Tuberculosis and the Inflammatory Processes of Obesity in Human Evolution

To the Editor: In his Commentary, Dr Roth¹ proposed that the proinflammatory state of obesity might have provided an evolutionary advantage during tuberculosis pandemics. Although tuberculosis is likely to have played an important role in shaping human evolution, I believe the notion that obesity-associated inflammation favors protection or survival from tuberculosis is not well supported.

Roth's statement that the “immune systems [of obese persons] . . . are especially robust and more easily triggered” is not supported by current data, which, although controversial, point toward a state of immunosuppression rather than immune enhancement in obesity.² Furthermore, although levels of proinflammatory cytokines are increased in obesity, this does not necessarily result in increased defenses against tuberculosis for 2 reasons.

First, with the exception of IL-6, increased levels of proinflammatory cytokines in obesity are restricted to the local microenvironment of inflamed adipose tissue and steatotic organs, rather than being a systemic response.³ Since defenses against tuberculosis require production of tumor necrosis factor (TNF), interferon-γ, and other mediators in the lung, which does not readily accumulate ectopic fat, it is unlikely that obesity would be associated with enhanced levels of protective factors in the location where they would be required. Second, in contrast with the restricted local increase of proinflammatory cytokines, systemic levels of anti-inflammatory factors, including soluble TNF receptors, IL-1 receptor antagonist, and IL-10, are highly elevated in obesity³ and thus likely to reach a distant organ, such as the lung, where they could exert inhibitory activities against the local protective immunity mounted to counter infection with Mycobacterium tuberculosis.

Moreover, obesity and the metabolic syndrome are associated with low levels of vitamin D,⁴ which (as discussed by Roth) exerts protective effects against tuberculosis and was probably one of the targets of early therapies (exposure to sun) for this condition. Although it is highly plausible that tuberculosis has acted as a strong evolutionary factor in human history, possibly pushing toward selection of thrifty genes to improve survival after infection, I believe the currently available evidence does not support the connection between obesity and altered regulation of the inflammatory response as the most likely target for the selection process.