Plasma Membrane Subdomain Compartmentalization Contributes to Distinct Mechanisms of Ceramide Action on Insulin Signaling

Blouin, Cédric M.; Prado, Cecilia; Takane, Karen K.; Lasnier, Françoise; Garcı́a-Ocaña, Adolfo; Ferré, Pascal; Dugail, Isabelle; Hajduch, Éric

doi:10.2337/db09-0897

Cited by 98 publications

(90 citation statements)

References 52 publications

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“…Such event, if reproduced in the adipose tissue, might corroborate the increment in Ser phosphorylation of IRS-1 observed in rats treated with dexamethasone in vivo [15] , a context associated with decreased JNK and IKKβ phosphorylation. In accordance, it was shown that, in 3T3-L1 cells, PKCζ mediates the negative effect of ceramide in the insulin-stimulated PKB phosphorylation [35] . Since ceramide production seems to be necessary for dexamethasone effects on peripheral insulin action [32] , PKCζ can be a promising mediator of dexamethasone effects on PKB functionality, independently of JNK and IKKβ.…”

Section: Research Highlightsupporting

confidence: 58%

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

Rafacho

Nunes²,

Bordin³

2015

Inflamm Cell Signal

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Glucocorticoid (GC) hormone exerts numerous physiological roles that include modulation of immune, nervous, cardiovascular and metabolic systems. Synthetic GCs such as dexamethasone and prednisone/prednisolone are widely prescribed in the clinical context to the treatment of inflammatory-related diseases. In spite of its positive therapeutic effect, GC-based therapies may cause several adverse effects including glucose intolerance and peripheral insulin resistance. Reduction of insulin sensitivity in the adipocytes and adipose tissue caused by GC treatment is associated with increased lipolysis and abnormal Ser phosphorylation of insulin substrate receptor (IRS)-1 and protein kinase B (PKB). However, there is no consensus about the precise mechanisms whereby GC treatment promotes such attenuation in the insulin signaling pathway. In this paper, we will briefly discuss and present some molecular evidences that might be involved with this negative impact of GC in the insulin signaling in the adipose tissue.

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Section: Research Highlightsupporting

confidence: 58%

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

Rafacho

Nunes²,

Bordin³

2015

Inflamm Cell Signal

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“…We delved deeper into the mechanism and showed that in enterocytes the effects of C 2 -ceramide on AKT phosphorylation involved the activation of the PKC pathway. This ceramide-activated pathway has previously been observed to mediate deleterious ceramide effects on insulin signaling in different insulin-sensitive cell types (31,32).…”

Section: Akt Phosphorylation In Cell Lysates Was Analyzed By Western mentioning

confidence: 87%

“…Inhibitory Effect of Ceramide on Insulin-stimulated AKT Phosphorylation Is Mediated by PKC Activity but Not by PP2A Activity-In 3T3-L1 adipocytes and L6 muscle cells, it has been reported that protein kinase C (PKC) and protein phosphatase 2A (PP2A) are involved in the inhibitory effect of ceramide on insulin signaling (31,32). To determine whether PKC and/or PP2A pathways are also involved in enterocytes, we pre-treated Caco-2/TC7 cells with either a broad PKC inhibitor (Ro 31.8220) or a PP2A inhibitor (okadaic acid, OKA), before the addition of C 2 -ceramide and insulin (Fig.…”

Section: Alteration Of Insulin Signaling In Intestinal Cells By Palmimentioning

confidence: 99%

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Tran¹,

Postal²,

Demignot³

et al. 2016

Journal of Biological Chemistry

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The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulinsignaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.The worldwide obesity epidemic has stimulated numerous research efforts to identify factors that affect energy balance. As compared with the liver, pancreas, muscle, or adipose tissues, the intestine has received little attention with regard to its potential role in the onset of metabolic disorders. Nevertheless, the intestine could also contribute to the development of metabolic disease, especially through its role in postprandial lipemia.The increased amplitude and duration of the postprandial peak of circulating triglyceride-rich lipoproteins (TRL) 5 are known risk factors for atherosclerosis and cardiovascular diseases (1, 2). Postprandial hypertriglyceridemia can be due to impaired TRL catabolism, and/or lipoprotein remnant uptake, and may also result from intestinal TRL overproduction (3). Thus, investigating intestinal lipoprotein secretion might help to understand aberrant postprandial lipemia (4).The intestine ensures the transport of alimentary fat, which is the most calorie-dense nutrient. Enterocytes produce intestinal TRLs (chylomicrons) along a multistep pathway, which includes long chain fatty acid uptake, triglyceride synthesis in the endoplasmic reticulum, and assembly with apolipoproteins (apo) such as apoB48. Chylomicrons are then secreted into the lymph and ultimately into the blood. Overproduction of intestinal TRL may be an important contributor of both fasting and postprandial dyslipidemia (3, 5). Microsomal triglyceride transfer protein (MTP) transports neutral lipids (6) and plays a cen...

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“…The sphingolipid antagonizes Akt/PKB via at least 2 pathways, culminating on different Akt/PKB domains (38,39). Some recent attention has been placed on the idea that glucosylceramide, rather than ceramide itself, is the primary antagonist of insulin signaling, as inhibitors of glucosylceramide are potently insulin sensitizing (40,41).…”

Section: Discussionmentioning

confidence: 99%

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

et al. 2011

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Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid-induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

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Plasma Membrane Subdomain Compartmentalization Contributes to Distinct Mechanisms of Ceramide Action on Insulin Signaling

Cited by 98 publications

References 52 publications

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

How much we know about the attenuation of insulin signaling in the adipose tissue caused by glucocorticoid treatment?

Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

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