Complement Factor C3 Methylation and mRNA Expression Is Associated to BMI and Insulin Resistance in Obesity.

Daniel Castellano-Castillo,Francisco José Tinahones,María Isabel Queipo-Ortuño,Isabel Moreno-Indias,Manuel Castro-Cabezas,Jose Carlos Fernandez-Garcia,Fernando Cardona,Mercedes Clemente-Postigo

doi:10.3390/genes9080410

Daniel Castellano-Castillo, Francisco José Tinahones + Show 6 more

Open Access

https://doi.org/10.3390/genes9080410

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Abstract

Epigenetic marks, and especially DNA methylation, are becoming an important factor in obesity, which could help to explain its etiology and associated comorbidities. Adipose tissue, now considered as an important endocrine organ, produces complement system factors. Complement component 3 (C3) turns out to be an important protein in metabolic disorders, via either inflammation or the C3 subproduct acylation stimulating protein (ASP) which directly stimulates lipid storage. In this study, we analyze C3 DNA methylation in adipose tissue from subjects with a different grade of obesity. Adipose tissue samples were collected from subjects with a different degree of obesity determined by their body mass index (BMI) as: Overweight subjects (BMI ≥ 25 and <30), obese class 1/2 subjects (BMI ≥ 30 and <40) and obese class 3 subjects (BMI ≥ 40). C3 DNA methylation was measured for 7 CpGs by pyrosequencition using the Pyromark technology (Qiagen, Madrid Spain). C3 messenger RNA (mRNA) levels were analyzed by pre-designed Taqman assays (Applied biosystems, Foster City, CA, USA) and ASP/C3a was measured using a ELISA kit. The data were analyzed using the statistic package SPSS. C3 DNA methylation levels were lower in the morbid obese group. Accordingly, C3 methylation correlated negatively with BMI and leptin. However, C3 mRNA levels were more associated with insulin resistance, and positive correlations with insulin, glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) existed. ASP correlated negatively with high density lipoprotein (HDL) cholesterol. C3 methylation levels were associated to adiposity variables, such as BMI and leptin, while the C3 mRNA levels were associated to glucose metabolism.

Highlights

Obesity is a major public health problem and a significant risk factor for obesity-related diseases, such as type 2 diabetes, hypertension or cardiovascular disease [1]
component 3 (C3) DNA methylation, and that C3 DNA methylation shows a positive association with adiposity parameters (BMI and leptin)
C3 messenger RNA (mRNA) levels were related to insulin resistance and glucose homeostasis, which is in line with previous results from our group [22] and from other authors [23]

Summary

Introduction

Obesity is a major public health problem and a significant risk factor for obesity-related diseases, such as type 2 diabetes, hypertension or cardiovascular disease [1]. Human adipose tissue produces and secretes many factors of the complement pathway, complement component 3 (C3) being a key molecule in this pathway. C3a, a subproduct of C3, is converted in the acylation stimulating protein (ASP), which plays an important role in lipid metabolism by stimulating lipid storage [5,6]. Adipose tissue C3 production is strongly stimulated in the postprandial state, and in parallel, a peak of ASP at the adipocyte microenvironment level has been shown [7,8,9]. The specific adipocyte factor D (adipsin) is necessary for ASP production. ASP could have a central role in the interplay between the complement system and the metabolism [5]

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Conclusion