Oxid Med Cell Longev. 2015;2015:729191. doi: 10.1155/2015/729191.

Urinary F2-isoprostanes and metabolic markers of fat oxidation.

 

Il’yasova D1, Wagenknecht LE2, Spasojevic I3, Watkins S4, Bowden D5, Wang F3, D’Agostino RB Jr2.
  • 1School of Public Health, Georgia State University, 140 Decatur Street, Urban Life Building, Atlanta, GA 30303, USA.
  • 2Wake Forest School of Medicine, Public Health Sciences, Winston-Salem, NC 27157, USA.
  • 3Duke Cancer Institute, Duke University Medical Center, 2424 Erwin Road, Durham, NC 27705, USA.
  • 4Lipomics Technologies, Division of Metabolon, 3410 Industrial Boulevard, West Sacramento, CA 95691, USA.
  • 5Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

 

Abstract

Metabolomic studies of increased fat oxidation showed increase in circulating acylcarnitines C2, C8, C10, and C12 and decrease in C3, C4, and C5. We hypothesize that urinary F2-isoprostanes reflect intensity of fatty acid oxidation and are associated with circulating C2, C8, C10, and C12 directly and with C3, C4, and C5 inversely. Four urinary F2-isoprostane isomers and serum acylcarnitines are quantified using LC-MS/MS within the Insulin Resistance Atherosclerosis Study nondiabetic cohort (n = 682). Cross-sectional associations between fasting urinary F2-isoprostanes (summarized as a composite index) and the selected acylcarnitines are examined using generalized linear models. F2-isoprostane index is associated with C2 and C12 directly and with C5 inversely: the adjusted beta coefficients are 0.109, 0.072, and -0.094, respectively (P < 0.05). For these acylcarnitines and for F2-isoprostanes, the adjusted odds ratios (ORs) of incident diabetes are calculated from logistic regression models: the ORs (95% CI) are 0.77 (0.60-0.97), 0.79 (0.62-1.01), 1.18 (0.92-1.53), and 0.51 (0.35-0.76) for C2, C12, C5, and F2-isoprostanes, respectively. The direction of the associations between urinary F2-isoprostanes and three acylcarnitines (C2, C5, and C12) supports our hypothesis. The inverse associations of C2 and C12 and with incident diabetes are consistent with the suggested protective role of efficient fat oxidation.

PMID: 25802683

 

Why to study the link between F2-isoprostanes and fat oxidation?

This metabolomics study examined a link between urinary F2-isoprotanes, validated indices of oxidative status, and markers of increased fat oxidation. We describe the history of this topic to explain why this connection is so interesting and intriguing.

Oxidative stress and antioxidant therapy research presents an example of a perplexing disagreement between the experimental biological evidence of harmful influences of reactive oxygen species (ROS) and the failure of antioxidant supplementation trials to produce beneficial effects. Our research was inspired by this discrepancy. Seeking an explanation, we reasoned that the major methodological gap in antioxidant trials was lack of oxidative status measurements. All participants were indiscriminately given antioxidants under the assumption that all (all smokers, for example) had elevated oxidative status. We argued that oxidative status must vary in any human populations – not all smokers develop oxidative stress, as not all smokers develop lung cancer either – and that a beneficial effect of antioxidants can be expected only among those with high oxidative status. We thought that it was important to demonstrate a wide variability of oxidative status in a diverse relatively healthy population and to prove that only those with high oxidative status are at a risk of developing a specific chronic condition.

In 2003, we initiated a pilot study to examine a prospective association between urinary F2-isoprotanes and incident type 2 diabetes in the Insulin Resistance and Atherosclerosis Risk Study (IRAS). Three main features of this study were careful measurement of oxidative status, diverse multi-ethnic study population, and prospective study design. We chose F2-isoprostanes as validated oxidative indices. All the existing cross-sectional data pointed to a positive associations between F2-isoprotanes and diabetes or its main risk factor obesity. We measured F2-isoprotanes in baseline urine specimens of 52 individuals free of diabetes, 26 of which developed diabetes during the 5-year follow-up. As expected, urinary F2-isoprostanes varied dramatically from 0.18 to 2.60 ng/mg creatinine. However, it was a complete surprise to find a negative association between urinary F2-isoprotane levels and diabetes risk (OR=0.32, 95% CI: 0.12-0.81), meaning that individuals with elevated F2-isoprotanes have lower risk of diabetes.

How then can the positive cross-sectional associations be explained? A close examination of this topic revealed another paradox. Physical exercise is one of the best preventive strategies for type 2 diabetes and it undeniably increases F2-isoprostanes for at least several hours, exposing an individual to a repetitive sharp increases over the years. Considering these paradoxes, we developed a hypothesis, which was published in 2005. The main premise of this hypothesis is an assumption (which so far has not been challenged) that mitochondrial metabolism presents the major endogenous source of ROS and therefore, the source of F2-isoprotanes. We reasoned that there must be a compensatory mechanism involved in the relationship between F2-isoprotanes and obesity and diabetes and postulated that this compensatory mechanism is related to mitochondrial fatty acid oxidation as a major player in the maintenance of energy balance.

Positive energy balance is manifested as an increase in body mass, with the majority of the gained mass being fat. Correspondingly, negative energy balance is manifested as a loss of body mass, with fat loss being the predominant component of this change as well. A physiological control of energy balance promotes shifts in energy expenditure as metabolic adaptation to counteract both negative balance (by a decrease in energy expenditure) and positive balance (by an increase in energy expenditure). With fat mass being the predominant element of body mass changes, it is not surprising that fat oxidation plays an essential role in control of energy balance. Compensatory, in obese individuals fat oxidation rates on average are higher, whereas weight loss decreases fat oxidation rates. At the same time, efficient fat oxidation lowers the risk of weight gain and thereby, the risk of obesity and diabetes (Figure 1).

 

Slide1

In 2009-2012, we expanded our study to the entire IRAS cohort (n=852). We confirmed that greater levels of urinary F2-isoprostanes predict lower risk of diabetes. We also found that high F2-isoprostanes predict a lower risk of weight gain, just as predicted by our hypothesis. In light of these findings, a connection between F2-isoprostanes and fat oxidation rates becomes especially intriguing. Continuing our inquiry, we reasoned: if exercise promotes efficient fat oxidation, exercise training should increase F2-isoprostane levels not only immediately after the training but also in a resting state. We showed such a tendency of increased urinary F2-isoprostanes after a 14-week aerobic training. We also demonstrated that fasting free fatty acids levels, which are known to promote fat oxidation in skeletal muscles, are positively associated with urinary F2-isoprostanes. Exploring racial differences, we found lower F2-isoprostane levels in African Americans, a racial group with lower fat oxidation and high risk of obesity and diabetes. Finally, this metabolomics study presents additional evidence along this line. We demonstrated associations between F2-isoprostanes and acylcarnitines, which levels change in the physiological states of intensive fat oxidation. Moreover, these acylcarnitines are associated with incident diabetes: C2 is positively associated with F2-isoporstanes and like F2-isoporstanes predicts a lower risk of diabetes (OR=0.77). In contrast, C5 is negatively associated with F2-isoporstanes and shows a tendency of a direct association with diabetes risk (OR=1.18).

Taking our findings to a broader context, we contend that both the antioxidant and the physical exercise paradoxes reflect an incorrect assumption that elevated oxidative status measured by systemic F2-isoporstane levels constitutes a harmful oxidative stress. Instead, F2-isoporstanes may reflect efficient mitochondrial metabolism and fat oxidation specifically. This hypothesis, however, does not rule out a possibility that locally elevated reactive oxygen/nitrogen species at the tissue level may promote development of pathological changes; but it argues that local oxidative stress contributes insignificantly to the systemic levels of oxidative status. Then, the systemic levels of F2-isoprostanes can be viewed as a beneficial metabolic trait reflecting healthy metabolism, allowing an effective physiological control of energy balance, and thereby, preventing obesity and type 2 diabetes. Such interpretation of urinary F2-isoporstanes and the compensatory concept presents a new conceptual framework for the existing and emerging facts about the relationships between oxidative status and multiple chronic conditions that are thought to be associated with oxidative stress.

 

References:

Il’yasova D, Morrow JD, Wagenknecht LE. Urinary F2-isoprostanes are not associated with increased risk of type 2 diabetes. Obes Res. 2005;13(9):1638-44.

Il’yasova D, Spasojevic I, Wang F, Tolun AA, Base K, Young SP, Marcom PK, Marks J, Mixon G, DiGiulio R, Millington DS. Urinary biomarkers of oxidative status in a clinical model of oxidative assault. Cancer Epidemiol Biomarkers Prev. 2010;19(6):1506-10.

Jones LW, Eves ND, Spasojevic I, Wang F, Il’yasova D. Effects of aerobic training on oxidative status in postsurgical non-small cell lung cancer patients: a pilot study. Lung Cancer. 2011;72(1):45-51.

Il’yasova D, Wang F, Spasojevic I, Base K, D’Agostino RB Jr, Wagenknecht LE. Racial differences in urinary F2-isoprostane levels and the cross-sectional association with BMI. Obesity (Silver Spring). 2012 Oct;20(10):2147-50.

Il’yasova D, Scarbrough P, Spasojevic I. Urinary biomarkers of oxidative status. Clin Chim Acta. 2012;413(19-20):1446-53.

Il’yasova D, Spasojevic I, Base K, Zhang H, Wang F, Young SP, Millington DS, D’Agostino RB Jr, Wagenknecht LE. Urinary F2-isoprostanes as a biomarker of reduced risk of type 2 diabetes. Diabetes Care. 2012;35(1):173-4.

Il’yasova D, Wang F, Spasojevic I, Base K, D’Agostino RB Jr, Wagenknecht LE. Urinary F2-isoprostanes, obesity, and weight gain in the IRAS cohort. Obesity (Silver Spring). 2012;20(9):1915-21.

 

Dora1_2WEB

Dr. Dora Il’yasova

School of Public Health, Georgia State University

140 Decatur Street, Urban Life Building, Atlanta, GA 30303, USA.

 

 

 

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