The NALP3/NLRP3 Inflammasome Instigates Obesity-Induced Autoinflammation and Insulin Resistance

By B. Vandanmagsar, Y. Youm, A. Ravussin, J. Galgani, K. Stadler, R. Mynatt, E. Ravussin, J. Stephens, V. Dixit. Nature Medicine, 2011

1,658 citations recorded by the source corpus.

The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e0fe0065c26f7b72109f778b0422e2b8bdb32e5d

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Citations in the corpus

Pathophysiology of Type 2 Diabetes Mellitus (2020, result): “Preclinical data suggest that inflammation resolution could prevent the development of T2DM in obesity and prediabetes, which was substantiated by preclinical animal data showing that deletion of the macromolecular complex NLRP3 inflammasome, responsible for the production of IL-1β and IL-18, result”
Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, background): “Vandanmagsar et al showed that adding ceramide to adipose tissue explants led to NLRP3-dependent IL-1β production, suggesting that ceramide acts a danger signal to stimulate the NLRP3 inflammasome (130).”
Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. (2014, background): “[56] Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al.”
Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment (2011, neutral): “An Escherichia coli was isolated from mouse cæcum (Inserm U1048) and transformed with the plasmid pZE1R-GFP (gift from J. Oberto, CNRS UMR8621, Orsay, France) to induce the expression of green fluorescent protein (GFP) and b -lactamase conferring resistance to 100 m g/ml of ampicillin.”
NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases (2015, background): “…LRR, leucine-rich-repeat olymorphonuclear leukocytes; POP, PYD-only proteins; PRRs, pattern-recognition MCs, smooth muscle cells; TLRs, toll-like receptors; TNF, tumor necrosis factor; Trx, unfolded protein response eing Biology (B2A), UMR-8256/INSERM ERL-1164, Université Pierre et Marie Curie,”
Kupffer Cells in the Liver (2013, neutral): “associated with metabolic syndrome (26, 130, 145), it is not known if there is a role for these NLRs in ALD.”
Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes (2020, background): “It is unclear which cell compartments in AT express the inflammasome components; however, immunostaining of AT sections of obese mice confirmed a strong co-localization of NLRP3 with macrophage marker F4/80 in crown-like structures (Vandanmagsar et al., 2011).”