Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ

Lam, Tony K.T.; Yoshii, Hidenori; Haber, C. Andrew; Bogdanovic, Elena; Lam, Loretta; Fantus, I. George; Giacca, Adria

doi:10.1152/ajpendo.00038.2002

Cited by 181 publications

(150 citation statements)

References 59 publications

(71 reference statements)

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“…Notably, protein kinase C␦ is markedly induced. This was also seen in the progressive insulin resistance induced by free fatty acid in liver, which was associated with a increase in hepatic protein kinase C␦ (19). Similar observations have been reported in the vascular endothelium (1).…”

Section: Adipocytes Differentiated In High Glucose Fail To Down-regulsupporting

confidence: 78%

The Hyperglycemia-induced Inflammatory Response in Adipocytes

Lin

Berg

Iyengar

et al. 2005

Journal of Biological Chemistry

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434

298

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Hyperglycemia is a major independent risk factor for diabetic macrovascular disease. The consequences of exposure of endothelial cells to hyperglycemia are well established. However, little is known about how adipocytes respond to both acute as well as chronic exposure to physiological levels of hyperglycemia. Here, we analyze adipocytes exposed to hyperglycemia both in vitro as well as in vivo. Comparing cells differentiated at 4 mM to cells differentiated at 25 mM glucose (the standard differentiation protocol) reveals severe insulin resistance in cells exposed to 25 mM glucose. A global assessment of transcriptional changes shows an up-regulation of a number of mitochondrial proteins. Exposure to hyperglycemia is associated with a significant induction of reactive oxygen species (ROS), both in vitro as well as in vivo in adipocytes isolated from streptozotocin-treated hyperglycemic mice. Furthermore, hyperglycemia for a few hours in a clamped setting will trigger the induction of a pro-inflammatory response in adipose tissue from rats that can effectively be reduced by co-infusion of N-acetylcysteine (NAC). ROS levels in 3T3-L1 adipocytes can be reduced significantly with pharmacological agents that lower the mitochondrial membrane potential, or by overexpression of uncoupling protein 1 or superoxide dismutase. In parallel with ROS, interleukin-6 secretion from adipocytes is significantly reduced. On the other hand, treatments that lead to a hyperpolarization of the mitochondrial membrane, such as overexpression of the mitochondrial dicarboxylate carrier result in increased ROS formation and decreased insulin sensitivity, even under normoglycemic conditions. Combined, these results highlight the importance ROS production in adipocytes and the associated insulin resistance and inflammatory response.Many genetic and environmental factors can lead to the development of insulin resistance. Once a degree of insulin resistance is established, decreased glucose tolerance arises and occasional bouts of hyperglycemia ensue. Hyperglycemia can in turn cause a further deterioration of insulin sensitivity in a number of tissues, such as the vascular endothelium, muscle, and adipocytes (1).In the vascular endothelium, hyperglycemia has been shown to activate protein kinase C isoforms, give rise to increased levels of glucose-derived advanced glycation end products, and to cause an increased glucose flux through the aldose reductase pathway. Normalization of mitochondrial reactive oxygen species by a number of different approaches prevents these phenomena (2). In adipocytes, Tang and colleagues (3) have shown that a combination of hyperglycemia and hyperinsulinemia results in reduced insulin-stimulated glucose uptake that was in part because of reduced insulin receptor dephosphorylation.Gagnon and Sorisky (4) have previously assessed the effects of low and high glucose levels on 3T3-L1 adipocytes and reported effects on insulin-mediated IRS-1 1 phosphorylation and associated phosphatidylinositol kinase activity. Lu and coll...

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Section: Adipocytes Differentiated In High Glucose Fail To Down-regulsupporting

confidence: 78%

The Hyperglycemia-induced Inflammatory Response in Adipocytes

Lin

Berg

Iyengar

et al. 2005

Journal of Biological Chemistry

Self Cite

434

298

View full text Add to dashboard Cite

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“…Thus, insulin alone might not be sufficient to induce the adverse effects of PKC-␦ on insulin action. These effects of PKC-␦ had been reported after pharmacological activation using phorbol ester (32), stimulation with leptin (47), or lipid infusion (35). Following this aspect, it must be noted that we observed an insulin-dependent phosphorylation of Ser 357 , but this effect was weak compared with the phosphorylation intensity after stimulation with phorbol ester.…”

supporting

confidence: 83%

“…Data of the novel PKC isoform ␦ mirrored this positive and negative modulation of insulin signaling; PKC-␦ is shown to be important for insulin-stimulated glucose uptake (36), and it participates in the insulin-dependent activation of Akt (38). On the other hand, we and others have shown that activation of PKC-␦ by lipids and leptin is involved in the impairment of insulin signaling (35,47) and in the induction of apoptosis of insulin-secreting cells (48). Serine phosphorylation of IRS-1 appears to be a major mechanism for the adverse effects of PKC-␦ on insulin action (32,41,47).…”

Section: Discussionmentioning

confidence: 66%

Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

Waraich

Weigert

Kalbacher

et al. 2008

Journal of Biological Chemistry

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The activation of the protein kinase C (PKC) family of serine/ threonine kinases contributes to the modulation of insulin signaling, and the PKC-dependent phosphorylation of insulin receptor substrate (IRS)-1 has been implicated in the development of insulin resistance. Here we demonstrate Ser 357 of rat IRS-1 as a novel PKC-␦-dependent phosphorylation site in skeletal muscle cells upon stimulation with insulin and phorbol ester using Ser(P) 357 antibodies and active and kinase dead mutants of PKC-␦. Phosphorylation of this site was simulated using IRS-1 Glu 357 and shown to reduce insulin-induced tyrosine phosphorylation of IRS-1, to decrease activation of Akt, and to subsequently diminish phosphorylation of glycogen synthase kinase-3. When the phosphorylation was prevented by mutation of Ser 357 to alanine, these effects of insulin were enhanced. When the adjacent Ser To accomplish its fundamental role in maintaining in vivo metabolic homeostasis, insulin binds and activates insulin receptors, which in turn recruit insulin-receptor substrate (IRS) 2 proteins (1). By disruption of their respective genes in mice, IRS-1 and IRS-2 have been assigned a central role in mediating the normal actions of insulin. Defects at the level of the IRS proteins also comprise a major locus for the development of metabolic disorders, including insulin resistance and type 2 diabetes (2, 3). IRS proteins are regulated at several steps, including gene expression, protein degradation, and phosphorylation (4, 5). Although the phosphorylation of IRS-1 on tyrosine residues is mandatory for insulin-stimulated responses, serine/threonine phosphorylation appears to be the mechanism for the precise regulation and could either enhance or attenuate the insulin effects (6, 7). However, in most studies serine phosphorylation of IRS-1 has been implicated as a negative regulator of insulin signaling (8 -12). It can induce the dissociation of IRS-1 from its receptor and hinder the phosphorylation of tyrosine residues (8), release the IRS-1 from intracellular complexes that maintain them in close proximity to the receptor (13), or induce its protein degradation (14). These multiple effects suggest that the serine residues subjected to phosphorylation play a pivotal role in regulating IRS-1 function. Of note, the unbalanced chronic stimulation of IRS-1 serine kinases leads to hyperphosphorylation of IRS-1 and is a major pathophysiological mechanism in the development of insulin resistance. Among these IRS-1 kinases, members of the protein kinase C (PKC) family of serine/threonine kinases have received considerable attention for their regulatory role in insulin signaling. Although particularly the activation of atypical PKCs has been reported as positive modulation of insulin signaling (15, 16), the majority of studies has demonstrated that PKCs are implicated in impaired insulin signaling including classical (17-19), novel (20), and more recently also atypical PKC isoforms (21). Activation of PKC isoforms by insulin (11, 21, 22), hyperglycemia (1...

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“…Diacylglycerol is known to act as a second messenger for many signal transduction pathways, including the novel protein kinase C (PKC) family. PKC δ [27] and PKC θ [28] have been implicated in diacylglycerol-induced insulin resistance. Accordingly, we measured levels of these proteins in the liver and skeletal muscle of Il6 −/− and control mice.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

et al. 2010

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Aims/hypothesis The role of IL-6 in the development of obesity and hepatic insulin resistance is unclear and still the subject of controversy. We aimed to determine whether global deletion of Il6 in mice (Il6 −/− ) results in standard chow-induced and high-fat diet (HFD)-induced obesity, hepatosteatosis, inflammation and insulin resistance. Methods Male, 8-week-old Il6 −/− and littermate control mice were fed a standard chow or HFD for 12 weeks and phenotyped accordingly. Results Il6 −/− mice displayed obesity, hepatosteatosis, liver inflammation and insulin resistance when compared with control mice on a standard chow diet. When fed a HFD, the Il6 −/− and control mice had marked, equivalent gains in body weight, fat mass and ectopic lipid deposition in the liver relative to chow-fed animals. Despite this normalisation, the greater liver inflammation, damage and insulin resistance observed in chow-fed Il6 −/− mice relative to control persisted when both were fed the HFD. Microarray analysis from livers of mice fed a HFD revealed that genes associated with oxidative phosphorylation, the electron transport chain and tricarboxylic acid cycle were uniformly decreased in Il6 −/− relative to control mice. This coincided with reduced maximal activity of the mitochondrial enzyme β-hydroxyacyl-CoA-dehydrogenase and decreased levels of mitochondrial respiratory chain proteins. Conclusions/interpretation Our data suggest that IL-6 deficiency exacerbates HFD-induced hepatic insulin resistance and inflammation, a process that appears to be related to defects in mitochondrial metabolism.

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Free fatty acid-induced hepatic insulin resistance: a potential role for protein kinase C-δ

Cited by 181 publications

References 59 publications

The Hyperglycemia-induced Inflammatory Response in Adipocytes

The Hyperglycemia-induced Inflammatory Response in Adipocytes

Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-δ on Insulin Action in Skeletal Muscle Cells

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

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