Elsevier

Biomedicine & Pharmacotherapy

Volume 103, July 2018, Pages 482-489
Biomedicine & Pharmacotherapy

Proresolving protein Annexin A1: The role in type 2 diabetes mellitus and obesity

https://doi.org/10.1016/j.biopha.2018.04.024Get rights and content

Highlights

  • Annexin A1 (AnxA1) levels were higher in individuals with obesity.

  • AnxA1 and IL-6 levels were positively correlated.

  • Cleaved AnxA1 was observed in adipose tissue from individuals with obesity.

Abstract

Background

Annexin A1 (AnxA1) is a protein involved in inflammation resolution that might be altered in obesity-associated type 2 diabetes mellitus (DM), which is a chronic inflammatory disease. The aim of this study was to evaluate AnxA1 serum levels in individuals with and without DM stratified according to the body mass index (BMI), and the dynamic of AnxA1 expression in adipose tissue from humans with obesity and non-obesity.

Methods

Serum samples were obtained from 41 patients with DM (lean, overweight and obese) and 40 controls, and adipose tissue samples were obtained from 16 individuals with obesity (with or without DM), and 15 controls.

Results

DM patients showed similar AnxA1 serum levels when compared to controls. However, when the individuals were stratified according to BMI, AnxA1 levels were higher in individuals with obesity than lean or overweight, and in overweight compared to lean individuals. Moreover, AnxA1 was correlated positively with IL-6 levels. AnxA1 levels were also positively correlated with BMI, waist circumference and waist-to-hip ratio. Furthermore, higher levels of cleaved AnxA1 were observed in adipose tissue from individuals with obesity, independently of DM status.

Conclusions

Enhanced levels of AnxA1 in serum of individuals with obesity suggest an attempt to counter-regulate the systemic inflammation process in this disease. However, the higher levels of cleaved AnxA1 in the adipose tissue of individuals with obesity could compromise its anti-inflammatory and proresolving actions, locally. Considering our data, AnxA1 cleavage in the adipose tissue, despite increased serum levels of this protein, and consequently the failure in inflammation resolution, suggests an important pathophysiological mechanism involved in inflammatory status observed in obesity.

Introduction

Obesity is the most important predisposing factor for type 2 diabetes mellitus (DM) [1]. Several studies have shown that low-grade chronic inflammation is an important factor in the pathogenesis of DM and obesity [[2], [3], [4]]. Adipocytes from patients with obesity produce large amounts of pro-inflammatory chemokines and cytokines, such as interleukin 6 (IL-6) [5]. In addition, it has been demonstrated that increased expression of pro-inflammatory cytokines in the adipose tissue plays an important role on macrophage infiltration and insulin resistance [6]. Once macrophages are recruited into the adipose tissue, they secrete a variety of cytokines that intensify the local inflammatory response, triggering a systemic insulin resistance [5].

It is recognized that the resolution of inflammation is a dynamically regulated process orchestrated by proresolving mediators that play important counter-regulatory roles on inflammatory processes. However, compromised resolution of inflammation has been demonstrated in some chronic diseases such as rheumatoid arthritis, diabetes and atherosclerosis [7,8]. The main mediators of resolution process described in the literature are proresolving lipids such as lipoxins (e.g. lipoxin A4 – LXA4), resolvins, maresins and protectins, and proteins such as galectins and annexin A1 [[7], [8], [9], [10]].

Annexin A1 (AnxA1), also known as lipocortin 1, is a glucocorticoid-regulated protein involved with anti-inflammatory and proresolving properties. AnxA1 is widely expressed in tissues and has been found in a soluble form in biological fluids [9,[11], [12], [13], [14]]. Human and mouse neutrophils, monocytes and macrophages constitutively contain high levels of AnxA1 in their cytoplasm. Following cell activation, AnxA1 (37-kDa) is readily mobilized to the cell surface where it interacts with its receptor named formyl peptide receptor 2 (FPR2, also known as ALX or FPRL1) in a paracrine/autocrine form [9]. However, AnxA1 may be cleaved by proteases in inflammatory conditions, resulting in various fragments, such as the 33-kDa form, which lacks the main pharmacophore core contained in the N-terminal portion of the parent protein [15,16]. The pro-inflammatory nature of AnxA1 cleavage products, including the 33-kDa form, has also been supported by reports of their increased levels in inflammatory diseases, such as airway secretions of patients with cystic fibrosis [[17], [18], [19]] and in lung extracts from ovalbumin-sensitized mice (mouse model of asthma) [20].

AnxA1 levels have been measured in some chronic inflammatory diseases and may serve as a biomarker of inflammation [21,22]. Thereby, we aimed to evaluate AnxA1 levels in individuals with and without DM stratified according to BMI, and to associate with the inflammatory status, as well as clinical and biochemical characteristics. Moreover, in order to evaluate the importance of the adipose tissue on AnxA1 production, we compared AnxA1 levels and its dynamic of cleavage in human visceral adipose tissue from individuals with obesity and non-obesity.

Section snippets

Subjects

This study included 41 patients with clinical and laboratory diagnosis of DM (8 men and 33 women) aged from 32 to 70 years, and 40 controls matched by age, gender (8 men and 32 women) and BMI. DM and diabetic kidney disease (DKD) diagnosis was based on the American Diabetes Association (ADA) [23], which defined, as albumin excretion, rate > 30 mg/24 h at least 2 of 3 specimens collections within a 3- to 6-month, and without coexisting renal diseases from causes other than diabetes. Controls

Subjects characteristics

Clinical and biochemical characteristics of patients and controls are presented in Table 1. As expected, fasting blood glucose levels were significantly higher in DM group. The waist-to-hip ratio (WHR) was also significantly higher in patients than in controls. Moreover, IL-6 levels in DM patients (2.49 (3.68) pg/mL) were higher than controls (1.02 (1.07) pg/mL). Systemic arterial hypertension was more frequent in DM group. The other parameters did not present significant differences between

Discussion

In this study we evaluated the serum levels of the anti-inflammatory and proresolving protein AnxA1 in diabetic patients and controls (with or without obesity) and investigated the correlation between the concentration of this molecule and a pro-inflammatory mediator, IL-6, which is widely known to be increased in diabetes mellitus and obesity [[25], [26], [27]]. Moreover, we also analyzed AnxA1 levels in visceral adipose tissue of humans with non-obesity, obesity solely and obesity with DM, in

Conclusions

In conclusion, AnxA1 levels could be increased in obesity in an attempt to counter-regulate the inflammatory response seen in this condition. However, the higher levels of cleaved AnxA1 observed in the adipose tissue of individuals with obesity suggest that its anti-inflammatory and proresolving actions are compromised, or yet their levels are not enough to override the huge amount of pro-inflammatory mediators that is found in such disease. AnxA1 cleavage, and consequently the failure in

Funding sources

This work was supported by CAPES, CNPq and FAPEMIG.

Disclosure

The authors declare that they have no conflict of interest.

All authors have approved the final article.

Authors contributions

  • 1)

    Nathalia T. Pietrani, Lirlândia P. Sousa, Karina B. Gomes: conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content, final approval of the version to be submitted.

  • 2)

    Cláudia N. Ferreira, Kathryna F. Rodrigues, Luiza O. Perucci, Fernanda S. Carneiro, Marina C. Oliveira, Solange S. Pereira: acquisition of data. Luiza O. Perucci also contributed by writing the manuscript.

  • 3)

    Adriana A.

Acknowledgements

ALT, JIAL, AVF, LPS and KBG is grateful to CNPq Research Fellowship (PQ).

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    KG and LS contributed equally to this study.

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