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

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.

Spatial mapping reveals human adipocyte subpopulations with distinct sensitivities to insulin

“…However, testing this in vivo requires clinical studies applying spatial transcriptomics to determine the effects of caloric oversupply and/or weight loss-inducing diets/drugs. The role of Adipo SAA is less clear, but the observation that it expresses a set of genes encoding retinol-binding proteins (RBP4, SAA1/-2), with established pro-inflammatory effects (Kilicarslan et al, 2020;Moraes-Vieira et al, 2020;Yang et al, 2006), suggests that Adipo SAA may modulate WAT inflammation.…”

Biological Functions of RBP4 and Its Relevance for Human Diseases

“…Mechanistically, RBP4 was shown to induce expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase in liver and to impair insulin signaling in muscle ( Yang et al, 2005 ). However, follow-up studies by the same laboratory implicated the immune system, in particular antigen-presenting cells, such as dendritic cells, macrophages, and also CD4 T cells as the drivers of an inflammatory response that is induced by RBP4 within adipose tissue ( Norseen et al, 2012 ; Moraes-Vieira et al, 2014 , 2016 , 2020 ). Strikingly, this inflammatory reaction was independent of RBP4’s association with retinol ( Norseen et al, 2012 ) and mediated by an activation of toll-like receptors 2/4 (TLR2/4) and proinflammatory cytokine secretion from macrophages, involving nuclear factor κ-B (NFκB), c-Jun N-terminal kinases (JNK), and interleukin 1β ( Moraes-Vieira et al, 2014 , 2020 ; Figure 3A ).…”

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“…1, TX pretreatment significantly enhanced glucose uptake as compared to ELAS and SAL. DISCUSSION: Adipose tissue is the primary contributor for the development of obesity and IR by secreting a large number of inflammatory cytokines and chemokines which can modulate inflammation, lipid and glucose metabolism 22 . Among the adipokines, TNFα plays a major role in obesity-related IR and inflammation.…”