Fatty Acids and NLRP3 Inflammasome–Mediated Inflammation in Metabolic Tissues

Abstract

Worldwide obesity rates have reached epidemic proportions and significantly contribute to the growing prevalence of metabolic diseases. Chronic low-grade inflammation, a hallmark of obesity, involves immune cell infiltration into expanding adipose tissue. In turn, obesity-associated inflammation can lead to complications in other metabolic tissues (e.g., liver, skeletal muscle, pancreas) through lipotoxicity and inflammatory signaling networks. Importantly, although numerous signaling pathways are known to integrate metabolic and inflammatory processes, the nucleotide-binding and oligomerization domain-like receptor, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is now noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome can be influenced by various metabolites, including fatty acids. Specifically, although saturated fatty acids may promote NLRP3 inflammasome activation, monounsaturated fatty acids and polyunsaturated fatty acids have recently been shown to impede NLRP3 activity. Therefore, the NLRP3 inflammasome and associated metabolic inflammation have key roles in the relationships among fatty acids, metabolites, and metabolic disease. This review focuses on the ability of fatty acids to influence inflammation and the NLRP3 inflammasome across numerous metabolic tissues in the body. In addition, we explore some perspectives for the future, wherein recent work in the immunology field clearly demonstrates that metabolic reprogramming defines immune cell functionality. Although there is a paucity of information about how diet and fatty acids modulate this process, it is possible that this will open up a new avenue of research relating to nutrient-sensitive metabolic inflammation.

Association of lifestyle factors and inflammation with sarcopenic obesity: data from the PREDIMED‐Plus trial

“…An inadequate intake of vitamin C contributes to small overgrowth, transcytosis of enteric bacteria, and an elevation of lipopolysaccharides, which elicits a low‐grade inflammatory response . On the other hand, saturated fat can activate transmembrane proteins (toll‐like receptors 2 and 4) involved in the activation of the innate immune system, leading to the activation of proinflammatory pathways and the secretion of proinflammatory cytokines, which predispose to adipose tissue inflammation and subsequent insulin resistance …”

“…37 On the other hand, saturated fat can activate transmembrane proteins (toll-like receptors 2 and 4) involved in the activation of the innate immune system, leading to the activation of proinflammatory pathways and the secretion of proinflammatory cytokines, which predispose to adipose tissue inflammation and subsequent insulin resistance. 38 The sarcopenia condition of the study participants could be assumed as a chronic condition considering that all subjects of the study were overweight or obese and had metabolic syndrome. Chronic sarcopenia is likely to be associated with permanent and progressive processes such as ageing, obesity, and metabolic syndrome.…”

Monounsaturated Fatty Acids in a High‐Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome

“…Self‐sustained lipolysis orchestrates the accumulation of monocyte‐derived macrophages in the obese WAT, where they polarize or switch from an M2 anti‐inflammatory phenotype toward an M1 pro‐inflammatory phenotype . Such a pathological WAT remodeling particularly occurs with long‐lasting ingestion of Westernized, high‐fat diets (HFDs) rich in saturated fatty acids (SFAs) in both humans and murine models . Conversely, a growing body of evidence points the benefits from replacing dietary SFAs with monounsaturated fatty acids (MUFAs) or omega‐3 polyunsaturated fatty acids (PUFAs) on blood lipid and WAT homeostasis .…”

“…Such a pathological WAT remodeling particularly occurs with long‐lasting ingestion of Westernized, high‐fat diets (HFDs) rich in saturated fatty acids (SFAs) in both humans and murine models . Conversely, a growing body of evidence points the benefits from replacing dietary SFAs with monounsaturated fatty acids (MUFAs) or omega‐3 polyunsaturated fatty acids (PUFAs) on blood lipid and WAT homeostasis . This occurrence is likely due to the promiscuity of the master regulator of adipocyte differentiation, the nuclear peroxisome proliferator‐activated receptor γ (PPARγ) in terms of its interaction with selective dietary fatty acids …”

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

“…Studies have also shown that NLRP3 inflammasome activity is attenuated by mono-and polyunsaturated fatty acids, which are endogenous PPARA agonists (Forman et al, 1997;Kliewer et al, 1997;Mochizuki et al, 2006;Ralston et al, 2017;Shen et al, 2017). Considering these studies, a regulatory mechanism was proposed whereby fatty acids mobilized from adipose tissue during fasting activate PPARA, which in turn suppresses the NLRP3 inflammasome by strong induction of the TXNIP-suppressing lncRNA gene Gm15441, which is antisense to Txnip.…”