Elsevier

Life Sciences

Volume 148, 1 March 2016, Pages 183-193
Life Sciences

Review article
Oxidative stress and metabolic disorders: Pathogenesis and therapeutic strategies

https://doi.org/10.1016/j.lfs.2016.02.002Get rights and content

Abstract

Increased body weight and metabolic disorder including insulin resistance, type 2 diabetes and cardiovascular complications together constitute metabolic syndrome. The pathogenesis of metabolic syndrome involves multitude of factors. A number of studies however indicate, with some conformity, that oxidative stress along with chronic inflammatory condition pave the way for the development of metabolic diseases. Oxidative stress, a state of lost balance between the oxidative and anti-oxidative systems of the cells and tissues, results in the over production of oxidative free radicals and reactive oxygen species (ROS). Excessive ROS generated could attack the cellular proteins, lipids and nucleic acids leading to cellular dysfunction including loss of energy metabolism, altered cell signalling and cell cycle control, genetic mutations, altered cellular transport mechanisms and overall decreased biological activity, immune activation and inflammation. In addition, nutritional stress such as that caused by high fat high carbohydrate diet also promotes oxidative stress as evident by increased lipid peroxidation products, protein carbonylation, and decreased antioxidant system and reduced glutathione (GSH) levels. These changes lead to initiation of pathogenic milieu and development of several chronic diseases. Studies suggest that in obese person oxidative stress and chronic inflammation are the important underlying factors that lead to development of pathologies such as carcinogenesis, obesity, diabetes, and cardiovascular diseases through altered cellular and nuclear mechanisms, including impaired DNA damage repair and cell cycle regulation. Here we discuss the aspects of metabolic disorders-induced oxidative stress in major pathological conditions and strategies for their prevention and therapy.

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.

References (156)

  • C. Sawan et al.

    Histone modifications and cancer

    Adv. Genet.

    (2010)
  • N. Yahagi et al.

    p53 involvement in the pathogenesis of fatty liver disease

    J. Biol. Chem.

    (2004)
  • N. Karaouzene et al.

    Effects of the association of aging and obesity on lipids, lipoproteins and oxidative stress biomarkers: a comparison of older with young men

    Nutr. Metab. Cardiovasc. Dis.

    (2011)
  • P. Codoñer-Franch et al.

    Elevated advanced oxidation protein products (AOPPs) indicate metabolic risk in severely obese children

    Nutr. Metab. Cardiovasc. Dis.

    (2012)
  • H. Sies et al.

    Nutritional, dietary and postprandial oxidative stress

    J. Nutr.

    (2005)
  • H. Lee et al.

    Reactive oxygen species facilitate adipocyte differentiation by accelerating mitotic clonal expansion

    J. Biol. Chem.

    (2009)
  • K.·.V. Tormos et al.

    Mitochondrial complex III ROS regulate adipocyte differentiation

    Cell Metab.

    (2011)
  • N. Inoue et al.

    Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance

    J. Biol. Chem.

    (2008)
  • L. Fajas et al.

    E2Fs regulate adipocyte differentiation

    Dev. Cell

    (2002)
  • C. Chrysohoou et al.

    The implication of obesity on total antioxidant capacity in apparently healthy men and women: the ATTICA study

    Nutr. Metab. Cardiovasc. Dis.

    (2007)
  • N. Matsuzawa-Nagata et al.

    Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity

    Metabolism

    (2008)
  • M. Kunitomo et al.

    Beneficial effect of coenzyme Q10 on increased oxidative and nitrative stress and inflammation and individual metabolic components developing in a rat model of metabolic syndrome

    J. Pharmacol. Sci.

    (2008)
  • L. Wojtczak et al.

    Effect of fatty acids on energy coupling processes in mitochondria

    Biochim. Biophys. Acta

    (1993)
  • S. Lenzen et al.

    Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues

    Free Radic. Biol. Med.

    (1996)
  • M. Sciacovelli et al.

    The metabolic alterations of cancer cells

    Methods Enzymol.

    (2014)
  • S.·.P. Wolff et al.

    Protein glycation and oxidative stress in diabetes mellitus and ageing

    Free Radic. Biol. Med.

    (1991)
  • Y. Furukawa-Hibi et al.

    FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress

    J. Biol. Chem.

    (2002)
  • S. Braun et al.

    The link between the metabolic syndrome and cancer

    Int. J. Biol. Sci.

    (2011)
  • NHLBI Website: http://www.nhlbi.nih.gov/health/health-topics/topics/ms (accessed Jan 14,...
  • WHO website: http://www.who.int/mediacentre/factsheets/fs311/en/ (accessed Jan 14,...
  • E.S. Ford et al.

    Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey

    J. Am. Med. Assoc.

    (2002)
  • E.E. Calle et al.

    Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults

    N. Engl. J. Med.

    (2003)
  • E.J.N.R. Gallagher et al.

    The Increased Risk of Cancer in Obesity and Type 2 Diabetes: Potential Mechanisms: Principles of Diabetes Mellitus

    (2010)
  • G. Gandhi et al.

    Assessment of DNA damage in obese individuals

    Res. J. Biol.

    (2012)
  • H.A. Al-Aubaidy et al.

    Oxidative DNA damage and obesity in type-2 diabetes mellitus

    Eur. J. Endocrinol.

    (2011)
  • S. Furukawa et al.

    Increased oxidative stress in obesity and its impact on metabolic syndrome

    J. Clin. Invest.

    (2004)
  • B. Hansel et al.

    Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity

    J. Clin. Endocrinol. Metab.

    (2004)
  • P. Holvoet

    Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease

    Verh. K. Acad. Geneeskd. Belg.

    (2008)
  • A. Marques de Mattos et al.

    Protein oxidative stress and dyslipidemia in dialysis patients

    Ther. Apher. Dial.

    (2012)
  • P. Holvoet et al.

    The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort

    Diabetes

    (2004)
  • A. Fortuño et al.

    Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome

    Diabetes

    (2006)
  • M.P. Murphy

    How mitochondria produce reactive oxygen species

    Biochem. J.

    (2009)
  • R. Hutcheson et al.

    The metabolic syndrome, oxidative stress, environment, and cardiovascular disease: the great exploration

    Exp. Diabetes Res.

    (2012)
  • G. Davì et al.

    In vivo formation of 8-iso-prostaglandin f2 alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation

    Circulation

    (1999)
  • U.·.C. Yadav et al.

    Cysteinyl leukotrienes (CysLTs): role in obesity-induced asthma

    Curr. Mol. Med.

    (2015)
  • F. Jiang et al.

    Systemic upregulation of NADPH oxidase in diet-induced obesity in rats

    Redox Rep.

    (2011)
  • J.S. Beckman et al.

    Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly

    Am. J. Physiol.

    (1996)
  • P.L. Huang

    Unraveling the links between diabetes, obesity, and cardiovascular disease

    Circ. Res.

    (2005)
  • M.H. Shishehbor et al.

    Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy

    JAMA

    (2003)
  • Y. Ma et al.

    Obesity and risk of colorectal cancer: a systematic review of prospective studies

    PLoS One

    (2013)
  • Cited by (780)

    View all citing articles on Scopus

    All authors contributed equally to the manuscript.

    View full text