In a diverse community-dwelling sample of older adults, a systematic marker of oxidative stress, F2-isoprostanes, was found to be positively associated with total and regional adiposity in women. Among men, a more limited pattern was evident, with significant relationships found only for total percent body fat. Significant sex interactions between F2-isoprostanes and most measures of adiposity confirmed that adiposity is more strongly associated with oxidative stress for older women than older men. Further, adipocytokines lie in the causal pathway between adiposity and F2-isoprostanes among women, given that a substantial proportion of associations were mediated by these adipose tissue hormones for both total and regional measures. Finally, higher baseline F2-isoprostane levels were associated with a loss of total adiposity over time among women.
In previous studies, oxidative stress, as measured either by isoprostanes or myeloperoxidase (an oxidative enzyme produced by macrophages), has been found to be positively associated with measures of total adiposity as well as regional adipose tissue deposits.(17
) This study confirms and extends these findings by examining a wide range of measures of both total and regional adiposity in men and women using a more sensitive measure of oxidative stress, plasma F2
-isoprostanes. In addition, although some previous studies have found no sex differences in the association between oxidative stress and measures of adiposity,(18
) we found a significant sex interaction with stronger associations among women than men for most total and regional adiposity measures included in the analysis. Differences between the present and prior research may be due to our measurement of plasma, versus urinary, F2
-isoprostanes or to age differences in study samples.
Sex differences found here may be due to greater adipose tissue volume in women than men. Women in the highest F2-isoprostane tertile had higher mean adiposity than their male counterparts for BMI and waist circumference, total body fat, and abdominal and thigh subcutaneous fat. This may indicate a threshold effect, with oxidative stress occurring only at the higher levels of adiposity found more commonly among women. However, a sex interaction was also found for weight and for abdominal visceral fat, both of which were lower on average among women than men by F2-isoprostanes tertile. More research is needed to identify the sources of sex differences in F2-isoprostane-adiposity associations.
Although there has been little consideration of mechanistic links between adiposity and oxidative stress, prior research has established associations between adipose tissue and both circulating inflammatory biomarkers and urinary isoprostane concentrations.(22
) In the present analysis, leptin, a weight-regulatory hormone, was determined to play a significant explanatory role in relation to oxidative stress and both total and regional adiposity among women; we found a nominal mediating effect for TNF-α. Leptin is released into the circulatory system by adipose tissue, signaling the brain to decrease food intake and increase energy expenditure to maintain the size of the body fat stores.(26
) Although leptin elevation may play an important role in energy balance at leaner weight levels, leptin insensitivity at higher levels of adiposity,(29
) and subsequent excess leptin production, may have a detrimental effect on oxidative stress among women. Additionally, women have been found to have markedly higher leptin concentrations than men for any given degree of fat mass;(30
) leptin may thus contribute to sex differences in associations between total and regional adiposity and F2
We found that adiponectin, an anti-inflammatory adipocytokine, was positively associated with F2
-isoprostanes in both men and women, a novel finding. Despite this positive association, adiponectin strengthened the association between total and regional adiposity and F2
-isoprostane levels, implying negative confounding. The relationship between adiponectin and oxidative stress is less studied and more controversial. Some studies have found no association,(21
) and two studies observed an inverse correlation between adiponectin and urinary isoprostane levels.(20
) Interestingly, these latter studies were both conducted in middle-aged Japanese populations, and one showed significant inverse associations primarily among those with normal glucose tolerance.(32
) Older age is associated with increased adiponectin levels, and studies in older populations have found a positive association between adiponectin and heart disease (9
) and mortality.(34
). This finding of a positive association between adiponectin and F2
-isoprostanes may be related to the theorized compensatory mechanism that may increase adiponectin levels as a response to age-related comorbidities such as insulin resistance and heart disease.
Because repeated measures of F2-isoprostanes were unavailable in the survey, we were unable to assess whether F2-isoprostane levels change over time relative to higher initial adiposity. However, the analysis found that higher F2-isoprostane levels among women at baseline were associated with loss of total adiposity over a 5-year period. This finding suggests a more complex relationship between the two factors than has previously been established, given that prior studies have been cross-sectional. This negative association may signal a physiological response to address excess adiposity, and/or a catabolic response to inflammation that causes adiposity to slowly diminish in older individuals. It is also possible that the pattern is due to unmeasured confounders, such as comorbidities that cause unintended loss of adipose tissue in individuals with elevated levels of oxidative stress, particularly among women in this age group.
Strengths of the study included a diverse, community-based sample; previous studies have focused mainly on Whites. The data included a wide range of measures of both total and regional adiposity, which enabled us to establish a consistent association between F2-isoprostanes and adiposity among women. However, this study was subject to important limitations. As stated earlier, measures of F2-ispoprostanes were available at baseline only, which restricted our ability to infer that adiposity results in greater oxidative stress over time. Given that the sample was limited to older adults, results may not generalize to the overall adult population or to younger age groups. The sample included only Whites and Blacks, so findings may not apply to other racial or ethnic populations.
In conclusion, F2-isoprostanes were associated with measures of total and regional adiposity in women, and with total percent body fat in men. Associations among women were partially explained by adipocytokines. F2-isoprostanes predicted loss of total adiposity over time among women. Higher adipose tissue volume in women may explain sex differences.