Obesity-Induced CerS6-Dependent C16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance

Turpin, Sarah M.; Nicholls, Hayley T.; Willmes, Diana M.; Mourier, Arnaud; Brodesser, Susanne; Wunderlich, Claudia M.; Mauer, Jan; Xu, Elaine; Hammerschmidt, Philipp; Brönneke, Hella S.; Trifunović, Aleksandra; LoSasso, G; Wunderlich, Frank; Kornfeld, Jan-Wilhelm; Blüher, Matthias; Krönke, Martin; Brüning, Jens C.

doi:10.1016/j.cmet.2014.08.002

Cited by 560 publications

(736 citation statements)

References 30 publications

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“…Recent publications are in agreement with our data, suggesting that ceramide synthesis in myeloid cells is not critical for dietinduced inflammation. Deletion of CerS6, which is up-regulated in the white adipose tissue of high fat-fed mice, in macrophages failed to prevent diet-induced adipose tissue inflammation or insulin resistance (46). In our experiments, adipose tissue macrophages highly express both CerS5 and CerS6.…”

Section: Discussioncontrasting

confidence: 40%

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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Section: Discussioncontrasting

confidence: 40%

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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“…Relative to C24:0 ceramide, we detected low circulating levels of C16:0 ceramide (0.9% of total ceramide) which is synthesized by ceramide synthase 6 (Turpin et al. 2014). …”

Section: Resultsmentioning

confidence: 99%

“…2014; Turpin et al. 2014). Nevertheless, our measured increase in serum C16:0 ceramide that developed concurrently with lower circulating cholesterol and reduced waist circumference is a paradoxical observation.…”

Section: Resultsmentioning

confidence: 99%

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

et al. 2017

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The 2010 USDA Dietary Guidelines for Americans (DGA) recommends a diet largely composed of fruit and vegetables. Consuming a diet high in fruit and vegetables and low in refined carbohydrates and saturated fat may reduce an individual's risk for type 2 diabetes, nonalcoholic fatty liver disease, low‐grade chronic inflammation, and metabolic syndrome (MetS). Several recent studies have implicated the bioactive sphingolipid ceramide as an associative and causative biomarker for the development of these conditions. Considering that the intake of fruit and vegetables is frequently inadequate in young adults, we performed a pilot investigation to assess the efficacy of a free‐living fruit and vegetable intervention on overall metabolic health, circulating ceramide supply, and inflammatory status in young adults. We discovered that adoption of the recommended DGA for fruit and vegetable intake for 8 weeks decreased waist circumference, systolic blood pressure, and circulating cholesterol. Lipidomics analysis revealed that nutritional intervention can lower circulating ceramides, including C24:0 ceramide, a known inhibitor of insulin signaling. Unexpectedly, we observed an increase in C16:0 ceramide, suggesting that this form of ceramide in circulation is not associated with metabolic disease in humans. We also observed an improved inflammatory status with enhanced fruit and vegetable intake that was correlated with ceramide concentrations. These data suggest that adopting the recommended DGA is associated with a reduction of many, but not all, ceramide species and may help to prevent or mitigate MetS. Future research needs to assess whether the ceramide‐lowering ability of nutritional intervention is associated with reduced risk of developing metabolic disease.

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“…In mice with altered expression of ceramide synthase 2 and ceramide synthase 6, increases in long‐chain ceramide species (eg, C16:0 ceramide) and decreases in very–long‐chain species (eg, C22:0 and C24:0 ceramides) in metabolic tissues are associated with diet‐induced glucose intolerance, nonalcoholic steatohepatitis, and insulin resistance 5, 6. In retrospective case‐control studies of patients with coronary heart disease (CHD), high plasma C16:0 ceramide, low C24:0 ceramide, and low C24:0/C16:0 ceramide ratios were directly related to cardiovascular mortality over 3 years 7, 8.…”

Section: Introductionmentioning

confidence: 99%

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

Peterson

Xanthakis

Duncan

et al. 2018

JAHA

126

106

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BackgroundRecent studies suggest that circulating concentrations of specific ceramide species may be associated with coronary risk and mortality. We sought to determine the relations between the most abundant plasma ceramide species of differing acyl chain lengths and the risk of coronary heart disease (CHD) and mortality in community‐based samples.Methods and ResultsWe developed a liquid chromatography/mass spectrometry assay to quantify plasma C24:0, C22:0, and C16:0 ceramides and ratios of these very–long‐chain/long‐chain ceramides in 2642 FHS (Framingham Heart Study) participants and in 3134 SHIP (Study of Health in Pomerania) participants. Over a mean follow‐up of 6 years in FHS, there were 88 CHD and 90 heart failure (HF) events and 239 deaths. Over a median follow‐up time in SHIP of 5.75 years for CHD and HF and 8.24 years for mortality, there were 209 CHD and 146 HF events and 377 deaths. In meta‐analysis of the 2 cohorts and adjusting for standard CHD risk factors, C24:0/C16:0 ceramide ratios were inversely associated with incident CHD (hazard ratio per average SD increment, 0.79; 95% confidence interval, 0.71–0.89; P<0.0001) and inversely associated with incident HF (hazard ratio, 0.78; 95% confidence interval, 0.61–1.00; P=0.046). Moreover, the C24:0/C16:0 and C22:0/C16:0 ceramide ratios were inversely associated with all‐cause mortality (C24:0/C16:0: hazard ratio, 0.60; 95% confidence interval, 0.56–0.65; P<0.0001; C22:0/C16:0: hazard ratio, 0.65; 95% confidence interval, 0.60–0.70; P<0.0001).ConclusionsThe ratio of C24:0/C16:0 ceramides in blood may be a valuable new biomarker of CHD risk, HF risk, and all‐cause mortality in the community.

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Obesity-Induced CerS6-Dependent C16:0 Ceramide Production Promotes Weight Gain and Glucose Intolerance

Cited by 560 publications

References 30 publications

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

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

Efficacy of nutritional interventions to lower circulating ceramides in young adults: FRUVEDomic pilot study

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

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