Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes

Abstract

Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet or synthesized endogenously. In addition to serving as an important source of energy, they produce a variety of both beneficial and detrimental effects. They play essential roles as structural components of all cell membranes and as signaling molecules regulating metabolic pathways through binding to nuclear or membrane receptors. However, under conditions of FFAs overload, they become toxic, inducing ROS production, ER stress, apoptosis and inflammation. SFAs (saturated fatty acids), unlike UFAs (unsaturated fatty acids), have recently been proposed as triggers of the NLRP3 inflammasome, a molecular platform mediating the processing of IL-1β in response to infection and stress conditions. Interestingly, UFAs, especially ω-3 FAs, inhibit NLRP3 inflammasome activation in various settings. We focus on emerging models of NLRP3 inflammasome activation with a special emphasis on the molecular mechanisms by which FFAs modulate the activation of this complex. Taking into consideration the current literature and FFA properties, we discuss the putative involvement of mitochondria and the role of cardiolipin, a mitochondrial phospholipid, proposed to be sensed by NLRP3 after release, exposure and/or oxidation. Finally, we review how this SFA-mediated NLRP3 inflammasome activation contributes to the development of both insulin resistance and deficiency associated with obesity/type 2 diabetes. In this context, we highlight the potential clinical use of ω-3 FAs as anti-inflammatory compounds.

Introduction

The incidence of type 2 diabetes (T2D) worldwide has increased markedly and constitutes one of the major threats to global health. Insulin resistance (IR), a hallmark of T2D, is associated with low-grade systemic inflammation, characterized by upregulated cytokines production and inflammatory pathways [1].

Since free fatty acids (FFAs) levels are increased in the blood of humans with obesity/T2D, FFAs have been proposed to mediate inflammatory cascade activation through toll-like receptors (TLRs), leading to the NF-κB-dependent production of inflammatory cytokines [2], [3]. Very recently, FFAs have also been implicated as putative triggers of the NLRP3 (nucleotide-binding domain, leucine-rich repeat and pyrin domain containing protein 3) inflammasome, a molecular platform required for the maturation of the proinflammatory cytokines IL (interleukin)-1β and IL-18 that plays a role in the development of IR/T2D [4], [5].

In this review, we will discuss FFA chemical properties, their metabolism, and their roles as signaling compounds and toxic metabolites (Section 2); the current models of NLRP3 inflammasome activation (Section 3); recent data in vitro showing modulation of the NLRP3 inflammasome in response to saturated versus unsaturated fatty acids and the putative underlying mechanisms (Section 4); the involvement of SFAs in NLRP3 inflammasome activation in the context of obesity/T2D (Section 5).