Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans

Goossens, Gijs H.; Blaak, Ellen E.; Theunissen, Ruud; Duijvestijn, A. M.; Clément, Karine; Tervaert, Jan-Willem Cohen; Thewissen, Mariëlle

doi:10.1016/j.molimm.2012.01.005

Cited by 100 publications

(93 citation statements)

References 26 publications

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“…Thus, the described has dramatically increased over the last decade. Prior observations indicated that activation of the NLRP3 inflammasome plays a role in T2DM pathogenesis, possibly by driving inflammation, obesity and insulin resistance (7,9,10,18,19). Nevertheless, its role as specific pharmacological target for drug therapy of insulin resistance and related metabolic uptake in skeletal muscle after NLRP3 modulation is mainly due to activation of the IRS-1/Akt/GSK-3β pathway.…”

Section: Discussionmentioning

confidence: 99%

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Chiazza

Couturier-Maillard

Benetti

et al. 2015

Mol Med

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Although the molecular links underlying the causative relationship between chronic low-grade inflammation and insulin resistance are not completely understood, compelling evidence suggests a pivotal role of the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Here we tested the hypothesis that either a selective pharmacological inhibition or a genetic downregulation of the NLRP3 inflammasome results in reduction of the diet-induced metabolic alterations. Male C57/BL6 wild-type mice and NLRP3 -/-littermates were fed control diet or high-fat, high-fructose diet (HD). A subgroup of HD-fed wild-type mice was treated with the NLRP3 inflammasome inhibitor BAY 11-7082 (3 mg/kg intraperitoneally [IP]). HD feeding increased plasma and hepatic lipids and impaired glucose homeostasis and renal function. Renal and hepatic injury was associated with robust increases in profibrogenic markers, while only minimal fibrosis was recorded. None of these metabolic abnormalities were detected in HD-fed NLRP3 -/-mice, and they were dramatically reduced in HD-mice treated with the NLRP3 inflammasome inhibitor. BAY 11-7082 also attenuated the diet-induced increase in NLRP3 inflammasome expression, resulting in inhibition of caspase-1 activation and interleukin (IL)-1β and IL-18 production (in liver and kidney). Interestingly, BAY 11-7082, but not gene silencing, inhibited nuclear factor (NF)-κB nuclear translocation. Overall, these results demonstrate that the selective pharmacological modulation of the NLRP3 inflammasome attenuates the metabolic abnormalities and the related organ injury/dysfunction caused by chronic exposure to HD, with effects similar to those obtained by NLRP3 gene silencing.

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Section: Discussionmentioning

confidence: 99%

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Chiazza

Couturier-Maillard

Benetti

et al. 2015

Mol Med

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“…As recently reviewed (110), one factor may be their actions on fuel metabolism in immune cells. Increases in glucose uptake, glycolysis, and the activity of the pentose phosphate pathway (which generates NADPH), as well as decreases in AMPK and presumably sirtuin activity, have been observed in M1 macrophages and T helper cells (110), both of which are more numerous in inflamed adipose tissue (111). Conversely, noninflammatory cells, such as M2 macrophages, regulatory T cells, and quiescent memory T cells, have lower glycolytic rates and higher rates of oxidative metabolism, presumably related to their higher AMPK and SIRT1 activities.…”

Section: Additional Evidence Of Ampk and Sirt1 Links To Inflammationmentioning

confidence: 99%

AMPK, insulin resistance, and the metabolic syndrome

Ruderman¹,

Carling²,

Prentki³

et al. 2013

J. Clin. Invest.

723

531

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IntroductionThe fuel-sensing enzyme AMP-activated protein kinase (AMPK) was first described as an enzyme activated by changes in the AMP/ATP ratio that could both increase cellular ATP generation (e.g., fatty acid oxidation) and diminish ATP use for less critical processes (e.g., fatty acid, triglyceride, and protein synthesis) (1). In addition to glucose transport, lipid and protein synthesis, and fuel metabolism, AMPK regulates a wide array of other physiological events, including cellular growth and proliferation, mitochondrial function and biogenesis, and factors that have been linked to insulin resistance (IR), including inflammation, oxidative and ER stress, and autophagy ( Figure 1A). Furthermore, AMPK does so by phosphorylating both key enzymes and transcriptional activators and coactivators.Here, we examine 2 hypotheses suggested by more recent studies: (a) dysregulation of AMPK plays an important role in the pathogenesis of IR and metabolic syndrome-associated diseases in humans and experimental animals; and (b) strategies that activate AMPK can be harnessed for the prevention and treatment of these abnormalities. These hypotheses emanated from associations between the metabolic syndrome and some downstream targets of AMPK, such as glucose transport and lipogenesis (2-8). In addition, exercise (9) and electrically induced contractions (10) were shown to activate AMPK. These observations, coupled with epidemiological evidence that diseases associated with the metabolic syndrome (e.g., type 2 diabetes, hypertension, atherosclerotic cardiovascular disease [ASCVD], and even certain cancers) are less prevalent in physically active people (11-13) and the demonstration that regular exercise improves whole-body insulin action (11, 12), suggest a central role for AMPK in regulating insulin sensitivity. Such studies also raise the possibility that pharmacological AMPK activators as well as exercise could be used for ameliorating IR in type 2 diabetes (4,8).In model systems, sustained decreases in AMPK activity accompany IR, whereas AMPK activation increases insulin sensitivity (5, 6, 13). In addition, decreases in AMPK activity accompanying IR were described in adipose tissue of humans with Cushing's syndrome, an effect attributable to high levels of glucocorticoids (14), and in a subgroup of very obese patients undergoing bariatric surgery who were insulin resistant (15, 16). The latter comprise approximately 75% of bariatric surgery patients and show a greater predisposition to metabolic syndrome-associated diseases than do the remaining 25% of such patients who are equally obese, but less hyperinsulinemic and more insulin sensitive (17-19). Insulin resistance in physiology and diseaseStudies with a perfused rat hindquarter preparation demonstrated that insulin-stimulated glucose uptake in skeletal muscle is reduced in fed versus fasted rats (20) and in sedentary versus recently exercised rats (21), suggesting that the fed and sedentary rats are essentially more insulin resistant. Such IR is physiological, rat...

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“…The biological pathways driving this innate immune program are well defined (4). In the context of obesity, triggers that engage Toll-like receptors to initiate transcriptional priming of the NLRP3 inflammasome include adipose tissue hypertrophy with macrophage infiltration and cytokine secretion, elevated circulating saturated fatty acids, and/or obesity-linked endotoxemia (5)(6)(7)(8). These, in turn activate NF-κB-dependent transcription to upregulate genes encoding NLRP3 and pro-IL-1β.…”

Section: Introductionmentioning

confidence: 99%

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects

Traba¹,

Kwarteng-Siaw²,

Okoli³

et al. 2015

Journal of Clinical Investigation

148

149

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BACKGROUND. Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity. METHODS.We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation. RESULTS.In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting. CONCLUSIONS.Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease. TRIAL REGISTRATION. ClinicalTrials.gov NCT02122575 and NCT00442195.

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Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans

Cited by 100 publications

References 26 publications

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

AMPK, insulin resistance, and the metabolic syndrome

Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects

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