Inhibitory effect of ceramide on insulin-induced protein kinase Cζ translocation in rat adipocytes

Miura, Asako; Kajita, Kazuo; Ishizawa, Masayoshi; Kanoh, Yoshinori; Kawai, Yasunori; Natsume, Yoshiyuki; Sakuma, Hajime; Yamamoto, Yuhei; Ishizuka, Tatsuo

doi:10.1053/meta.2003.50011

Cited by 14 publications

(8 citation statements)

References 28 publications

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“…Generation of ceramide induces insulin resistance in a number of tissues through ceramide-mediated activation of protein kinase and/or protein phosphatase 2A (20), which inhibit tyrosine phosphorylation of IRS-1 and phosphatidylinositol-3-kinase enzyme activity (59,60). Ceramide inhibition of Akt phosphorylation was previously demonstrated in PHTs (19).…”

Section: Discussionmentioning

confidence: 91%

Adiponectin Inhibits Insulin Function in Primary Trophoblasts by PPARα-Mediated Ceramide Synthesis

Aye

Gao

Weintraub

et al. 2014

Molecular Endocrinology

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Maternal adiponectin (ADN) levels are inversely correlated with birth weight, and ADN infusion in pregnant mice down-regulates placental nutrient transporters and decreases fetal growth. In contrast to the insulin-sensitizing effects in adipose tissue and muscle, ADN inhibits insulin signaling in the placenta. However, the molecular mechanisms involved are unknown. We hypothesized that ADN inhibits insulin signaling and insulin-stimulated amino acid transport in primary human trophoblasts by peroxisome proliferator-activated receptor-α (PPARα)-mediated ceramide synthesis. Primary human term trophoblast cells were treated with ADN and/or insulin. ADN increased the phosphorylation of p38 MAPK and PPARα. ADN inhibited insulin signaling and insulin-stimulated amino acid transport. This effect was dependent on PPARα, because activation of PPARα with an agonist (GW7647) inhibited insulin signaling and function, whereas PPARα-small interfering RNA reversed the effects of ADN on the insulin response. ADN increased ceramide synthase expression and stimulated ceramide production. C2-ceramide inhibited insulin signaling and function, whereas inhibition of ceramide synthase (with Fumonisin B1) reversed the effects of ADN on insulin signaling and amino acid transport. These findings are consistent with the model that maternal ADN limits fetal growth mediated by activation of placental PPARα and ceramide synthesis, which inhibits placental insulin signaling and amino acid transport, resulting in reduced fetal nutrient availability.

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Section: Discussionmentioning

confidence: 91%

Adiponectin Inhibits Insulin Function in Primary Trophoblasts by PPARα-Mediated Ceramide Synthesis

Aye

Gao

Weintraub

et al. 2014

Molecular Endocrinology

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“…Indeed, a PKR activator (Ruvolo et al , 2001), ceramide, has been shown to inhibit IRS1 activity by up-regulating the Ser phosphorylation and blocking the Tyr phosphorylation of IRS1 (Kanety et al , 1996; Miura et al , 2003). Given the effects of PKR on the phosphorylation of IRS1, we further asked whether PKR mediates the up-regulation of the serine and down-regulation of the tyrosine phosphorylation of IRS1 by ceramide through gene silencing and inhibition studies.…”

Section: Resultsmentioning

confidence: 99%

The Double-stranded RNA–dependent Protein Kinase Differentially Regulates Insulin Receptor Substrates 1 and 2 in HepG2 Cells

Yang

Nath

Opperman

et al. 2010

MBoC

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“…This evidence can be briefly summarized as follows:

Palmitate-independent increases in ceramide in various cells are sufficient to blunt cellular insulin response in vitro. Cell-permeable ceramide analogs have been shown to antagonize insulin signaling in myotubes [7, 16] and adipocytes [17]. The mechanisms of these effects of ceramide involve an inhibition of Akt-1, key mediator of the insulin signaling cascade.

…”

Section: Introductionmentioning

confidence: 99%

“…Cell-permeable ceramide analogs have been shown to antagonize insulin signaling in myotubes [7, 16] and adipocytes [17]. The mechanisms of these effects of ceramide involve an inhibition of Akt-1, key mediator of the insulin signaling cascade.…”

Section: Introductionmentioning

confidence: 99%

The twists and turns of sphingolipid pathway in glucose regulation

Deevska

Nikolova‐Karakashian

2011

Biochimie

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Palmitic acid is a saturated fat found in foods that lead to obesity, cardiovascular disease, and Type II diabetes. It is linked to the development of resistance to insulin stimulation in muscle, liver and other organs involved in glucose metabolism, which, in turn, underlines the onset of Type II diabetes. The cellular and molecular mechanisms of this insulin resistance are complex and not completely understood. This article is focused on the role of palmitic acid as a precursor in the synthesis of sphingolipids, a class of lipid molecules that participate in cellular stress response. Recent evidence had indicated that increased dietary supply of palmitate can stimulate the rate of sphingolipid synthesis in “lean” tissues and generate excessive amounts of sphingolipid metabolites that have a negative effect on the insulin signaling cascade. Many experimental results point to the existence of a causative link between sphingolipid synthesis, insulin response, and hyperglycemia. It is not yet clear, however whether ceramides or glycosphingolipids are involved as both have been implicated to be inhibitors of the insulin signaling cascade. Evidence for a coordinated regulation of sphingolipid and tri/diacylglycerol metabolism complicates further the delineation of a single mechanism of sphingolipid effect on glucose homeostasis.

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Inhibitory effect of ceramide on insulin-induced protein kinase Cζ translocation in rat adipocytes

Cited by 14 publications

References 28 publications

Adiponectin Inhibits Insulin Function in Primary Trophoblasts by PPARα-Mediated Ceramide Synthesis

Adiponectin Inhibits Insulin Function in Primary Trophoblasts by PPARα-Mediated Ceramide Synthesis

The Double-stranded RNA–dependent Protein Kinase Differentially Regulates Insulin Receptor Substrates 1 and 2 in HepG2 Cells

The twists and turns of sphingolipid pathway in glucose regulation

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