Abstract
Metabolic inflammation (metaflammation) is characteristic of obesity-related metabolic disorders, associated with increased risk of development of type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), or cardiovascular disease. Metaflammation refers to a chronic, low-grade systemic inflammation as opposed to the classical transient and acute inflammatory responses of the innate immune system. Metaflammation is driven by a range of adverse dietary factors, including saturated fatty acids and some sugars, suggesting that certain dietary triggers may be particularly relevant beyond simple excessive dietary intake presenting as obesity. Importantly, obese patients with diabetes have a higher risk of infection and display gut microbiota profiles characteristic of dysfunctional immunity. Targeting metaflammation has also emerged as a strategy to attenuate metabolic disease. In this review we explore how different nutrition interventions may reconfigure disrupted metabolic inflammation in type 2 diabetes and nonalcoholic fatty liver disease by reestablishing a conventional proinflammatory program in innate immune cells and/or correcting dysbiosis to dampen systemic inflammation. We begin by reviewing concepts of metabolic inflammation relating to IL-1β inflammation and how it is induced by dietary and/or metabolic stressors. We then explore whether and how dietary interventions may attenuate processes pertaining to metaflammation, either directly or indirectly via the microbiome. Hence, we hope to bring new perspectives to alleviate the metaflammation typifying metabolic disease.
Highlights
From athe Macrophage Homeostasis Research Group, School of Biochemistry and Immunology, and bthe Trinity Biomedical Sciences Institute, Trinity College Dublin; cthe Nutrigenomics Research Group, School of Public Health Physiotherapy and Sports Science, University College Dublin; dthe University College Dublin Institute of Food and Health/Diabetes Complications Research Centre, University College Dublin Conway Institute, University College Dublin; and ethe Institute for Global Food Security, Queens University Belfast
Obesity-related metabolic disruption occurring in obese individuals leads to the development of multiple conditions, type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD)
The comorbidities are associated with hallmarks of severely dysregulated whole-body metabolism and a chronic systemic subinflammatory status characteristic of metaflammation, of which the NLRP3 inflammasome appears to be the key mediator
Summary
The unique innate immune sensor NLRP3 senses obesity-associated danger signals.[11] in animals exposed to a high-fat diet (HFD) or obese leptin-deficient animals, such signals induce a proinflammatory response in innate immune cells located in the adipose tissue via induction of the NLRP3/IL-1b axis.[11] IL-1b induces insulin resistance by serine phosphorylation of IRS1 in target tissues, affecting glucose and lipid metabolism as well as promoting inflammation via TNF-a production.[12] Consistent with this, the clustered regularly interspaced short palindromic repeats/Cas[9] method has been successfully used to disrupt NLRP3 expression in macrophages, increasing insulin sensitivity and reducing adipose inflammation in an HFD-induced T2D mouse model.[13] Regarding the liver, inflammation and NLRP3 inflammasome are recognized as important factors implicated in NAFLD persistence.[14] Animals fed an HFD display inflammasome activation and steatohepatitis,[15] and therapies targeting NLRP3 inflammasome activation have been successful in preventing NAFLD in mice exposed to an HFD.[16] In humans, 1 of the first studies targeting IL-1b signaling used the recombinant human IL-1 receptor antagonist anakinra to inhibit IL-1 receptor, improving glycemia and reducing markers of systemic inflammation in patients with T2D.7. We will discuss the PRR-associated signals linked to metaflammation activation during consumption of a WD, with an emphasis on the inflammasome/IL-1 pathway
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