Impact of obesity and overweight on DNA stability: Few facts and many hypotheses

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Abstract

Health authorities are alarmed worldwide about the increase of obesity and overweight in the last decades which lead to adverse health effects including inflammation, cancer, accelerated aging and infertility. We evaluated the state of knowledge concerning the impact of elevated body mass on genomic instability. Results of investigations with humans (39 studies) in which DNA damage was monitored in lymphocytes and sperm cells, are conflicting and probably as a consequence of heterogeneous study designs and confounding factors (e.g. uncontrolled intake of vitamins and minerals and consumption of different food types). Results of animal studies with defined diets (23 studies) are more consistent and show that excess body fat causes DNA damage in multiple organs including brain, liver, colon and testes. Different molecular mechanisms may cause genetic instability in overweight/obese individuals. ROS formation and lipid peroxidation were found in several investigations and may be caused by increased insulin, fatty acid and glucose levels or indirectly via inflammation. Also reduced DNA repair and formation of advanced glycation end products may play a role but more data are required to draw firm conclusions. Reduction of telomere lengths and hormonal imbalances are characteristic for overweight/obesity but the former effects are delayed and moderate and hormonal effects were not investigated in regard to genomic instability in obese individuals. Increased BMI values affect also the activities of drug metabolizing enzymes which activate/detoxify genotoxic carcinogens, but no studies concerning the impact of these alterations of DNA damage in obese individuals are available. Overall, the knowledge concerning the impact of increased body weight and DNA damage is poor and further research is warranted to shed light on this important issue.

Introduction

Obesity and overweight are characterized by abnormal accumulation of body mass and are associated with increased health risks, in particular with diseases such as type 2 diabetes (T2D), cardiovascular diseases, polycystic ovary syndrome, infertility and cancer [1]. Scientists and health authorities are alarmed by the fact that the increase of overweight/obesity is a worldwide phenomenon. A global estimate indicates that about 640 million adults were obese in 2014, this number corresponds to a 6-fold increase since 1975 [2]. Obesity has a prevalence of 10.8% among men and 14.9% among women [3]. The worldwide incidence of childhood overweight and obesity increased from 4.2% in 1990 to 6.7% in 2010. This trend is expected to reach 9.1% or 60 million, in 2020 [4].

A typical feature of excess body weight is the formation of ROS and of cytokines which are characteristic for inflammation. These processes lead to damage of the genetic material which in turn plays a key role in the induction of cancer and infertility; these disorders are increased in overweight/obese humans [5,6]. Aim of this article is to describe the current state of knowledge of the relation between excess body weight and genomic instability. Recently, several studies have been published which concern the association between MetS and DNA damage [[7], [8], [9]], however they are based on mechanistic considerations but not on a systematic evaluation of experimental data. The first part of the present paper focuses on the description of results of animal and human studies in which different parameters of DNA instability and chromosomal damage were measured in overweight/obese individuals in somatic and germ cells. Furthermore, we describe also measurements which were performed in these studies concerning biological processes that lead to DNA stability such as inhibition of DNA repair processes, decrease of the telomere lengths, changes of the redox status and of the activities of antioxidant enzymes, lipid peroxidation and of the immune status.

The association between overweight/obesity and cancer is well documented; it is, apart from cardiovascular diseases, the most important health consequence of excess body weight. In 2016, the IARC published a report which is based on the evaluation of more than 1000 individual epidemiological studies. The Agency comes to the conclusion that the absence of excess body fatness lower the risks of most cancer [2]. A comprehensive study from the US states that 14% of all cancer cases in man and 20% in women are due to obesity [10].

Numerous investigations showed that gene mutations as well as chromosomal aberrations play a key role in malignant transformation [11,12]. Nevertheless, it is apparent that most studies which concerned the mechanisms by which excess body weight leads to cancer focused on other modes of action such as alterations of signaling pathways, increased production of growth factors and hormones and activation of transcription factors (for reviews see [[13], [14], [15]]).

In the last decades, a variety of methods was developed which enable the investigation of DNA stability in human and animal models [16]. These approaches were frequently used to study occupational, lifestyle and dietary factors [[16], [17], [18], [19], [20]]. Furthermore, in vitro assays [21] and rodent mutagenicity tests [22,23] are conducted worldwide for routine monitoring of chemicals. These models can be also used to identify drugs and dietary components which protect humans against DNA damage and its consequences [16,24,25].

This review describes human and animal studies which concern the impact of overweight/obesity on DNA integrity. The results of these investigations may contribute to a better understanding of the mechanisms by which excess body weight causes adverse health consequences such as cancer and infertility and can also contribute to the development of strategies to prevent these effects. We included also investigations concerning the MetS, which is the most important consequence of abdominal obesity. Studies concerning T2D and the polycystic ovary syndrome were excluded; these disorders are related to obesity but are characterized by severe additional pathological changes, which may have an impact on DNA stability but are not attributable to excess body weight [26,27].

The following chapter defines the search strategy (chapter 2) and the methods which were used (chapter 3). The subsequent paragraphs describe investigations with humans (chapter 4) and animals (chapter 5), the impact of obesity on mutations in oncogenes (chapter 6) and in vitro studies (chapter 7). Furthermore we describe the molecular mechanisms by which overweight/obesity may cause DNA damage (chapter 8), the consequence of obesity induced DNA damage and the links between DNA damage and cancer (chapter 9) and define knowledge gaps and future research strategies (chapter 10).

Section snippets

Data collection

The literature search was performed by using the MedLine/PubMed data-base (National Library of Medicine, http://www.ncbi.nlm.nih.gov/PubMed), SCOPUS (Elsevier, http://www.scopus.com), Thomson ISI’s Web of Science (Thomson Reuters Corporation, http://apps.webofknowledge.com), Google Scholar (http://www.google.scholar.com) and covered the period between December 1961 and August 2017.

Additionally, a manual search of the reference list of studies and of reviews was conducted. References of

Methods used in investigations concerning associations between genetic instability and overweight/obesity

Fig. 1 gives an overview of the methods which are used in studies with overweight/ obese humans and laboratory animals.

Table 1 describes different methods which were used to study impact of overweight/obesity on DNA stability. Most of these approaches are also used to investigate the effect of chemicals, lifestyle factors and chemical exposure in somatic cells, for studies with sperm cells additional test systems such as TUNEL assay and SCS assays were employed.

The most frequently method in

Human studies

The following chapters describe results which were obtained with somatic cells of healthy individuals (chapter 4.1) and MetS patients (chapter 4.2), chapter 4.3 summarizes the results with sperm cells and the last paragraph contains a comprehensive evaluation of the human studies.

DNA damage in somatic cells

Different models were used in experiments with laboratory rodents. In most trials, the animals were fed with a high fat diet (HFD) or a cafeteria diet (CAF) for several weeks which lead to an increase of the body fat and also to excess body weight. These studies were mainly conducted with C57BL/6 j mice; these animals develop symptoms which are characteristic for obese humans namely hyperinsulinemia, hyperglycemia, and hypertension [86]. In some studies Zucker rats were used; obesity is in

Impact of obesity/overweight on mutations in oncogenes

Only few studies concerned mutations in cancer associated genes of laboratory rodents and humans. These investigations are important as they enable to establish direct causal links between overweight induced genomic instability and malignant transformation.

Shen et al. [115] found in whole genome sequencing experiments with tissue from hepatocellular carcinomas of obese mice increased rates of mutations in the carboxyl ester lipase (Cel) gene and in the Harvey rat sarcoma virus oncogene 1 (Hras

Results of in vitro studies

It is not possible to investigate biochemical changes which are caused by excessive calorie intake and elevated body weight under in vitro conditions. Nevertheless, results of studies were published with mammalian and human cells which reflect physiological conditions that are characteristic for obese individuals such as increased concentrations of glucose, fatty acids and insulin. These findings contribute to a better understanding of the mechanisms by which overweight/obesity lead to the

Molecular mechanisms

The following paragraphs concern mechanisms which may play a role in the association between excess body weight and genomic instability (Fig. 2). Apart from enzymatic processes which lead to formation of ROS also other modes of action could be involved. Lipid peroxidation (LP) processes are induced by ROS and lead to formation of DNA reactive products. Furthermore, inhibition of DNA repair and induction of inflammation have been found in a number of studies. Also formation of advanced glycation

Consequences of obesity induced DNA damage

Overweight/obesity are associated with increased prevalence of different forms of cancer in humans [243,244]. The assumption of an association between excess body weight and cancer is also supported by results of rodent experiments [2,[90], [91], [92]]. We are not aware of any targeted studies in which correlations between DNA damage and cancer rates were investigated in obese humans and animals; however, direct links can be postulated on the basis of mechanistic studies.

Another relevant issue

Conclusions and knowledge gaps

Obesity and metabolic diseases are among the most relevant health risk factors for humans worldwide. The evaluation of the literature show that the impact of overweight/obesity on DNA stability which plays a key role in the etiology of cancer, infertility and ageing is not adequately investigated. We found in total 27 human studies concerning the effects of obesity/overweight individuals and MetS patients on genomic instability in somatic cells, 12 human and 5 animal investigations concerning

Conflict of interest statement

There are no conflict of interest.

Acknowledgments

This works was supported by Austrian Science Funds (Fonds zur Förderung der wissenschaftlichen Forschung (FWF); AP2658721) and by COST Action, CA15132 (hCOMET project); the authors are also thankful to participants of this research initiative for discussions.

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