Children

“…In order to identify genes with a potential relevance for BAT development and brown adipocyte formation, we analyzed the Illumina transcriptome profiles of brown (positive for UCP1 protein in histological analyses, UCP1 + ) vs. white (negative for UCP1 protein in histological analyses, UCP1 − ) AT samples of patients included in the Leipzig AT Childhood cohort [ 24 , 25 , 26 ]. There were six perirenal and four subcutaneous UCP1 + AT samples available, and we compared them to two available perirenal and four subcutaneous (matched for age, sex and BMI SDS of probands) UCP1 − AT samples.…”

“…The measurement of global gene expression in AT samples of selected probands was performed with Illumina HumanHT-12 v4 BeadChip arrays [ 26 ].…”

Case report: Molecular characterisation of adipose-tissue derived cells from a patient with ROHHAD syndrome

“…These potential changes in IL-6 therefore need to be confirmed and interpreted with care. In addition, IL-6 expression is also increased in obese children without ROHHAD ( 35 , 36 ), which means it is likely not discriminatory for ROHHAD syndrome.…”

“…We performed biological pathway analysis using gene ontology (GO) and demonstrated enrichment of genes with pathways that were not highlighted in relation to childhood obesity alone ( 36 , 37 ). These included developmental processes including “anatomical structural development” (GO: 0048856, Pcorrected = 2.932 × 10–59), “system development” (GO: 0048731, Pcorrected = 3.761 × 10–56), multicellular organism development’ (GO: 0007275, Pcorrected = 4.32 × 10–56), developmental process (GO:0032502, Pcorrected = 3.773 × 10–52) and “multicellular organismal process” (GO: 0032501, Pcorrected = 1.615 × 10–47) ( Figure 4A ).…”

“…In keeping with this recent report, pathway analysis highlighted cytokine-cytokine receptor interaction as important as well as associated downstream signalling pathways. As cytokine-cytokine receptor interactions are also characteristic of obesity alone, this may not be specific to ROHHAD syndrome ( 36 , 38 ).…”