Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4

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Abstract

Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type 2 diabetes (T2D), retinol binding protein 4 (RBP4), the major retinol carrier in serum, is elevated in AT and has proinflammatory effects which are mediated partially through Toll-like receptor 4 (TLR4). We now show that RBP4 primes the NLRP3 inflammasome for interleukin-1β (IL1β) release, in a glucose-dependent manner, through the TLR4/MD2 receptor complex and TLR2. This impairs insulin signaling in adipocytes. IL1β is elevated in perigonadal white AT (PGWAT) of chow-fed RBP4- overexpressing mice and in serum and PGWAT of high-fat diet-fed RBP4-overexpressing mice vs. wild-type mice. Holo- or apo-RBP4 injection in wild-type mice causes insulin resistance and elevates PGWAT inflammatory markers, including IL1β. TLR4 inhibition in RBP4-overexpressing mice reduces PGWAT inflammation, including IL1β levels and improves insulin sensitivity. Thus, the proinflammatory effects of RBP4 require NLRP3-inflammasome priming. These studies may provide approaches to reduce AT inflammation and insulin resistance in obesity and diabetes.

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Moraes-Vieira, P. M., Yore, M. M., Sontheimer-Phelps, A., Castoldi, A., Norseen, J., Aryal, P., … Kahn, B. B. (2020). Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4. Proceedings of the National Academy of Sciences of the United States of America, 117(49), 31309–31318. https://doi.org/10.1073/pnas.2013877117

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