PLCγ Participates in Insulin Stimulation of Glucose Uptake through Activation of PKCζ in Brown Adipocytes

Lorenzo, Margarita; Teruel, Teresa; Hernández, Rosario; Kayali, Ayse G.; Webster, Nicholas J. G.

doi:10.1006/excr.2002.5570

Cited by 28 publications

(28 citation statements)

References 53 publications

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“…This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/PI3-kinase/PKB, as observed previously in the case of rosiglitazone [22]. However, another insulin pathway, namely that involving PKCζ, is also involved in translocation of SLC2A4 [16]; it was inhibited in the presence of TNFα, but was not restored by T0901317. Accordingly, synthetic NR1HR agonists have been reported to improve glucose tolerance in genetic and dietary models of type 2 diabetes [6,8] and to increase glucose-induced insulin secretion by islets [7], very similar effects to those elicited by thiazolidinediones [34] and synthetic activators of RXR [35].…”

Section: Discussionsupporting

confidence: 80%

“…Next, we investigated in the downstream PI3-kinase pathways the role of PKB and PKCζ, which have been proposed to mediate glucose uptake in brown adipocytes [15,16], as shown in Fig. 4.…”

Section: T0901317 Ameliorates the Insulin Resistance Induced Bymentioning

confidence: 99%

“…Brown adipose tissue is a target tissue for insulin action, especially during late fetal development, when insulin promotes adipogenic and thermogenic differentiation and regulates glucose uptake, as reviewed [14]. Acute insulin treatment stimulates glucose transport in fetal brown adipocytes largely by mediating translocation of SLC2A4 to the plasma membrane, a process involving the activation of phosphatidylinositol (PI) 3-kinase, protein kinase B (PKB) and protein kinase C (PKC)ζ [15,16]. Brown adipose tissue is also a target for nuclear receptor agonists, since it produces abundant PPARγ, NR1HRα and β [9,17].…”

Section: Introductionmentioning

confidence: 99%

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Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

et al. 2006

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Aims/hypothesis The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFα has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFα-induced insulin resistance in brown adipocytes. Methods Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B (Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFα and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting. Results NR1HR agonists ameliorate TNFα-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFα. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFα. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase ζ and/or the increase of Slc2a4 expression. Conclusions/interpretation Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance. Keywords

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Section: Discussionsupporting

confidence: 80%

“…Next, we investigated in the downstream PI3-kinase pathways the role of PKB and PKCζ, which have been proposed to mediate glucose uptake in brown adipocytes [15,16], as shown in Fig. 4.…”

Section: T0901317 Ameliorates the Insulin Resistance Induced Bymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

et al. 2006

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“…There is evidence for and against the possibility that insulin induces an increase in intracellular [Ca 2+ ] [29][30][31][32][33]. In newborn rat brown adipocytes it was shown that the insulininduced elevation of intracellular [Ca 2+ ] was PI3 kinase dependent [34]. On the other hand, it was shown that glucose transport induced by means other than insulin appeared to involve Ca 2+ activation of cPKC [35].…”

Section: Mechanisms Of Activationmentioning

confidence: 99%

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Sampson

Cooper

2006

Molecular Genetics and Metabolism

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Recent studies implicate specific PKC isoforms in the insulin-signaling cascade. Insulin activates PKCsα, βII, δ and ζ in several cell types. In addition, as will be documented in this review, certain members of the PKC family may also be activated and act upstream of PI3 and MAP kinases. Each of these isoforms has been shown one way or another either to mimic or to modify insulin-stimulated effects in one or all of the insulin-responsive tissues. Moreover, each of the isoforms has been shown to be activated by insulin stimulation or conditions important for effective insulin stimulation. Studies attempting to demonstrate a definitive role for any of the isoforms have been performed on different cells, ranging from appropriate model systems for skeletal muscle, liver and fat, such as primary cultures, and cell lines and even in vivo studies, including transgenic mice with selective deletion of specific PKC isoforms. In addition, studies have been done on certain expression systems such as CHO or HEK293 cells, which are far removed from the tissues themselves and serve mainly as vessels for potential protein-protein interactions. Thus, a clear picture for many of the isoforms remains elusive in spite of over two decades of intensive research. The recent intrusion of transgenic and precise molecular biology technologies into the research armamentarium has opened a wide range of additional possibilities for direct involvement of individual isoforms in the insulin signaling cascade. As we hope to discuss within the context of this review, whereas many of the long soughtafter answers to specific questions are not yet clear, major advances have been made in our understanding of precise roles for individual PKC isoforms in mediation of insulin effects. In this review, in which we shall focus our attention on isoforms in the conventional and novel categories, a clear case will be made to show that these isoforms are not only expressed but are importantly involved in regulation of insulin metabolic effects.

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“…Acute insulin treatment stimulates glucose transport in brown adipocytes largely by mediating translocation of GLUT4 from an intracellular compartment to the plasma membrane, involving the activation of phosphatidylinositol (PI) 3-kinase, Akt 1 and 2 isoforms and the atypical protein kinase C (PKC) isoform ζ [19,20,21]. We have previously described that TNF-α caused insulin resistance in brown adipocytes by decreasing IRS-2 Tyr phosphorylation and IRS-2-associated PI 3-kinase activity, while IRS-1 signalling was unaffected [22].…”

Section: Introductionmentioning

confidence: 99%

Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-α induction of p38 and p42/p44 mitogen-activated protein kinases

et al. 2004

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Aims/hypothesis. TNF-α caused insulin resistance on glucose uptake and on insulin signalling in fetal brown adipocytes. Since treatment with TNF-α activates stress kinases, including c-jun NH2 terminal kinase (JNK), and p42/p44 and p38 mitogen-activated protein kinases (MAPK), we explored the contribution of these pathways to insulin resistance by TNF-α. Rosiglitazone is used to treat Type 2 diabetes as it improves insulin sensitivity in vivo. However, its ability to ameliorate TNF-α-induced insulin resistance in brown adipocytes remains to be explored. Methods. We used fetal rat primary brown adipocytes cultured with TNF-α, with or without stress kinase inhibitors or rosiglitazone, and further stimulated with insulin. Then, we measured glucose uptake and GLUT4 translocation. To determine the insulin signalling cascade, we submitted cells to lysis, immunoprecipitation and immunoblotting.

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PLCγ Participates in Insulin Stimulation of Glucose Uptake through Activation of PKCζ in Brown Adipocytes

Cited by 28 publications

References 53 publications

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

Liver X receptor agonists ameliorate TNFα-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression

Specific protein kinase C isoforms as transducers and modulators of insulin signaling

Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-α induction of p38 and p42/p44 mitogen-activated protein kinases

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