Will Immunotherapy Provide a New Treatment for Obesity?

Obesity is widely associated with low grade inflammation and previous studies have noted increased incidence of allergic responses in obese individuals pointing to a possible role of immune response in the regulation of metabolism and body weight.

Last week Nature Medicine published three separate articles, which together may well herald in an entirely new area of obesity research: immunometabolism or metabolic immunology. Although all studies reports finding in mouse models of obesity and diabetes, their observations may well have important implications for human obesity.

In the first study, Satoshi Nishimura and colleagues from the University of Tokyo show that CD8+ effector T cells play an important role in macrophage recruitment and adipose tissue inflammation. They not only found that large numbers of CD8+ T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet (while there was a depletion of CD4+ T ells), but also that this infiltration preceded the accumulation of macrophages in fat tissue. On the other hand immunological and genetic depletion of CD8+ T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8+ T cells, macrophages and adipose tissue. These results support the notion that CD8+ T cells have an essential role in the initiation and propagation of adipose inflammation.

In the second study, Markus Feuerer and colleagues from Harvard Medical School, Boston, USA, showed that CD4+ regulatory T cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but, similar to the observation by Nishimura and colleagues, their numbers were strikingly and specifically reduced in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these regulatory T cells influenced the inflammatory state of adipose tissue, insulin resistance, and glucose uptake.

In the third study, Shawn Winer and colleagues from The Hospital for Sick Children, University of Toronto, Canada, showed that immunotherapy with CD4+ (but not CD8+) T cell transfer into lymphocyte-free obese mice reversed weight gain and insulin resistance. In other obese mice, brief treatment with CD3-specific antibody or its F(ab’)2 fragment reversed insulin resistance for months, despite continuation of a high-fat diet.

Together these papers not only document the important role of immune response in the development of obesity and its complications but also identify a number of novel targets and strategies that could be harnessed to treat obesity in manners similar to the treatment of other immunological abnormalities including allergies.

The studies certainly lend credence to those who have long suggested that obesity may be related to allergic or other immunological responses to allergens and environmental toxins.

How these findings will translate into better treatments for obesity obviously remains to be seen.

AMS
Edmonton, Alberta