Two of the most fundamental requirements to our survival are the ability to survive periods of starvation and the capacity to mount an effective response against pathogenic invaders. The former selects for metabolic efficiency–the ability to store calories when food supplies are intermittent. The capacity to ward off infection produces populations that have enhanced immune function.
Overtime, these selective pressures gave us the ability to withstand starvation and disease. However, the availability of food (often in caloric excess) and the combination of enhanced sanitation practices and access to anti-infective therapies has resulted in a population that is well-adapted to storing calories with an immune system that can be overly sensitive.
In this month’s first article, The World is Getting…Larger, we saw alarming facts and figures documenting the increase in obesity and diabetes. Once thought to be an issue only associated with Western cultures, “diabesity” is one of the world’s leading public health issues today. Over the past several years, the scientific community has realized that one of the factors contributing to obesity-driven diseases is the presence of low-level, chronic inflammation. Many investigators are referring to this as Immunometabolism.
Our first hints that inflammation plays a role in diabetes date back over a century. In 1876, it was discovered that large doses of sodium salicylate, an aspirin-like compound, were shown to decrease glucose excretion in the urine of patients with the “milder form” of diabetes (presumably Type 2). In 1901, this observation was repeated. Perhaps the best evidence for this link came in 1957 when a patient with diabetes who was suffering with arthritis associated with rheumatic fever was treated with high-dose aspirin. That patient no longer required daily insulin and showed normal blood glucose levels both fasting and post-glucose challenge, despite ending insulin treatment and treatment with aspirin alone. This observation led to additional studies using high-dose aspirin which were also successful in reducing blood glucose to normal levels.
Since these early observations, data has emerged demonstrating the presence of obesity-driven adiposity. C-reactive protein (CRP) levels, a serum marker of inflammation, are elevated in obese individuals. Type 2 diabetics also show elevated levels of this marker along with fibrinogen, haptoglobin, serum amyloid A and plasminogen activator inhibitor–all markers of systemic inflammation. Further, high serum levels of CRP and the inflammatory cytokines IL-1β and IL-6 are predictive of the development of Type 2 diabetes in various populations while weight loss produces decreases in CRP, IL-6 and other pro-inflammatory cytokines.
How does obesity drive inflammation? While the answer to this question is complex, one aspect has to do with the character of the immune cells associated with adipose (fat) tissue. Macrophages are important immune cells that exist in various tissue beds. These cells perform many tasks that are important in cleaning up tissue debris and in modulating the behavior of other cell types. Macrophages can behave as either pro- or anti-inflammatory modifiers. In lean adipose tissue, these cells have all the characteristics of anti-inflammatory modifiers. With increased caloric intake and the following expansion of adipose tissue, additional macrophages are recruited to that tissue bed. These cells then take on the characteristics of classically activated cells–ones we would think of as being able to kill bacteria or tumors and release many pro-inflammatory mediators. Modulating this pro-inflammatory activity is a new avenue for therapeutic approaches and is a topic for discussion in a later article on Eureka.
The inflammation produced by obesity is an area of intense study and having appropriate models with which to investigate these pathways is important. The mouse has been most studied in this regard due to its size, ease of handling and its well-characterized genome with respect to both metabolic and immune defects. The next article in this series on obesity covers the use and selection of these models for the study of immunometabolic disorders.