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      Genetics of Oxidative Stress in Obesity

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          Abstract

          Obesity is a multifactorial disease characterized by the excessive accumulation of fat in adipose tissue and peripheral organs. Its derived metabolic complications are mediated by the associated oxidative stress, inflammation and hypoxia. Oxidative stress is due to the excessive production of reactive oxygen species or diminished antioxidant defenses. Genetic variants, such as single nucleotide polymorphisms in antioxidant defense system genes, could alter the efficacy of these enzymes and, ultimately, the risk of obesity; thus, studies investigating the role of genetic variations in genes related to oxidative stress could be useful for better understanding the etiology of obesity and its metabolic complications. The lack of existing literature reviews in this field encouraged us to gather the findings from studies focusing on the impact of single nucleotide polymorphisms in antioxidant enzymes, oxidative stress-producing systems and transcription factor genes concerning their association with obesity risk and its phenotypes. In the future, the characterization of these single nucleotide polymorphisms (SNPs) in obese patients could contribute to the development of controlled antioxidant therapies potentially beneficial for the treatment of obesity-derived metabolic complications.

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          Most cited references117

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          Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.

          Superoxide dismutases are an ubiquitous family of enzymes that function to efficiently catalyze the dismutation of superoxide anions. Three unique and highly compartmentalized mammalian superoxide dismutases have been biochemically and molecularly characterized to date. SOD1, or CuZn-SOD (EC 1.15.1.1), was the first enzyme to be characterized and is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. SOD2, or Mn-SOD (EC 1.15.1.1), exists as a tetramer and is initially synthesized containing a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. SOD3, or EC-SOD (EC 1.15.1.1), is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized containing a signal peptide that directs this enzyme exclusively to extracellular spaces. What role(s) these SODs play in both normal and disease states is only slowly beginning to be understood. A molecular understanding of each of these genes has proven useful toward the deciphering of their biological roles. For example, a variety of single amino acid mutations in SOD1 have been linked to familial amyotrophic lateral sclerosis. Knocking out the SOD2 gene in mice results in a lethal cardiomyopathy. A single amino acid mutation in human SOD3 is associated with 10 to 30-fold increases in serum SOD3 levels. As more information is obtained, further insights will be gained.
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            A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.

            The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.
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              PGC1α and mitochondrial metabolism--emerging concepts and relevance in ageing and neurodegenerative disorders.

              PGC1α is a transcriptional coactivator that is a central inducer of mitochondrial biogenesis in cells. Recent work highlighted that PGC1α can also modulate the composition and functions of individual mitochondria. Therefore, it is emerging that PGC1α is controlling global oxidative metabolism by performing two types of remodelling: (1) cellular remodelling through mitochondrial biogenesis, and (2) organelle remodelling through alteration in the intrinsic properties of mitochondria. The elevated oxidative metabolism associated with increased PGC1α activity could be accompanied by an increase in reactive oxygen species (ROS) that are primarily generated by mitochondria. However, increasing evidence suggests that this is not the case, as PGC1α is also a powerful regulator of ROS removal by increasing the expression of numerous ROS-detoxifying enzymes. Therefore, PGC1α, by controlling both the induction of mitochondrial metabolism and the removal of its ROS by-products, would elevate oxidative metabolism and minimize the impact of ROS on cell physiology. In this Commentary, we discuss how the biogenesis and remodelling of mitochondria that are elicited by PGC1α contribute to an increase in oxidative metabolism and the preservation of ROS homeostasis. Finally, we examine the importance of these findings in ageing and neurodegenerative disorders, conditions that are associated with impaired mitochondrial functions and ROS balance.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                Molecular Diversity Preservation International (MDPI)
                1422-0067
                February 2014
                20 February 2014
                : 15
                : 2
                : 3118-3144
                Affiliations
                Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology, Centre for Biomedical Research, University of Granada, 18100 Armilla, Granada, Spain
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: caguiler@ 123456ugr.es ; Tel.: +34-958-241-000 (ext. 20314); Fax: +34-958-248-960.
                Article
                ijms-15-03118
                10.3390/ijms15023118
                3958901
                24562334
                d3b7e208-cf9b-4091-a28b-44a4873d7f5b
                © 2014 by the authors; licensee MDPI, Basel, Switzerland

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 15 January 2014
                : 12 February 2014
                : 12 February 2014
                Categories
                Review

                Molecular biology
                polymorphism,oxidative stress,reactive oxygen species,antioxidant enzymes,obesity

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