Monocyte gene expression in childhood obesity is associated with obesity and complexity of atherosclerosis in adults

G C Keustermans,A O Kraaijeveld,J Garssen,F W Asselbergs,J Waltenberger,H S Schipper,J Meerding,R Nuboer,E Kalkhoven,J W Sels,I E Hoefer,D Kofink,W De Jager,G Pasterkamp,B J Prakken,A Eikendal,J W Jukema

doi:10.1038/s41598-017-17195-3

Abstract

Childhood obesity coincides with increased numbers of circulating classical CD14++CD16- and intermediate CD14++CD16+ monocytes. Monocytes are key players in the development and exacerbation of atherosclerosis, which prompts the question as to whether the monocytosis in childhood obesity contributes to atherogenesis over the years. Here, we dissected the monocyte gene expression profile in childhood obesity using an Illumina microarray platform on sorted monocytes of 35 obese children and 16 lean controls. Obese children displayed a distinctive monocyte gene expression profile compared to lean controls. Upon validation with quantitative PCR, we studied the association of the top 5 differentially regulated monocyte genes in childhood obesity with obesity and complexity of coronary atherosclerosis (SYNTAX score) in a cohort of 351 adults at risk for ischemic cardiovascular disease. The downregulation of monocyte IMPDH2 and TMEM134 in childhood obesity was also observed in obese adults. Moreover, downregulation of monocyte TMEM134 was associated with a higher SYNTAX atherosclerosis score in adults. In conclusion, childhood obesity entails monocyte gene expression alterations associated with obesity and enhanced complexity of coronary atherosclerosis in adults.

Highlights

The childhood obesity epidemic has alarming cardiovascular consequences, and thereby limits the worldwide increase in life expectancy[1,2]
An unbiased clustering approach revealed a clear separation in monocyte gene expression profiles between lean and obese individuals (Fig. 1)
Childhood obesity coincides with increased circulating numbers of classical and intermediate monocytes[7], which prompts the question as to whether the monocytosis in childhood obesity contributes to atherogenesis over the years

Summary

Introduction

The childhood obesity epidemic has alarming cardiovascular consequences, and thereby limits the worldwide increase in life expectancy[1,2]. Monocytes show an activated and inflammatory phenotype in obesity. We have shown that childhood obesity is accompanied by increased numbers and an activated phenotype of the classical CD14++CD16− monocyte subset[7]. These monocytes are equivalent to GR1+Ly6chigh monocytes in mice, that differentiate into inflammatory macrophages and foam cells in various atherosclerosis models[12,13]. Monocyte gene expression profiles were compared with an established cohort of 351 adults at risk for ischemic cardiovascular disease, to study whether monocyte gene expression profiles in childhood obesity overlap with an atherogenic monocyte phenotype in adults. The adult cohort encompassed several clinical parameters, but we focused on the relation between monocyte gene expression and the SYNTAX atherosclerosis score because it is an established angiographic grading system for evaluating the complexity of coronary atherosclerotic lesions, widely used as a readout for atherosclerotic burden[14,15,16,17,18]

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