Review articleOxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies☆
Graphical abstract
Introduction
Disruption of normal metabolic processes resulting in energy and redox imbalance sets the seed of many pathophysiological conditions in body which are collectively called metabolic disorders. The key hallmarks of metabolic disorder include risk factors such as dyslipidaemia, leptin resistance, reduced adiponectin, insulin refractoriness, defective insulin secretion, glucose intolerance which collectively referred to as metabolic syndrome [1]. According to National heart, lung and blood institute an individual must have at least three risk factors to be diagnosed with metabolic syndrome [2]. These risk factors contribute to cellular dysfunction and redox imbalance that contribute towards progression of pro-oxidative environment leading to damaged biomolecules, which are highly reactive in nature and can promote cell and tissue dysfunction leading to metabolic diseases. A clear correlation has emerged between oxidative stress and metabolic disorders which can be helpful in the identification of novel biomarkers, molecular targets, and effective drug development for prevention and therapy of these diseases.
Metabolic disorder, emanating from elevated body weight and obesity, has reached epidemic proportions in industrialized countries. According to World Health Organisation (WHO) in 2014, more than 1.9 billion adults, which included 18 years and older, were overweight. Of these more than 600 million were obese [3]. According to a systematic analysis for the Global Burden of disease study in 2013, the USA led the list of countries with maximum obese persons followed by China and India, respectively [4].
The prevailing oxidative and inflammatory conditions constitute major risk factors for the development of a number of pathologies such as tumour development, diabetes and cardiovascular complications. Obese people have relatively enhanced risk of developing colon cancer, gastric cardia, oesophageal adenocarcinoma and cholangiocarcinoma [5], whereas diabetes is reported to predict mortality from cancer of the colon, pancreas, female breast, male liver and bladder [6]. Furthermore, a high BMI could lead to increased risk of developing non-Hodgkins lymphoma and multiple myeloma in gender independent manner [7]. Although a clear mechanism is not available, however, increased oxidative stress in obesity and metabolic syndrome has been linked with DNA damage and subsequent malignancies [8]. A positive correlation between serum 8-hydroxy 2′-deoxy-guanosine (8-OHdG) and increased body mass index has been shown which suggests that oxidative DNA damage may be caused due to obesity condition [9]. DNA damage can alter regulation of cell cycle along with other cellular process including transcription, signal transduction pathways, replication mismatch, DNA damage repair and resultant genomic instability, which may eventually lead to tumorigenesis [10]. Furthermore, reactive oxygen species (ROS) generated during metabolic disorder can cause increased inflammatory condition in body by upregulating redox signalling pathways, altered gene expression of inflammatory cytokines, chemokines and growth factors resulting in the development of pathologies such as insulin resistance, diabetes and cardiovascular damage [11].
The preceding evidences suggest that metabolic disorder and obesity have myriads of effect on cellular physiology and affect the body negatively leading to development of pathological conditions. Since ROS and oxidative stress have been implicated in several cellular signalling and pathological conditions, in the present review we have particularly focused on how metabolic disorder creates redox imbalance that lead to complications such as carcinogenesis, diabetes, and cardiovascular diseases and how understanding the mechanisms may be helpful in developing potential preventive and therapeutic strategies.
Section snippets
Oxidative stress in metabolic disorders
Oxidative stress is mainly defined as a disparity in the production and degradation of ROS. Available evidences indicate that elevated systemic oxidative stress is closely associated with metabolic syndrome [11], [12]. A positive correlation has been established between presence of oxidative stress and increased low-density lipoprotein (LDL) and low high-density lipoprotein (HDL) in the animal models. Several mechanisms have been proposed that elevate the oxidative stress in metabolic disorder.
Oxidative stress in metabolic disorder leading to Carcinogenesis
Obesity and metabolic disorder have been identified as a major risk factor associated with cancer. Individuals with high BMI are at risk of developing several types of cancer including endometrial, colorectal, and ovarian and breast cancers [28], [29], [30]. The incidence of cancer due to obesity is estimated to be approximately 20% of all causes of cancers [30]. The development of cancer in obese population is associated with the redox alteration caused by adipokines such as leptins,
Oxidative stress in metabolic disorder leading to obesity, diabetes and cardiovascular diseases
A balanced metabolic system and cellular homeostasis are fundamental requirements for normal functioning of cells and maintaining fundamental attributes of life and health. Any dysregulation in the metabolism and nutrient sensing mechanism can lead to a cluster of metabolic disorders including obesity, type 2 diabetes and cardiovascular diseases. Diabetes and obesity are closely inter-related and frequently occur together in patients and result from poor metabolic conditions. Together, they are
Therapeutic strategies to overcome oxidative stress induced metabolic abnormalities
The best strategies to get rid of unhealthy oxidative stress are to restore the body's redox balance. The goal may include to restore healthy BMI by physical activity and consuming low-fat low-carbohydrate diet containing a plenty of antioxidants. A clinical study has shown that cardiovascular risk associated with obesity can be improved through weight reduction which subsequently decreases markers of oxidative stress and increased antioxidant system [128]. The diet regimen containing natural
Conclusion and future prospects
Life-style and diet-related chronic non-communicable diseases have already become a major burden on global health care. A multi-pronged strategy of dealing with this epidemic must be rapidly evolved and implemented to stem the rising tide of diseases of metabolic syndrome. Along with advocating the adoption of healthy life style, a massive influx of funding for research in the area of metabolic syndrome is the need of the hour. Since oxidative stress has emerged as a central player in chronic
Conflict of interest
All the authors declare that there is no conflict of interest regarding the publication of this paper.
Acknowledgements
Award of Ramanujan Fellowship from Department of Science and Technology (DST), Government of India SR/S2/RJN-102/2012 (UCSY); fund support from Department of Biotechnology (DBT), Government of India BT/PR3978/17/766/2011 (VR) and Abraham A. Mitchell Cancer Research Scholar Endowment Grant (KP) are acknowledged. Assistance of Drs. Chinnadurai Mani and Neha Atale for assisting with preparation of the manuscript is also acknowledged.
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All authors contributed equally to the manuscript.