Obesity and sepsis

A new study by Wang and colleagues in the journal Obesity describes a link between obesity and the risk of sepsis.

This work is important because it provides another explanation for the increase in all-cause mortality that accompanies increases in waist circumference, and also because it points toward an explanation for why we get fat in the first place.

The classic understanding is that fat represents a means of storing excess energy. In this view, fat has an adaptive function to protect against starvation during nutritional scarcity.

The immunologic role of visceral fat challenges that simplistic view. Visceral fat is immunologically active and is a site of abundant resident macrophages. Adipocytes and fat-associated white blood cells are an important source of body-wide inflammation.

Because of its role in inflammation, visceral fat is linked to many of the complications of obesity, including hypertension, atherosclerosis and diabetes.

In a parallel development, recent work has identified the gut as a source of translocating bacteria and bacterial endotoxin. These immune agonists are an important cause of visceral fat accumulation, obesity, and subsequent chronic low grade inflammation. In addition, translocation of gut bacteria has been compared to low-grade septicemia, and is thought to be a precursor to gut derived sepsis. If gut bacteria are a root cause of both sepsis and visceral fatness, then a relationship between obesity and sepsis makes sense.

Many recent studies support the concept that gut bacteria are responsible for obesity. These findings raise the possibility that visceral adiposity might have an adaptive function aimed at gut bacteria. If so, visceral fat accumulation might be an adaptation with costs and benefits. While the costs include increased risk of cardiovascular and metabolic diseases, a potential benefit of visceral fat is the capacity to mobilize immune defenses against invasive gut bacteria.

Along these lines, Hegde and Dhurandar recently wrote a review on the infection-fat link and the antimicrobial effects of fat in Clinical Microbiology and Infection:

“In addition to the immune cells of adipose tissue, evidence is emerging that even pre-adipocytes and adipocytes are likely to interact with invading microbes.

These lines of evidence imply that fat itself is not the cause of sepsis, but constitutes a defense against invasive gut bacteria. In the Wang et al. study, in fact, only the morbidly obese had a higher risk of sepsis. That result is in line with expectations of the hypothesis that visceral fat has a host defense function. Moderate obesity, in fact, might protect against certain infections, which may explain decreased mortality among the overweight, known as the obesity paradox,

If visceral fat has a host defense function, it makes sense that its removal would not improve inflammation and might in fact increase the risk of septic death.

It is worth pointing out that the concept of a host defense function of abdominal fat is not new. In 1906, Rutherford Morison termed visceral fat in the omentum “the abdominal policeman” for its role in preventing sepsis. Morison wrote:

Abscesses in connexion with the vermiform appendix are locked up, and pus is generally prevented from escaping into the general peritoneal cavity by the omentum.

This observation comports with the hypothesis that the main function of visceral fat is to contain and prevent the spread of gut bacteria into sterile sites. Not only does containment occur anatomically as described by Morison, but at a microscopic level as well. Visceral fat acts as an immunological organ that provides fuel for the immune system, generates pro-inflammatory cytokine mobilization, and houses phagocytic cells that mop up bacteria that escape the gut.

If further research substantiates a host defense function of fat, it will add an adaptive lens with which to view the complex web of metabolic and inflammatory changes in obesity. Appreciating the physiologic function of fat, and the selective pressure induced by gut microbes, will be critical to discovering new ways of treating obesity and related diseases.

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