Improve insulin sensitivity and reduce oxidative stress -
In line with this, obesity is accompanied by changes in hematologic counts such as increased macrophage and monocyte tissue infiltration, and higher total leukocyte, neutrophil and lymphocyte counts [ 44 ]. In our cohort, WBC derived inflammatory indexes, as well as traditional inflammatory markers such as uric acid, directly correlated with altered erythrocyte physiology hematocrit, hemoglobin, MCV, and MCH and increased osmotic fragility, whilst the relationship was inverse between these erythroid parameters and dehydrogenases activities and TAC, respectively, suggesting a positive role of erythroid antioxidant defenses in the maintenance of red blood cell physiology.
Uric acid is a well-known trigger of NLRP3 priming. NLRP3 acts as an intracellular sensor of danger signals which, after assembly, mediates a process of caspase 1-dependent cytokine release through gasdermin-D activation.
After gasdermin-D activation, a pore is formed in the inner cell membrane, so pyroptotic cell death and further cytokine release are accomplished [ 45 ]. Probably, as an effect of gasdermin-D mediated pyroptotic PBMCs death, this resulted in higher levels of NLRP3 and IL-1β in plasma as well.
Circulating levels of NLRP3 have been associated with MS components [ 46 ] and other pathologies in which it may serve as a predictive biomarker [ 47 , 48 ].
This pathological mechanism could at least partially explain the reduced white blood cell counts in this group and therefore, the lower levels of inflammation markers in the LP-OBIR group.
Moreover, circulating inflammasome components could represent a pathological endocrine mechanism of inflammatory response [ 49 ]. Accordingly, ex vivo PMBCs from a set of healthy young adult volunteers incubated with uric acid, resulted in reduced cell viability Additional file 1 : Fig. S3A , increased levels of cellular and free NLRP3 and IL-1β proteins until extremely cytotoxic uric acid concentrations were reached Additional file 1 : Figure S1.
These harmful effects were reverted with the addition of ascorbic acid to the cultures Additional file 1 : Figs.
S2 and S3B. Nevertheless, the role of uric acid in hepatic steatosis and IR through NLRP3 inflammasome activation has already been described [ 52 ], and compounds targeting serum uric acid levels have been proposed as therapeutic approaches for nonalcoholic fatty liver disease treatment [ 53 ].
Overnutrition induces β-cell dysfunction affecting insulin secretion through mitochondrial ROS generation and NLRP3 activation [ 54 , 55 ]. NLRP3 pathway inhibition avoids adipose tissue inflammation and diminishes obesity and related metabolic disorders [ 49 ], and the use of natural compounds with antioxidant capacity, such as polyphenols or carotenoids, has been described as having beneficial effects in the control of diabetic complications through NLRP3 pathway control [ 56 , 57 , 58 , 59 , 60 ].
This data should be interpreted with caution, since it has been derived from an observational study with no follow-up. In this vein, it should be noted that the multifactorial nature of childhood obesity, along with the observational design of our study, makes it difficult to weigh the importance of each factor analyzed in the outcome.
It would be desirable to perform long-term prospective studies to properly identify relative risks, and determine whether treatment with antioxidant-rich functional nutrition could reverse this situation despite weight excess.
In summary, we have found that not every child with obesity and IR has OS and deleterious inflammation, and that IR as we define it today [ 20 ], is not a precise marker of obesity related complications.
Our data suggest that the appearance of altered prandial insulin secretion reflected in OGTT is a better indicator of increased inflammasome activation and OS damage and therefore, of a higher risk of the development of obesity-related metabolic complications.
Finally, uric acid could be useful to identify children with obesity at higher risk of delayed insulin response, OS and inflammasome activation. Altered insulin secretion dynamics in response to glucose along an OGTT effectively identifies children with obesity suffering OS and inflammasome activation, despite similar basal glucose, insulin and lipid profiles as well as classical inflammatory markers.
This should lead to a rethink of our actual definition of IR in children, drive the search for better and less invasive biomarkers, and to explore the potential benefits of anti-oxidants beyond weight loss.
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Int J Mol Sci. Moreover, both systemic markers of oxidative stress and ROS production in skeletal muscle mitochondria are reported to be elevated in human obesity [1] , [4] , [5].
The mitochondrial dysfunction hypothesis of insulin resistance has arisen mainly from studies showing reduced expression of genes involved in mitochondrial biogenesis or reduced ATP production in healthy relatives of type 2 diabetes individuals [6].
Reduced expression of genes involved in mitochondrial biogenesis is also observed following isocaloric high fat diet, or following prolonged lipid infusion with the parallel induction of peripheral insulin resistance in healthy humans [7] , [8] , [9].
However, other studies have shown that mitochondrial dysfunction is not a prerequisite for insulin resistance in humans [5] , [10] , [11] , [12].
Rodents that are fed a high fat diet for 4—20 weeks have increases in the more functional measures of skeletal muscle oxidative capacity, despite developing insulin resistance and diabetes [13] , [14] , [15].
Together, these findings challenge the role of mitochondrial dysfunction as a primary factor in the development of insulin resistance. We, and others, have previously shown that short term overfeeding decreases the glucose infusion rate necessary to maintain euglycemia during a hyperinsulinemic-euglycemic clamp [16] , [17].
In this study, we focused on factors in skeletal muscle that may contribute to the insulin resistance that was observed during overfeeding. The specific aims were to determine the effects of 3 and 28 days of overfeeding on i skeletal muscle markers of oxidative stress, and ii mitochondrial content and function.
We hypothesized that overfeeding would increase oxidative stress and this would be associated with a reduction in markers of mitochondrial content and function. This study was conducted according to the principles expressed in the declaration of Helsinki. All participants provided written informed consent for the collection of samples and subsequent analysis.
The protocol for this study and supporting CONSORT checklist are available as supporting information Protocol S1 and Checklist S1. Of the individuals pre-screened for the study over the telephone, 64 were excluded Figure 1.
Fifty eight individuals were screened at the Clinical Research Facility of which 17 were excluded 3 did not meet the inclusion criteria, 13 changed their mind after the study was explained and 1 due to difficulty in cannulating; Figure 1.
Forty one participants were enrolled 36 Caucasian, 5 Asian and 1 individual withdrew due to a viral infection. Forty individuals completed the study 20 men and 20 women; 37±2 years.
All participants were recruited and followed up between and as reported previously [17] , [18]. Study timeline and diet regimen were described in detail previously [17]. Overfeeding was achieved by supplementing the baseline diet with energy-dense snacks that were provided to study participants.
A vastus lateralis muscle biopsy was performed, as previously described [19]. Samples were then snap-frozen in liquid nitrogen, within 90 seconds of collection.
Blood glucose and plasma lactate were assessed by YSI YSI Life Sciences and serum insulin by RIA Linco Research, St Charles. Serum non esterified fatty acids NEFA were analyzed by an enzymatic colorimetry assay Wako, Osaka, Japan.
Urinary-F2-isoprostane was analyzed using gas chromatography-mass spectrometry in spot urine samples that were centrifuged at 4°C, snap-frozen with butylated hydroxytoluene BHT, 0. The results were normalized to creatinine content [20]. Frozen muscle samples were resuspended in radioimmunoprecipitation buffer supplemented with protease and phosphatase inhibitors as described [15] , [19].
Beta-actin Santa Cruz Biotechnology, CA was used to verify that equal amounts of proteins were loaded. Immunolabelled bands were quantified by densitometry.
Muscle lysates were subjected to 3 freeze-thaw cycles. Citrate synthase, β-hydroxyacyl CoA dehydrogenase, hexokinase and phosphofructokinase were determined at 30°C, as described [19] , using a Spectra max microplate spectrophotometer Molecular Devices, Sunnyvale, CA.
Palmitate oxidation was measured at baseline and day 28 only, as previously described [15] with modified concentration of the reaction mixture and substrates. Substrate was 0. Data presented as mean ±SEM.
Repeated measures ANOVA was used to detect the effect of overfeeding on the outcome measures on the whole cohort and between men and women, unless otherwise stated. Skeletal muscle protein activity and level were expressed relative to baseline and statistical significance was tested by t-test.
Insulin data were log 10 -transformed. SPSS Statistics 19 Chicago, IL was used, without adjustment for multiplicity. Any missing data was removed from the analysis, and not carried forward or replaced. Here, we report that none of the markers of oxidative stress or skeletal muscle mitochondrial content measured were different between groups at baseline or in response to overfeeding, and thus groups were combined for the statistical analyses below.
Overfeeding led to an average weight gain of 0. Body fat also increased significantly at day 28, without a significant difference between men and women Table 1. The mean energy, macronutrient composition and their contribution to total energy of baseline and overfeeding diets is provided for the whole cohort in Table 2.
Likewise, insulin resistance by the homeostasis model of assessment of insulin resistance HOMA-IR increased significantly and glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased significantly with overfeeding and the response was not significantly different between men and women Table 1.
Serum antioxidative capacity was unchanged 1. Protein content of complex I, but not complex III, of the mitochondrial electron transport chain was elevated at day 3 Figure 3A , and there was no difference in response between men and women data not shown.
However, despite continued overfeeding this was not sustained at day Similarly, a transient increase in MnSOD was observed at day 3 Figure 3B. No relationships were observed between the change in insulin resistance and the change in F2-isoprostanes and protein carbonylation with overfeeding or between UCP3, complex I or MnSOD and markers of oxidative stress with overfeeding.
Urine F 2 -isoprostane A , skeletal muscle protein carbonyls quantification B and representative blots C and the association between protein carbonyls and peripheral insulin resistance at end of overfeeding D. Data are expressed as mean±SEM at baseline white , day 3 striped and day 28 black of overfeeding.
Skeletal muscle complexes of the electron transport chain a , Mn-superoxide dismutase SOD , uncoupling protein-3 UCP3 , PPAR-coactivator 1α PGC1α , and carnitine palmitoyltransferase CPT1b proteins and representative samples of the Western blots b and skeletal muscle citrate synthase CS , hydroxyacyl-CoA dehydrogenase βHAD , hexokinase and phosphofructokinase PFK activities c.
Protein levels of complexes I, II and V of the mitochondrial electron transport chain Figure 3A and PGC1α Figure 3B transiently increased at day 3, suggesting an increase in mitochondrial biogenesis, and there was no difference in response between men and women data not shown.
However, more functional markers of mitochondrial oxidative capacity and content, namely palmitate oxidation rate by muscle homogenates ex vivo and citrate synthase activity, were not altered by overfeeding 23±4 vs.
Muscle carnitine palmitoyltransferase CPT 1b protein level tended to increase at day 3 and this was statistically significant at day 28 Figure 3B , reflecting an increase in fatty acid entry into the mitochondria.
However, β-hydroxyacyl CoA dehydrogenase βHAD activity was unchanged Figure 3C. The activity of the glycolytic enzymes hexokinase and phosphofructokinase PFK were increased at day 3 Figure 3C and this was consistent with the transient increase in the respiratory quotient RQ and fasting plasma lactate and the decrease in plasma NEFA at that time point Table 1.
Notably, while NEFA concentrations were significantly decreased in both men and women at day 3, the decrease was greater in women compared with men Table 1. Short term overfeeding reduces insulin sensitivity in healthy non-obese individuals [16] , [17] , however the mechanisms underlying this are unclear.
In this study, we report that whilst the reduction in insulin sensitivity following overfeeding was modest, it occurred without a reduction in any of the markers of mitochondrial content and function examined.
However, we observed that systemic and skeletal muscle markers of oxidative stress were increased, and therefore may have contributed to the insulin resistance observed.
The role of ROS in mediating insulin resistance is debated [22]. Chronic ROS production by skeletal muscle mitochondria can inhibit insulin action but paradoxically, acute increases in ROS through NADPH-oxidase NOX are required for normal intracellular signalling [23].
Increased ROS production is common to different models of cellular insulin resistance, including those induced by TNF-α, insulin and palmitate treatments [2] , [3]. Moreover, mitochondria-targeted antioxidant treatment partially preserves insulin sensitivity both in vivo [1] , [2] , [3] and in vitro [2] , [3].
In the present study, we observed that both urinary F2-isoprostane and skeletal muscle protein carbonyls were increased, with the latter increased as early as 3 days of overfeeding.
This finding suggests that increased oxidative stress may be an early event during over-nutrition in humans.
Protein carbonylation is a non-reversible modification by highly reactive aldehydes, by-products of lipid peroxidation that cause loss of function or trigger degradation of proteins with a cysteine, histidine or lysine side chain, typically enzymes [24]. Also, in the postprandial state, fat and carbohydrate have a differential effect on the oxidative stress response [25].
Importantly, participants in the present study were placed on the same snacks, rich in both sugar and fat, to increase their energy intake and thus we cannot differentiate the effect of particular macronutrients on the outcomes. The two principal sites of superoxide generation in mitochondria are complexes I and III of the electron transport chain.
In this study, we observed an increase in protein content of complex I, but not complex III, at day 3 of overfeeding. However, despite continuous overfeeding and potentially increased availability of reducing equivalents in the mitochondria, this was not sustained. Consistent with this, it has previously been shown that MnSOD transgenic mice are partially protected from high fat feeding-induced insulin resistance [2].
In the present study, we observed that MnSOD was increased transiently, possibly in an attempt to limit oxidative damage.
Magnesium Mg , Se, Zn, and iron Fe have been reported deficiently in morbidly obese patients [ 94 ]. In the study by Aasheim and Bohmer [ 95 ], morbidly obese male and female patients have the most noticeable reduction in vitamins A, B6, C, D, and E. The cross-sectional study of Barzegar-Amini et al.
Low carotenoids, vitamins C and E are related to increased BMI [ 97 — 99 ]. OxS has been implicated in the development of comorbidities in obesity and could be an early marker of metabolic dysfunction in obesity-related IR. Furthermore, obesity per se may induce systemic OxS, and increased OxS in accumulated adipose tissue is, at least in part, the underlying cause of adipocytokine dysregulation and MS development [ ].
The excess supply of energy substrates to metabolic pathways in obesity may increase mitochondrial dysfunction and RONS production [ ].
Notwithstanding, RONS are essential signaling molecules, if not well controlled, they can cause damage to cellular proteins, lipids, and DNA, potentially having detrimental effects on functions.
While mounting evidence suggests that RONS overproduction in obesity leads to altered signaling and IR, other data reported that RONS is essential for insulin secretion by β-cells as well as insulin sensitivity [ , ]. A wide-ranging approach designed to decrease oxidation markers and improve antioxidant defenses in obese subjects includes weight loss associated with physical activity and different dietary factors, which could be helpful to prevent and treat obesity comorbidities.
AP and JS wrote the manuscript and contributed conception. ERI and ESM designed, wrote, and supervised the manuscript. All authors contributed to manuscript revision, read and approved the submitted version. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Home Exploration of Medicine Articles Abstract Keywords Introduction AOS Obesity and IR OxS in obesity and IR AOS in obesity and IR Conclusions Abbreviations Declarations References. Farrer, Boston University School of Medicine, USA This article belongs to the special issue Reactive Oxygen Species ROS in Pathophysiological Conditions.
See in References. Abstract Since obesity is one of the main factors in the development of insulin resistance IR and is also associated with increased oxidative stress OxS rate, this study aims to review the published literature to collate and provide a comprehensive summary of the studies related to the status of the OxS in the pathogenesis of obesity and related IR.
Keywords Antioxidant defense system, inflammation, insulin resistance, obesity, oxidative stress, reactive oxygen and nitrogen species. Introduction Oxidative stress OxS derives from an imbalance between the production of reactive oxygen and nitrogen species RONS and the capacity of the antioxidant defense system AOS to neutralize RONS [ 1 ].
AOS A steady-state of RONS level is maintained through a complex AOS that includes endogenous enzymatic and non-enzymatic antioxidants. Obesity and IR A state of obesity is characterized by an increase in body mass and excessive fat accumulation in the visceral tissues and organs.
OxS in obesity and IR The production of RONS and generation of OxS associated with obesity are strongly related to the activation of the innate immune system in adipose tissue and subsequent low-grade chronic systemic inflammation [ 27 ]. Display full size. AOS in obesity and IR β-cells of the pancreas have relatively low expression of many antioxidant enzymes, which makes β-cells susceptible to RONS-induced damage [ 61 ].
Evidence from animal studies At the onset of obesity, antioxidant enzymes expression and activity increase in tissues to counteract the damaging effects of OxS which was reported in studies on animal models Table 1.
Table 1. AOS in obesity and IR in animal model studies. Evidence from human studies There is mounting evidence that attenuation of antioxidant enzymes and increased RONS production in obese subjects may contribute to further complications in obesity-related IR Table 2.
Table 2. AOS in obesity and IR in human studies. NAFLD: non-alcoholic fatty liver disease. Conclusions OxS has been implicated in the development of comorbidities in obesity and could be an early marker of metabolic dysfunction in obesity-related IR.
Abbreviations AOS: antioxidant defense system BMI: body mass index CAT: catalases Cu: copper FFAs: free fatty acids GPx: glutathione peroxidases GR: glutathione reductases GSH: glutathione GSSG: oxidized glutathione HFD: high-fat diet IL interleukin-1 IR: insulin resistance MDA: malondialdehyde Mn: manganese MS: metabolic syndrome NADPH: reduced nicotinamide adenine dinucleotide phosphate NFκB: nuclear factor kappa B OxS: oxidative stress PON: paraoxonase RONS: reactive oxygen and nitrogen species Se: selenium SOD: superoxide dismutases T2DM: type 2 diabetes mellitus TNF-α: tumor necrosis factor-alpha UPR: unfolded protein response Zn: zinc ZR: Zucker rats.
Declarations Author contributions AP and JS wrote the manuscript and contributed conception. Conflicts of interest The authors declare that they have no conflicts of interest. Availability of data and materials Not applicable.
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Department of Physiology oxidativee Smart-aging Imprvoe Research Center, Yeungnam University College of Sensltivity, Daegu, Korea. Download PDF. This research was supported by xnd from the Medical Research Metabolic health community Program R1A5A and the Basic Science Research Program R1A2C sensihivity the National Research Foundation of Korea NRFfunded by the Korean government. Improve insulin sensitivity and reduce oxidative stress, superoxide Electrolyte Balance Protocol 1; SOD2, superoxide dismutase Improve insulin sensitivity and reduce oxidative stress Insklin, knockout; OE, overexpression; HFD, high-fat diet; Hz, heterozygous; ROS, reactive oxygen species; GPx, glutathione peroxidase; PTP, protein-tyrosine phosphatase; GRx, glutaredoxin; Prx, peroxiredoxin; STZ mice, streptozotocin-injected mice; Msr, methionine sulfoxide reductase; SelW, selenoprotein W. Skip Navigation Skip to contents About Aims and scope About the journal Abstracting and indexing services Editorial board Best practice Journal management team Open access Readership Mass media Contact us Browse Articles Current issue All issues Ahead-of print Most view Article category Most download Most cited Funded articles Latest articles for citation Search Author index Publication Ethics Research and publication ethics For Contributors Instructions to authors For reviewers E-submission Article processing charge Copyright transfer agreement Permission Templates for JYMS E-Submission. Indexed in: ESCI, Scopus, PubMed, PubMed Central, CAS, DOAJ, KCI FREE article processing charge. Obesity has been associated Peer support in recovery oxidative stress. Obese patients are MRI imaging techniques increased risk for diabetic cognitive dysfunction, indicating a pathological link between obesity, strrss stress, and lnsulin cognitive dysfunction. Peer support in recovery can induce strews biological sensitivigy of oxidative stress by disrupting the adipose microenvironment adipocytes, macrophagesmediating low-grade chronic inflammation, and mitochondrial dysfunction mitochondrial division, fusion. Furthermore, oxidative stress can be implicated in insulin resistance, inflammation in neural tissues, and lipid metabolism disorders, affecting cognitive dysfunction in diabetics. The prevalence of obesity has been on the rise globally for the last half century 1. Obesity prevalence has doubled since in more than 70 countries.
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