title: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.
abstract: 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.
authors.affiliation: Laboratory of Neuroendocrine-Immunology, Louisiana State University, Baton Rouge, Louisiana, USA.
authors.forename: Bolormaa
authors.initials: B
authors.lastname: Vandanmagsar
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Youm
authors.forename: Anthony
authors.initials: A
authors.lastname: Ravussin
authors.forename: Jose E
authors.initials: JE
authors.lastname: Galgani
authors.forename: Krisztian
authors.initials: K
authors.lastname: Stadler
authors.forename: Randall L
authors.initials: RL
authors.lastname: Mynatt
authors.forename: Eric
authors.initials: E
authors.lastname: Ravussin
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Stephens
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology*; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D007328:Insulin; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020170:Caspase 1