Omega-3 Fatty Acids Prevent Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome Activation

Yan, Yiqing; Jiang, Wei; Spinetti, Thibaud; Tardivel, Aubry; Castillo, Rosa; Bourquin, Carole; Guarda, Greta; Tian, Zhigang; Tschopp, Jürg; Zhou, Rongbin

doi:10.1016/j.immuni.2013.05.015

Cited by 619 publications

(548 citation statements)

References 49 publications

(60 reference statements)

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“…It was shown that a short-term polyunsaturated fatenriched KD did not adversely alter lipid metabolism in adults (15). Also, supplementation of a high-fat diet with -3 polyunsaturated fatty acids has been shown to prevent high-fat diet-induced insulin resistance by reducing inflammasomedependent inflammation in rodents (41). However, in our study, the higher content of -3 fatty acids in the KD could not prevent proinflammatory effects on the long term.…”

Section: Discussioncontrasting

confidence: 68%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

123

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Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Long-term ketogenic diet causes glucose intolerance and reduced ␤-and ␣-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab 306: E552-E558, 2014. First published January 7, 2014 doi:10.1152/ajpendo.00453.2013.-High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and ␤-and ␣-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1␤, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from ␤-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in ␤-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also ␣-cell mass was markedly decreased, resulting in a lower ␣-to ␤-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in ␤-and ␣-cell mass, but no weight loss. This indicates that long-term high-fat, lowcarbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans. pancreatic islet; ketogenic diet; glucose intolerance; ␤-cell; ␣-cell

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Section: Discussioncontrasting

confidence: 68%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

123

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“…The fate of fatty acids following release from dying adipocytes is unclear, although a recent study has shown the importance of lysosomal biogenesis and metabolism of lipids in adipose tissue macrophages following DIO (9), suggesting that a portion may be metabolized. Other investigations have underscored the importance of the type of fatty acids in eliciting inflammation, because omega-3 supplementation is sufficient to reduce HFD-induced adipose tissue inflammation (48). In this publication, we have eliminated the possibility that palmitate entry into the nonoxidative pathway causes Nlrp3 inflammasome-driven inflammation.…”

Section: Discussionmentioning

confidence: 91%

Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity

Camell¹,

Nguyen²,

Jurczak³

et al. 2015

Journal of Biological Chemistry

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Dietary lipid overload and calorie excess during obesity is a low grade chronic inflammatory state with diminished ability to appropriately metabolize glucose or lipids. Macrophages are critical in maintaining adipose tissue homeostasis, in part by regulating lipid metabolism, energy homeostasis, and tissue remodeling. During high fat diet-induced obesity, macrophages are activated by lipid derived "danger signals" such as ceramides and palmitate and promote the adipose tissue inflammation in an Nlrp3 inflammasome-dependent manner. Given that the metabolic fate of fatty acids in macrophages is not entirely elucidated, we have hypothesized that de novo synthesis of ceramide, through the rate-limiting enzyme serine palmitoyltransferase long chain (Sptlc)-2, is required for saturated fatty aciddriven Nlrp3 inflammasome activation in macrophages. Here we report that mitochondrial targeted overexpression of catalase, which is established to mitigate oxidative stress, controls ceramide-induced Nlrp3 inflammasome activation but does not affect the ATP-mediated caspase-1 cleavage. Surprisingly, myeloid cell-specific deletion of Sptlc2 is not required for palmitatedriven Nlrp3 inflammasome activation. Furthermore, the ablation of Sptlc2 in macrophages did not impact macrophage polarization or obesity-induced adipose tissue leukocytosis. Consistent with these data, investigation of insulin resistance using hyperinsulinemic-euglycemic clamps revealed no significant differences in obese mice lacking ceramide de novo synthesis machinery in macrophages. These data suggest that alternate metabolic pathways control fatty acid-derived ceramide synthesis in macrophage and the Nlrp3 inflammasome activation in obesity. Diet-induced obesity (DIO)2 is a growing epidemic and has greatly augmented the number of humans diagnosed with metabolic diseases such as type 2 diabetes, cardiovascular disease, and atherosclerosis (1, 2). The importance of inflammation in driving metabolic dysregulation during DIO is well established, and research has highlighted the importance of the adipose tissue and resident immune cells in maintaining glucose homeostasis (3, 4).DIO induces adipose tissue inflammation that is largely characterized by infiltration of immune cells, including pro-inflammatory activated macrophages, T cells, and B cells (5-8). In lean adipose, resident macrophages exhibit anti-inflammatory characteristics, including expressing surface markers such as MGL1, CD206, and Arginase1. In contrast, infiltrating macrophages express increased amounts of inflammatory cytokines, such as TNF␣, MCP1, and IL1␤ (7). Infiltrating CCR2 ϩ macrophages surround dying adipocytes, forming crown-like structures, and contain large lipid droplets (9, 10), suggesting they are uniquely sensitive to the lipid-loaded microenvironment. Diet-induced inflammation is mediated through the activation of the NLRP3 (NLR family pyrin domain containing 3) inflammasome, a large cytosolic multiprotein scaffolding complex that activates caspase-1 and leads to the secretion...

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“…inflammasome [58,59,63] and can prevent its activation by other inducers [59]. The importance of unsaturated fatty acids in mediating inflammation is enhanced by a recent study showing a distinct fatty acid profile between MHO and unhealthy obese individuals, specifically for saturated fatty acids [64].…”

Section: Page 11 Of 24mentioning

confidence: 99%

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

Esser

Legrand-Poels

Piette

et al. 2014

Diabetes Research and Clinical Practice

1,567

1,064

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:It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammarory therapies could have a place in prevention and treatment of type 2 diabetes.

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Omega-3 Fatty Acids Prevent Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome Activation

Cited by 619 publications

References 49 publications

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

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