OBESITY AND DIABETES

Obesity is a major cause of morbidity and mortality and the most common metabolic disorder in the United States, where it affects >30% of adults. It is also a key risk factor for chronic diseases such as atherosclerosis and type 2 diabetes (T2D). It is now well accepted that macrophages accumulate in adipose tissue of obese mice and humans and are a key source of pro-inflammatory cytokines and chemokines.

While it is well established that macrophage inflammation is causally linked to insulin resistance in mice, the environmental conditions triggering inflammation, and molecular mechanisms mediating it are incompletely defined. Current understanding is based on a paradigm of classical M1 activation derived from bacterial exposure. However, we provide data that such a pathway is not engaged in ATMs from obese humans and mice, and that a fatty acid-driven ‘metabolically activated’ (MMe) phenotype is more representative. Although MMe and M1 macrophages both over-express inflammatory cytokines, they differ with respect to broad protein abundance patterns, functions, and signaling pathways driving inflammatory cytokine expression.

Using a combination of biochemistry, medicinal chemistry, animal models, and human studies, we are identifying MMe-specific pathways of macrophage inflammation and developing therapeutics that block it. Our overall goal is to attenuate ATM inflammation in obese/T2D patients to promote insulin sensitivity without predisposing patients to opportunistic infections.

Selected Publications

Coats, B.R., Schoenfelt2, K.Q., Barbosa-Lorenzi, V.C., Peris, E., Cui, C., Hoffman, A., Zhou, G., Fernandez, S. Zhai, L., Hall, B.A., Haka, A.S., Shah, A.M., Reardon, C.A., Brady, M.J., Rhodes, C.J., Maxfield, F.R., & Becker, L. (2017). Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep. 20, 3149-3161.

Kratz, M., Coats, B.R., Hisert, K.B., Hagman, D., Mutsov, V., Peris, E., Schoenfelt, K.E., Kuzma, J.N., Larson, I., Billing, P.S., Landerholm, R.W., Crouthamel, M., Gozal, D., Hwang, S., Singh, P., & Becker, L. (2014). Metabolic dysfunction drives a mechanistically distinct pro-inflammatory phenotype in adipose tissue macrophages. Cell Metab. 7, 614-625.

Team