Phorbol esters imitate in rat fat-cells the full effect of insulin on glucose-carrier translocation, but not on 3-<i>O</i>-methylglucose-transport activity

Mühlbacher, C; Karnieli, Eddy; Schaff, P.; Obermaier, B.; Mushack, Joanne; Rattenhuber, E.; Häring, Hans‐Ulrich

doi:10.1042/bj2490865

Cited by 74 publications

(56 citation statements)

References 27 publications

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“…Because changes in the rate of synthesis of phospholipids could result from an increased or decreased availability of glucose, experiments were carried out to determine the role of glucose availability in phorbol ester-mediated changes in the synthesis of PtdIns. Phorbol esters have been shown to enhance glucose uptake in adipose and muscle tissue (12). In C3A cells, TPA treatment enhances the disappearance of glucose from the extracellular medium in a manner similar to that seen with insulin ( Fig.…”

Section: Effect Of Substrate Availability On the Synthesis Of Ptdinsmentioning

confidence: 76%

Regulation of de novo phosphatidylinositol synthesis

Nuwayhid

Vega

Walden

et al. 2006

Journal of Lipid Research

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Mechanisms that function to regulate the rate of de novo phosphatidylinositol (PtdIns) synthesis in mammalian cells have not been elucidated. In this study, we characterize the effect of phorbol ester treatment on de novo PtdIns synthesis in C3A human hepatoma cells. Incubation of cells with 12-O-tetradecanoyl phorbol 13-acetate (TPA) initially (1-6 h) results in a decrease in precursor incorporation into PtdIns; however, at later times (18-24 h), a marked increase is observed. TPA-induced glucose uptake from the medium is not required for observation of the stimulation of PtdIns synthesis, because the effect is apparent in glucose-free medium. Inhibition of the activation of arachidonic acid substantially blocks the synthesis of PtdIns but has no effect on the synthesis of phosphatidylcholine (PtdCho). Increasing the concentration of cellular phosphatidic acid by blocking its conversion to diacylglycerol, on the other hand, enhances the synthesis of PtdIns and inhibits the synthesis of PtdCho. The TPA-induced stimulation of PtdIns synthesis is not the result of the concomitant TPA-induced G1 arrest, because G1 arrest induced by mevastatin has no effect on PtdIns synthesis. Inhibition of protein kinase C activity blocks the stimulatory action of TPA on de novo synthesis of PtdIns but has no effect on TPA-induced inhibition.Potential sites of enzymatic regulation are discussed.-Nuwayhid, S. J., M. Vega, P. D. Walden, and M. E. Monaco. Phosphatidylinositol (PtdIns) is an essential acidic phospholipid found in the membranes of mammalian cells (1) as well as on the chromatin (2). A single molecular species composed of stearate (R9) and arachidonate (R99) accounts for z80% of the total PtdIns. There are two pathways for the synthesis of PtdIns: the de novo pathway and the salvage pathway, which converge at the level of phosphatidic acid (PtdOH). The de novo pathway uses dihydroxyacetone phosphate derived from glucose to make glycerol phosphate, which is subsequently acylated at the sn-1 position with stearate and then at the sn-2 position with arachidonate to yield PtdOH. In the salvage pathway, diacylglycerol (DAG), derived from phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP 2 ), is converted to PtdOH through the action of DAG kinase. In the first instance, there is a net increase in PtdIns, whereas in the second, there is not. The central element of both pathways is the production of PtdOH. For the salvage pathway, it appears that the conversion of DAG to PtdOH by DAG kinase is stimulated as a result of agonist-induced polyphosphoinositide turnover. Whether this results from an increase in DAG substrate and/or an increase in DAG kinase enzyme activity is unclear. This laboratory has previously demonstrated that the two pathways can be differentiated in situ on the basis of the inhibition by triacsin C, a specific inhibitor of arachidonate-specific long-chain fatty acyl-CoA synthetase (ACSL4) in situ (3, 4).Although regulation of the salvage pathway via the activation ...

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Section: Effect Of Substrate Availability On the Synthesis Of Ptdinsmentioning

confidence: 76%

Regulation of de novo phosphatidylinositol synthesis

Nuwayhid

Vega

Walden

et al. 2006

Journal of Lipid Research

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“…Evidence has accumulated to show that direct PKC activation by phorbol esters or DAG leads to the stimulation of glucose transport in adipocytes [30,50,51] and skeletal muscle [35±37], and GLUT4 translocation to the cell surface in adipocytes [30,51,52]. Insulin [38,53] and muscle contraction [54,55] have been reported to activate the PKC pathway.…”

Section: Discussionmentioning

confidence: 99%

Changes in glucose transport and protein kinase Cβ 2 in rat skeletal muscle induced by hyperglycaemia

et al. 1999

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Skeletal muscle is quantitatively the most important tissue involved in maintaining glucose homeostasis, accounting for about 80 % of glucose disposal after a glucose infusion or ingestion [1]. Glucose transport is the rate-limiting step for glucose metabolism in insulin sensitive tissues [2,3]. In skeletal muscle, glucose transport is mediated by a process involving the translocation of glucose transporters (GLUT), namely GLUT4, from an intracellular site to the plasma membrane [4,5]. Glucose transporter 4 translocation Diabetologia (1999) Abstract Aims/hypothesis. We have previously reported that hyperglycaemia activates glucose transport in skeletal muscle by a Ca 2+ -dependent pathway, which is distinct from the insulin-signalling pathway. The aim of this study was to explain the signalling mechanism by which hyperglycaemia autoregulates glucose transport in skeletal muscle. Methods. Isolated rat soleus muscle was incubated in the presence of various concentrations of glucose or 3-O-methylglucose and protein kinase C and phospholipase C inhibitors. Glucose transport activity, cell surface glucose transporter 1 and glucose transporter 4 content and protein kinase C translocation was determined. Results. High concentrations of 3-O-methylglucose led to a concentration-dependent increase in [ 3 H]-3-O-methylglucose transport in soleus muscle. Dantrolene, an inhibitor of Ca 2+ released from the sarcoplasmic reticulum, decreased the V max and the K m of the concentration-response curve. Protein kinase C inhibitors (H-7 and GF109203X) inhibited the stimulatory effect of high glucose concentrations on hexose transport, whereas glucose transport stimulated by insulin was unchanged. Incubation of muscle with glucose (25 mmol/l) and 3-O-methylglucose (25 mmol/l) led to a three fold gain in protein kinase Cb 2 in the total membrane fraction, whereas membrane content of protein kinase Ca, b 1 , d, e and q were unchanged. A short-term increase in the extracellular glucose concentration did not change cell surface recruitment of glucose transporter 1 or glucose transporter 4, as assessed by exofacial photolabelling with [ 3 H]-ATB-BMPA bis-mannose. Conclusion/interpretation. Protein kinase Cb 2 is involved in a glucose-sensitive, Ca 2+ -dependent signalling pathway, which is possibly involved in the regulation of glucose transport in skeletal muscle. This glucose-dependent increase in 3-0-methylglucose transport is independent of glucose transporter 4 and glucose transporter 1 translocation to the plasma membrane and may involve modifications of cell surface glucose transporter activity. [Diabetologia (1999

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“…Such a decrease is, however, unlikely to explain the modulation of ob expression because, in contrast with a previous report in 3T3-L1 cells [9], saturated or unsaturated fatty acids had no influence on basal, dexamethasone-stimulated or insulininhibited ob gene expression in primary cultures. Thirdly, protein kinase C might be involved in the action of insulin [28], whose effects can partly be mimicked by phorbol esters [30]. This pathway does not seem to have a role in the regulation of the ob gene because PMA was without effect.…”

Section: Discussionmentioning

confidence: 99%

Insulin and insulin-like growth factor 1 antagonize the stimulation of ob gene expression by dexamethasone in cultured rat adipose tissue

Reul¹,

Ongemba²,

Pottier³

et al. 1997

Biochemical Journal

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The ob gene, specifically expressed in fat cells, encodes leptin, a hormone that induces satiety and increases energy expenditure. In this study, we investigated the interactions between glucocorticoids and insulin on ob gene expression in cultured explants of rat adipose tissue. Only low levels of ob mRNA were detected when adipose tissue from fasted rats was cultured for 12–24 h in minimal essential medium. However, the addition of dexamethasone to the medium increased ob gene expression in a concentration-dependent manner (EC50 10 nM). With 1 μM dexamethasone, ob mRNA levels were similar to those in fresh fat pads from fed rats, reaching a maximum after 12 h. The effect of dexamethasone was blocked by actinomycin D, which indicates an action on transcription. This effect was increased when a minimum amount of fuel (glucose or a mixture of lactate and pyruvate) was supplied in the medium. Unlike dexamethasone, insulin, even when combined with high glucose concentrations, did not induce ob expression, although it strongly increased the accumulation of mRNA species for fatty acid synthase (FAS), the insulin-sensitive glucose transporter GLUT4 and the γ isoform of peroxisome proliferator-activated receptor (PPARγ). Unexpectedly, insulin dose-dependently inhibited dexamethasone-induced ob mRNA accumulation. This effect was observed at low concentrations of insulin (IC50 1 nM) and was delayed in onset, beginning after 6–9 h of culture. It was mimicked by insulin-like growth factor 1 (IGF-1) (100 nM). The inhibition by insulin was only detectable when fuels were present and/or when a critical level of ob expression was reached. As this inhibitory effect was reversed by cycloheximide, this suggests that it required ongoing protein synthesis. In conclusion, unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression. On the other hand, insulin (and IGF-1) even inhibited the dexamethasone-induced accumulation of ob mRNA. The underlying mechanism involved ongoing synthesis of an inhibitory protein by insulin, which is in keeping with its delayed effect. Moreover, the expression of genes for FAS, GLUT4 and PPARγ may be inversely related to that of ob.

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Phorbol esters imitate in rat fat-cells the full effect of insulin on glucose-carrier translocation, but not on 3-O-methylglucose-transport activity

Cited by 74 publications

References 27 publications

Regulation of de novo phosphatidylinositol synthesis

Regulation of de novo phosphatidylinositol synthesis

Changes in glucose transport and protein kinase Cβ 2 in rat skeletal muscle induced by hyperglycaemia

Insulin and insulin-like growth factor 1 antagonize the stimulation of ob gene expression by dexamethasone in cultured rat adipose tissue

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