Basic Science Newsbrief June 2011
Considerations of studies aimed at understanding the role of the immune system in metabolic disease
- A Commentary by Barbara Nikolajczyk, PhD
Immunometabolism is a relatively new field of biomedical inquiry, in which the investigator identifies cellular processes and mechanisms that link the immune system to the etiology and pathogenesis of obesity and insulin resistance. The abundance of commercially available mice that lack various immune cells and immunomodulatory molecules significantly lowers the activation energy required to launch a new project in the field. Although experts in metabolic disease have long known that variables like the lot number of the feed can influence outcomes of metabolic studies in mice, analysis of immunocompromised mice takes such scientifically uninteresting (and often inexplicable) influences to a new level.
Mouse monocultures, typical of housing offered by research institutions, are perhaps not so different from cities (or grocery store lines) packed with people: both are almost certainly under continuous assault from infectious diseases, especially hard-to-detect viruses. This chronic attack occurs in all but the cleanest of mouse facilities, and the designation of a facility as “clean” always awaits further re-definition as additional pathogen tests develop. The efficient ability of the immune system to keep most of these infections at subclinical levels in both people and in mice is thought to be based on chronic low level sampling of the environment through surface receptors, and the subsequent chronic low level immune response that we define as “homeostasis”. However, many of the mice used for immunometabolism studies have compromised immune systems, including deletion of entire immune cell types, or lack of critical environmental sampling molecules, exemplified by toll-like receptor (TLR) knock-out mice. Genetic perturbation of the immune system often significantly changes the immune response to pathogens in experimental tests, and such studies are the basis for much of our understanding of this life-saving function of the immune system.
What are the implications for the immunometabolism researcher who is buying (or making) immunocompromised mice to probe the role a certain immune process or molecule plays in metabolic disease? We argue the implications are severe and probably underlie inconsistencies in the literature that describe diametrically opposed roles of, for example, T cell subsets or myeloid TLRs in obesity and insulin resistance. How does the metabolic researcher interpret results from already tricky metabolic models when a second layer of complication is added by exposure of the immunocompromised model to a virus-rich world? One answer might be to perform such studies only in the “cleanest of clean” animal facilities. The pitfall of such stringency is that the results may in no way recapitulate events in people who chronically launch low-level immune system responses. A second solution, to ignore chronic low-level immune system stimulation, is based on the reasoning that mice infected with pathogens common to many colonies may more closely resemble subclinically infected humans. The weakness in this approach is that mouse responses to mouse viruses may be significantly different from human responses to the fungi and viruses we battle daily. Furthermore, a genetically immunocompromised mouse may exhibit changes in baseline parameters that become apparent only upon addition of a second stress or as part of the ageing process, such that any differences in outcomes between „wild type‟ and mutant mice on different diets cannot be interpreted as evidence that a given immune process plays a role in insulin resistance. The solution likely lies somewhere in between these two extreme solutions.
1. Interpret single model studies from single mouse facilities with caution. Even the animal vendor facility can make a difference in immune system studies.
2. Include human tissue studies as much as possible. The token analysis of archived tissues is not sufficient. Human blood cells and human adipose cells are reasonably available and experiments that require the investigator simply to obtain “exempt” IRB protocols can be designed. One can even buy patient blood from some vendors (though the lab must operate under BL-2 safety requirements) and use it under exempt protocols.
3. Launch efforts to independently verify all immunometabolism studies. Use published studies as part of your control studies for efficient independent verification of conclusions at minimal cost. Highlight inconsistencies with previously published studies rather than hiding discordant new results.
4. Embrace and test the possibility that pathogens can alter the course of metabolic disease to better understand disease pathogenesis in the real clinical world.
5. Keep an open mind about the interpretation of any model study. Remember, our goal is find treatments for patients, not for highly inbred mice housed in monocultures.
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Send ideas to the Editors, Dr. Gerald Denis ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it "> This e-mail address is being protected from spambots. You need JavaScript enabled to view it ) or Dr. Barbara Nikolajczyk ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it "> This e-mail address is being protected from spambots. You need JavaScript enabled to view it ), for consideration.
