Traditionally obesity has been associated with an increased risk of disease, and it is often assumed from this that obesity also increases the risk of mortality. This makes sense because obesity is a disease characterised by metabolic dysfunction involving increased oxidative stress and inflammation, both of which are drivers of serious and chronic disease. However, the obesity paradox describes the apparent improved survival in obese compared to normal weight individuals. This recently reported phenomenon of a protective effect of increased fat mass is an enigma, and to date has not been fully explained. However, the large number of studies reporting the obesity paradox suggest that the effect is real and measurable and so further investigation is justified. A number of hypotheses have been suggested that might explain the obesity paradox, with the most simplistic being reverse causation. As people become ill they tend to lose weight, and skeletal muscle mass is inversely associated with mortality.
However, a study published in the American Journal of Clinical Nutrition1 investigated the risk of mortality amongst seriously ill subjects over time to determine if reverse causation was a credible explanation. To do this they analysed the data from the National Health and Nutrition Examination Surveys (NHANES) I, II and III from between 1971 and 1994. As with other studies, the authors noted a reduction in mortality for overweight individuals compared to normal weight referents, but only for those with a serious pre-existing compliant. Other studies too have also reported the obesity paradox only in those with serious ill health. In addition, the mortality rate for normal weight men did not change over the course of the study period, but did fall significantly for obese men in the NHANES III period from between 1988 and 1994. This suggests that the obesity paradox is not explained by reverse causation and that it is a relatively recent phenomenon. Therefore some other explanation is required.
Another explanation that has been suggested to explain the obesity paradox is that of the sequestration of toxins in the fat tissue of obese individuals2. Again using data from NHANES (from between 1999 to 2004), the researchers investigated whether the association between fat mass and mortality was modified by the serum concentrations of lipophilic toxins. The results of this study are interesting because they show that the presence of lipophilic toxins did indeed modify the association between obesity and mortality. In those subjects with low serum levels of lipophilic toxins there was no obesity paradox, whereas the paradox was present in those with high concentrations of lipophilic toxins in their blood. Fat is a relatively safe store of such toxins because the toxins are sequestered away from interaction with important metabolic pathways and cellular components. Weight loss amongst those with high levels of sequestered toxins may release them to circulation and increased the risk of disease and death.
Of course, there may be another more simple explanation for the obesity paradox. This explanation is compelling because it explains the observation that the association between body weight and a reduced risk of mortality is a recent phenomenon that has only surfaced in the last few decades, and that most studies have reported the paradox only in seriously ill patients. This hypothesis suggests that the obesity paradox is explained by selection bias in the diagnosis of disease. Those who are overweight are more likely to seek medical help and in this process are more likely to be tested for underlying disease. In other words, the obese are more effectively screened for disease and any condition is therefore more likely to be identified. Because normal weight individuals are more likely to be perceived as healthy, they are less likely to be considered suitable for advanced screening of disease and therefore at a higher risk of any underlying disorder going unnoticed for long periods, at which point the prognosis may be poor.
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