Editors' ChoiceInsulin Resistance and Obesity

Immune Regulators: Not Just for Type 1 Diabetes Anymore?

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Science Translational Medicine  01 Sep 2010:
Vol. 2, Issue 47, pp. 47ec135
DOI: 10.1126/scitranslmed.3001623

The concept that immune cells play a role in the development of obesity-induced inflammation and the development of metabolic conditions such as type 2 diabetes is well appreciated. As adipose tissue expands, macrophages and T cells infiltrate the tissue, and cytokine-mediated crosstalk between the adipocytes and immune cells promotes an inflammatory response. The exact role of T cells in this process is unknown, but specific subsets of T cells—including CD4+, CD8+, and regulatory T cells—appear to be involved, raising the possibility that T cell modulation could be a novel therapeutic option for obesity-induced disorders.

Now, for the first time, Kim et al. have shown that activation of 4-1BB (CD137/TNFRSF9), a member of the TNF receptor superfamily expressed on T lymphocytes, has favorable systemic metabolic effects. From an immunologic perspective, activation of 4-1BB suppresses CD4+ T cells and promotes CD8+ T cell expansion and activation. Given that these 4-11B–mediated immune responses are energy-demanding processes, Kim et al. hypothesized that 4-1BB stimulation might also affect energy metabolism. Specifically, using both a mouse model of diet-induced obesity and genetically obese/diabetic mice, Kim et al. showed that stimulation of 4-1BB with an agonistic antibody to 4-1BB reduces adiposity and body weight, modulates inflammatory cytokine levels, improves glucose and lipid metabolism, reduces hepatic steatosis and insulin resistance, and increases energy expenditure.

These data highly implicate 4-1BB immunoregulation in the management of obesity-induced inflammatory and metabolic disorders. And given the extent of these conditions worldwide, this may be a welcomed novel treatment strategy.

C. S. Kim et al., The immune signaling molecule 4-1BB stimulation reduces adiposity, insulin resistance, and hepatosteatosis in obese mice. Endocrinology 18 Aug 2010 (10.1210/en.2010-0346). [Abstract]

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