To give new insight to alterations of cardiac lipid metabolism accompanied by a fructose-rich diet (FRD), rats of both sexes were exposed to 10 % fructose in drinking water during 9 weeks. The ...protein level and subcellular localization of the main regulators of cardiac lipid metabolism, such as lipin 1, peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α), carnitine palmitoyltransferase I (CPTI), and CD36 were studied. Caloric intake in fructose-fed rats (FFR) of both sexes was increased. Circulating triacylglyceroles (TAG) and non-esterified fatty acids were increased in male FFR, while females increased visceral adiposity and blood TAG. Total expression of lipin 1 in cardiac cell lysate and its cytosolic and microsomal level were increased in the hearts of male FFR. PPARα and PGC-1α content were decreased in the nuclear extract. In addition, cardiac deposition of TAG in male FFR was elevated, as well as inhibitory phosphorylation of insulin receptor substrate 1 (IRS-1). In contrast, in female FFR, lipin 1 level was increased in nuclear extract only, while overall CPTI expression and phosphorylation of IRS-1 at serine 307 were decreased. The results of our study suggest that fructose diet causes gender-dependent alterations in cardiac lipid metabolism. Potentially detrimental effects of FRD seem to be limited to male rats. Most of the observed changes might be a consequence of elevated expression and altered localization of lipin 1. Increased inhibitory phosphorylation of IRS-1 is possible link between cardiac lipid metabolism and insulin resistance in FFR.
Fructose rich diet increases hepatic triglycerides production and has deleterious cardiac effects. Estrogens are involved in regulation of lipid metabolism as well, but their effects are cardio ...beneficial. In order to study effects of fructose rich diet on the main heart fatty acid transporter CD36 and the role of estrogens, we subjected ovariectomized female rats to the standard diet or fructose rich diet, with or without estradiol (E2) replacement. The following parameters were analyzed: feeding behavior, visceral adipose tissue mass, plasma lipids, cardiac CD36 expression, localization and insulin regulation, as well as the profile of cardiac lipids. Results show that fructose rich diet significantly increased plasma triglycerides and decreased plasma free fatty acid (FFA) concentration, while E2 additionally emphasized FFA decrease. The fructose diet increased cardiac plasma membrane content of CD36 in the basal and insulin-stimulated states, and decreased its low density microsomes content. The E2 in fructose-fed rats raised the total cardiac protein content of CD36, its presence in plasma membranes and low density microsomes, and cardiac deposition of triglycerides, as well. Although E2 counteracts fructose in some aspects of lipid metabolism, and separately they have opposite cardiac effects, in combination with fructose rich diet, E2 additionally enhances CD36 presence in plasma membranes of cardiac cells and triglycerides accumulation, which paradoxically might promote deleterious effects of fructose diet on cardiac lipid metabolism. Taken together, the results presented in this work are of high importance for clinical administration of estrogens in females with a history of type 2 diabetes.
Insulin and estradiol share some of signaling pathways and regulate same target molecules exerting mostly beneficial cardiac effects. In order to study their cardiac interaction, ovariectomized ...female rats were treated with hormones, separately or simultaneously (20, 30 or 40
min before analysis), and the phosphorylations of protein kinase B (Akt), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), endothelial nitric oxide synthase (eNOS) were analyzed, as well as the plasma membrane content of α2 subunit of Na
+/K
+-ATPase. Insulin, particularly, and estradiol stimulate Ser
473 Akt phosphorylation. The combined treatment was stimulatory, but less than insulin alone was. The general increase of Thr
308 Akt phosphorylation by insulin was stronger than at Ser
473 and reduced in the presence of estradiol, which also stimulated this phosphorylation given alone. The estradiol induction of ERK 1/2 phosphorylation was inverted to the decrease by the combined treatment, while insulin had no effect. Only insulin increased the plasma membrane content of α2. Estradiol did increase the phosphorylation of eNOS, whereas the insulin effect was controversial. The effect of the combined treatment on target molecules was generally opposite to single hormone treatment. In summary, both hormones exerted an effect on Akt phosphorylation, but only estradiol stimulated ERK 1/2 phosphorylation. The α2 plasma membrane content was increased only by insulin, while estradiol increased eNOS phosphorylation more consistently. Finally, if these hormones were administered together, it seems that they disturb each other in having a full effect on cardiac Akt, ERK 1/2, and downstream effectors, eNOS and Na
+/K
+-ATPase.
Fructose-rich diets (FRD) cause cardiac insulin resistance manifested by impairment of Akt/endothelial NO synthase (eNOS) signalling. In contrast, oestradiol (E2) activates this signalling pathway in ...the heart. To study the ability of E2 to revert the detrimental effect of fructose on cardiac Akt/eNOS, female rats were subjected to a FRD and ovariectomy followed with or without E2 replacement. We also analysed the effects of the FRD and E2 on cardiac extracellular signal-regulated kinase (Erk 1/2) signalling related to their role in cardiac hypertrophy development. Expression of Akt, eNOS and Erk 1/2, as well as regulatory phosphorylations of these molecules were determined. The protein expression of cardiac Akt and eNOS was not affected by the diet or E2 treatment. However, the FRD was accompanied by a decrease in Akt phosphorylation at Ser(473) and Thr(308), and eNOS at Ser(1177), while the phosphorylation of eNOS at Thr(495) was increased. E2 replacement in ovariectomised fructose-fed rats caused a reversion of the diet effect on Akt and eNOS serine phosphorylation, but mostly had no effect on threonine phosphorylation of the molecules. The FRD and E2 treatment did not influence Erk 1/2 expression and phosphorylation and heart mass as well. The data show that E2 selectively suppress the negative effects of a FRD on Akt/eNOS signalling and probably point to the different effects of E2 on kinase/phosphatase pathways responsible for phosphorylation/dephosphorylation of Akt and eNOS. Furthermore, the results suggest that the heart of females in the reproductive period is partially protected against the damaging effects of increasedfructose intake.
Background
Fructose consumption produces deleterious metabolic effects in animal models. The sites of fructose-induced insulin resistance are documented to be the liver, skeletal muscle, and adipose ...tissue, but effects of fructose-rich diet on cardiac insulin signaling and action were not investigated.
Purpose and methods
In order to study the potential fructose effects on development of cardiac insulin resistance, we analyzed biochemical parameters relevant for insulin action and phosphorylation of insulin signaling molecules, plasma membrane glucose transporter type 4 (GLUT4) content, and phosphorylation of endothelial nitric oxide synthase (eNOS), in ovariectomized female rats on fructose-enriched diet, in basal and insulin-stimulated conditions.
Results
Fructose-fed rats (FFR) had increased content of visceral adipose tissue, but not body weight. Food intake was decreased, while fluid and caloric intake were increased in FFR. Additionally, fructose diet increased plasma insulin, blood triglycerides level, and HOMA index. Stimulation of protein kinase B (Akt) signaling pathway by insulin was reduced in rats on fructose-enriched diet, but effect of fructose on extracellular signal-regulated kinase (Erk 1/2) phosphorylation was not observed. Furthermore, insulin-induced GLUT4 presence in plasma membranes of cardiac cells was decreased by fructose diet, as well as insulin stimulation of eNOS phosphorylation at Ser
1177
.
Conclusion
In summary, these results strongly support our hypothesis that fructose diet-induced changes of plasma lipid profile and insulin sensitivity are accompanied with decrease in cardiac insulin action in ovariectomized female rats.
Provider: - Institution: - Data provided by Europeana Collections- Insulin and estradiol play important role in regulation of carbohydrate and
lipid metabolism. Various clinical observations and ...experimental data suggest
that variations in the concentration of estrogens affect insulin action. The
aim of the present study was to compare the impact of estradiol on early
steps of insulin signaling in main target tissues of insulin (the liver) and
estradiol (the uterus), and in the heart, where both hormones realize
important effects. Ovariectomized female rats were treated with estradiol 6 h
prior to analysis of protein and mRNA content of insulin signaling molecules.
To delineate estradiol effects on phosphorylations and molecular associations
relevant for insulin signaling, animals were treated additionally with
insulin 30 min before the experiment. Treatment with estradiol did not change
the levels of plasma insulin and glucose, but it significantly decreased the
free fatty acid level and increased uterine weight. In liver, estradiol
treatment decreased IR phosphorylation and IRS-1 protein content, suggesting
that estradiol suppressed insulin action through IR/IRS-1 and probably
redirected it to alternative pathway. This conclusion is supported with
increase of IRS-2 protein content. In uterus, estradiol treatment resulted in
significant increase of protein content of almost all analyzed molecules. In
heart, estradiol increased IRS-1/p85 association, p85 protein and mRNA level,
and Ser473Akt phosphorylation. On the other hand, estradiol treatment
decreased tyrosine phosphorylation of cardiac IR, protein content of IRS-2,
and mRNA of both IRS proteins. These results suggest that estradiol treatment
induces tissue-specific changes in insulin signaling. Consequences of
estradiol treatment on insulin signaling molecules are more apparent in
uterus, but their physiological relevance for insulin action is probably more
important in liver. On the other hand, results obtained in heart suggest very
complex role of estradiol in heart physiology, represented by, amongst other
effects, combination of positive and negative, genomic and nongenomic actions
of this hormone on insulin signaling molecules.- Insulin i estradiol imaju važnu ulogu u regulaciji metabolizma ugljenih
hidrata i lipida. Različita klinička istraživanja i eksperimentalni podaci
ukazuju da varijacije u koncentraciji estrogena utiču na insulinsko
delovanje. Cilj ove studije je bilo poređenje uticaja estradiola na početne
molekule insulinskog signalnog puta u glavnim ciljnim tkivima za insulin
(jetra) i estradiol (uterus), kao i u srcu, u kome oba hormona ostvaruju
značajne efekte. Ovarijektomisane ženke pacova su tretirane estradiolom 6 h
pre analize sadržaja proteina i iRNK molekula signalnog puta insulina. Da bi
se istakli efekti estradiola na fosforilacije i asocijacije molekula
relevantne za insulinski signalni put, životinje su dodatno injecirane
insulinom 30 min pre eksperimenta. Tretman estradiolom nije promenio nivo
insulina i glukoze u plazmi, ali je doveo do značajnog smanjenja nivoa
slobodnih masnih kiselina i povećanja težine uterusa. U jetri, tretman
estradiolom je doveo do smanjenja fosforilacije IR, kao i smanjenja
proteinskog sadr.aja IRS-1, što navodi na zaključak da je estradiol
suprimirao efekte insulina preko IR/IRS-1 puta i verovatno ih usmerio na
alternativni put, što je potkrepljeno i povećanjem proteinskog sadržaja
IRS-2. U uterusu je tretman estradiolom nakon 6 h doveo do statistički
značajnog povećanja proteinskog sadržaja skoro svih ispitivanih molekula
signalnog puta insulina. U srcu je estradiol uzrokovao povećanje asocijacije
IRS-1/p85, povećanja sadržaja proteina i iRNK p85, kao i povećanje
fosforilacije Akt na Ser473. S druge strane, tretman estradiolom je u srcu
izazvao i smanjenje fosforilacije tirozina IR, smanjenje proteinskog sadržaja
IRS-2 i iRNK oba IRS proteina. Rezultati ove studije ukazuju na to da tretman
estradiolom indukuje tkivno specifične promene u insulinskom signalnom putu.
Posledice tretmana estradiolom na molekule insulinskog signalnog puta su
očiglednije u uterusu, ali je njihov fiziološki značaj za insulinsko
delovanje verovatno veći u jetri. S druge strane, rezultati dobijeni u srcu
sugerišu veoma kompleksnu ulogu estradiola u fiziologiji srca, koja se
manifestuje i kombinacijom pozitivnog i negativnog, genomskog i negenomskog
delovanja ovog hormona na molekule signalnog puta insulina.- All metadata published by Europeana are available free of restriction under the Creative Commons CC0 1.0 Universal Public Domain Dedication. However, Europeana requests that you actively acknowledge and give attribution to all metadata sources including Europeana
Insulin i estradiol imaju va.nu ulogu u regulaciji metabolizma ugljenih hidrata i lipida. Razli.ita klini.ka istra.ivanja i eksperimentalni podaci ukazuju da varijacije u koncentraciji estrogena ...uti.u na insulinsko delovanje. Cilj ove studije je bilo pore.enje uticaja estradiola na po.etne molekule insulinskog signalnog puta u glavnim ciljnim tkivima za insulin (jetra) i estradiol (uterus), kao i u srcu, u kome oba hormona ostvaruju zna.ajne efekte. Ovarijektomisane .enke pacova su tretirane estradiolom 6 h pre analize sadr.aja proteina i iRNK molekula signalnog puta insulina. Da bi se istakli efekti estradiola na fosforilacije i asocijacije molekula relevantne za insulinski signalni put, .ivotinje su dodatno injecirane insulinom 30 min pre eksperimenta. Tretman estradiolom nije promenio nivo insulina i glukoze u plazmi, ali je doveo do zna.ajnog smanjenja nivoa slobodnih masnih kiselina i pove.anja te.ine uterusa. U jetri, tretman estradiolom je doveo do smanjenja fosforilacije IR, kao i smanjenja proteinskog sadr.aja IRS-1, .to navodi na zaklju.ak da je estradiol suprimirao efekte insulina preko IR/IRS-1 puta i verovatno ih usmerio na alternativni put, .to je potkrepljeno i pove.anjem proteinskog sadr.aja IRS-2. U uterusu je tretman estradiolom nakon 6 h doveo do statisti.ki zna.ajnog pove.anja proteinskog sadr.aja skoro svih ispitivanih molekula signalnog puta insulina. U srcu je estradiol uzrokovao pove.anje asocijacije IRS-1/p85, pove.anja sadr.aja proteina i iRNK p85, kao i pove.anje fosforilacije Akt na Ser473. S druge strane, tretman estradiolom je u srcu izazvao i smanjenje fosforilacije tirozina IR, smanjenje proteinskog sadr.aja IRS-2 i iRNK oba IRS proteina. Rezultati ove studije ukazuju na to da tretman estradiolom indukuje tkivno specifi.ne promene u insulinskom signalnom putu. Posledice tretmana estradiolom na molekule insulinskog signalnog puta su o.iglednije u uterusu, ali je njihov fiziolo.ki zna.aj za insulinsko delovanje verovatno ve.i u jetri. S druge strane, rezultati dobijeni u srcu sugeri.u veoma kompleksnu ulogu estradiola u fiziologiji srca, koja se manifestuje i kombinacijom pozitivnog i negativnog, genomskog i negenomskog delovanja ovog hormona na molekule signalnog puta insulina.
Vascular smooth muscle cells (VSMCs) respond to arterial wall injury by intimal proliferation and play a key role in atherogenesis by proliferating and migrating excessively in response to repeated ...injury, such as hypertension and atherosclerosis. In contrast, fully differentiated, quiescent VSMCs allow arterial vasodilatation and vasoconstriction. Exaggerated and uncontrolled VSMCs proliferation appears therefore to be a common feature of both atherosclerosis and hypertension. Phosphorylation/dephosphorylation reactions of enzymes belonging to the family of mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) play an important role in the transduction of mitogenic signal. We have previously shown that among extracellular signal-regulated protein kinases (ERKs), the 42 and 44 kDa isoforms (ERK1/2) as well as Akt and cytosolic phospholipase 2 (cPLA2) participate in the cellular mitogenic machinery triggered by several VSMCs activators, including insulin (INS). The ability of INS to significantly increase VSMCs proliferation has been demonstrated in several systems, but understanding of the intracellular signal transduction pathways involved is incomplete. Signal transduction pathways involved in regulation of the VSMCs proliferation by INS remains poorly understood. Thus, this review examines recent findings in signaling mechanisms employed by INS in modulating the regulation of proliferation of VSMCs with particular emphasis on PI3K/Akt, cPLA2 and ERK1/2 signaling pathways that have been identified as important mediators of VSMCs hypertrophy and vascular diseases. These findings are critical for understanding the role of INS in vascular biology and hyperinsulinemia.
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