Gene expression levels of S100 protein family in blood cells are associated with insulin resistance and inflammation (Peripheral blood S100 mRNAs and metabolic syndrome)

https://doi.org/10.1016/j.bbrc.2013.02.096Get rights and content

Highlights

  • Microarray analysis and RT-PCR was performed in blood cells from 57 obese subjects.

  • Among genes relating to inflammation, 14 genes were associated with visceral fat.

  • S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity.

  • S100 family mRNA levels were associated with insulin resistance and inflammation.

Abstract

Objective

Visceral fat obesity is located upstream of metabolic syndrome and atherosclerotic diseases. Accumulating evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation. We recently analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells in human subjects and demonstrated the close relationship of visceral fat adiposity and disturbance of circadian rhythm in peripheral blood cells. In a series of studies, we herein investigated the association of visceral fat adiposity and mRNA levels relating to inflammatory genes in peripheral blood cells.

Approach and Results

Microarray analysis was performed in peripheral blood cells from 28 obese subjects. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted by using blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m2 according to the Japanese criteria. Gene expression profile analysis was carried out with Agilent whole human genome 4 × 44 K oligo-DNA microarray. Gene ontology (GO) analysis showed that 14 genes were significantly associated with visceral fat adiposity among 239 genes relating to inflammation. Among 14 genes, RT-PCR demonstrated that S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity in 57 subjects. Stepwise multiple regression analysis showed that S100A8 and S100A12 mRNA levels were closely associated with HOMA-IR and S100A9 mRNA was significantly related to adiponectin and CRP.

Conclusions

Peripheral blood mRNA levels of S100 family were closely associated with insulin resistance and inflammation.

Introduction

Obesity, especially visceral fat-accumulated obesity, is closely associated with the development of atherosclerotic diseases and is strongly linked to metabolic syndrome [1]. Molecular mechanism for metabolic syndrome has been investigated but it has not been fully understood at present. Increasing evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation, which develops into insulin resistance and metabolic syndrome [2]. Moreover, these immune cells interact with adipocytes through free fatty acids and adipocytokines, generating a vicious metabolic cycle that accelerates the development of metabolic syndrome and atherosclerosis [3], [4].

These pathologies in obese fat tissue suggest that gene expression profile in peripheral blood cells may reflect the visceral fat condition. Recently, we examined and analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells to search novel surrogate markers relating to visceral fat adiposity and to establish novel diagnostic tools for metabolic syndrome [5]. Interestingly, genes relating to circadian rhythm were significantly correlated with visceral fat adiposity, suggesting that visceral fat adiposity links to disturbance of circadian rhythm. In a series of studies for the impact of visceral fat adiposity on the gene expression profile in peripheral blood cells, we here analyzed the association of visceral fat adiposity and expression levels of inflammatory genes in peripheral blood cells.

Section snippets

Study population and clinical examinations

All subjects were inpatients of the Division of Endocrinology & Metabolism, Osaka University Hospital, Osaka, Japan. Written informed consent was obtained from each subject after explaining the purpose and potential complications of the study. The study protocol was approved by the human ethics committee of Osaka University and the study was registered with the University hospital Medical Information Network (Number: UMIN 000001663). Subjects and clinical examinations were described previously.

Characteristics of the subjects

The clinical characteristics of the participating subjects are listed in our previous report [5]. Briefly, the mean BMI, eVFA, and HOMA-IR of 57 patients were 30.6 kg/m2, 168.8 cm2, and 3.0, respectively. The proportion of patients with diabetes mellitus, dyslipidemia, and hypertension was 73%, 75%, and 58%, respectively. These clinical characteristics indicate that present study population is typical obesity with multiple complications.

Analysis of gene expression profiles

Microarray analysis was performed by using peripheral blood

Discussion

In the present study, we show that peripheral blood S100-relating genes were strongly associated with CRP, adiponectin, and HOMA-IR in obese subjects.

Our group for the first time demonstrated that S100A8 is highly expressed in obese adipose tissues and adipose S100A8 is significantly reduced by peroxisome proliferator-activated receptor-γ (PPARγ) agonist, indicating that S100A8 is one of adipocytokines [8]. Furthermore, we recently showed that circulating level of calprotectin (S100A8/A9

Sources of funding

This work was supported by Grants-in-Aid for Scientific Research (C) No. 22590979 (to N. M.), Scientific Research on Innovative Areas No. 22126008 (to T. F.), and Takeda Science Foundation (to N. M.).

Disclosures

None.

Acknowledgments

We thank Miyuki Nakamura, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, for the excellent technical assistance.

Reference (24)

  • M. Ryo et al.

    A new simple method for the measurement of visceral fat accumulation by bioelectrical impedance

    Diabetes Care

    (2005)
  • H. Nakatsuji et al.

    One -year reductions in body weight and blood pressure, but not in visceral fat accumulation and adiponectin, improve urinary albumin-to-creatinine ratio in middle-aged Japanese men

    Diabetes Care

    (2010)
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