Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding

Wright, Jordan; Kim, Jaetaek; Buchanan, Jonathan; Boudina, Sihem; Sena, Sandra; Bakirtzi, Kyriaki; Ilkun, Olesya; Theobald, Heather; Cooksey, Robert C.; Kandror, Konstantin V.; Abel, E. Dale

doi:10.1093/cvr/cvp017

Cited by 150 publications

(162 citation statements)

References 47 publications

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“…In other words, PKB/Akt/AS160 does not seem to be the rate-limiting step in the control of glucose uptake by insulin in the heart. A divergence between PKB/ Akt/AS160 signaling and glucose uptake was similarly shown in a model of diet-induced obesity where the insulin-induced glucose uptake was reduced whereas PKB/Akt/AS160 signaling was preserved (40).…”

Section: H475 Study Of the Insulin-sensitizing Effect Of Ampkmentioning

confidence: 68%

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

Ginion

Auquier

Benton

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The AMP-activated protein kinase (AMPK) is known to increase cardiac insulin sensitivity on glucose uptake. AMPK also inhibits the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway. Once activated by insulin, mTOR/p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling. AMPK was postulated to act on insulin by inhibiting this mTOR/p70S6K-mediated negative feedback loop. We tested this hypothesis in cardiomyocytes. The stimulation of glucose uptake by AMPK activators and insulin correlated with AMPK and protein kinase B (PKB/Akt) activation, respectively. Both treatments induced the phosphorylation of Akt substrate 160 (AS160) known to control glucose uptake. Together, insulin and AMPK activators acted synergistically to induce PKB/Akt overactivation, AS160 overphosphorylation, and glucose uptake overstimulation. This correlated with p70S6K inhibition and with a decrease in serine phosphorylation of IRS-1, indicating the inhibition of the negative feedback loop. We used the mTOR inhibitor rapamycin to confirm these results. Mimicking AMPK activators in the presence of insulin, rapamycin inhibited p70S6K and reduced IRS-1 phosphorylation on serine, resulting in the overphosphorylation of PKB/Akt and AS160. However, rapamycin did not enhance the insulin-induced stimulation of glucose uptake. In conclusion, although the insulin-sensitizing effect of AMPK on PKB/Akt is explained by the inhibition of the insulin-induced negative feedback loop, its effect on glucose uptake is independent of this mechanism. This disconnection revealed that the PKB/Akt/AS160 pathway does not seem to be the rate-limiting step in the control of glucose uptake under insulin treatment.adenosine 5=-monophosphate-activated protein kinase; protein kinase B/Akt; p70 ribosomal S6 kinase; insulin resistance; metformin A COMMON FEATURE OF TYPE 2 diabetes is insulin resistance of peripheral tissues like cardiac muscle. Insulin resistance is a major risk factor for the development of hypertension, cardiac hypertrophy, and heart failure. In addition, this resistance impairs metabolic effects of insulin such as glucose uptake, which is associated, after an ischemic episode, with a poor recovery of cardiac function during reperfusion (see Refs. 7, 8 for reviews). Knowing that ischemic heart disease is responsible for ϳ50% of the deaths in the diabetic population, the treatment of insulin resistance and the increase of glucose uptake in the diabetic heart remains an important issue. The decrease of the insulin-stimulated glucose uptake in insulinresistant heart is linked, in part, to the impairment of the translocation of the glucose transporter GLUT4 to the plasma membrane (see Ref. 10 for a review). The defect in GLUT4 translocation is, moreover, associated with an alteration of the insulin-induced activation of the protein kinase B (PKB)/Akt signaling pathway (17,26).In nondiabetic cardiomyocytes, insulin binding to its receptor induces th...

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Section: H475 Study Of the Insulin-sensitizing Effect Of Ampkmentioning

confidence: 68%

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

Ginion

Auquier

Benton

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…2002; Wright et al. 2009). The upregulation of PPAR α and PGC1 α seen in our study confirms observations by Duncan et al.…”

Section: Discussionmentioning

confidence: 99%

“…2005; Wright et al. 2009). Hence, the molecular changes observed in hearts from rats fed fructose‐enriched water for 6 weeks suggest that the initial stage of “feedforward” activation of β ‐oxidation has been replaced by a chronic PPAR α ‐driven increase in flux through this pathway.…”

Section: Discussionmentioning

confidence: 99%

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

et al. 2017

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Despite the fact that skeletal muscle insulin resistance is the hallmark of type‐2 diabetes mellitus (T2DM), inflexibility in substrate energy metabolism has been observed in other tissues such as liver, adipose tissue, and heart. In the heart, structural and functional changes ultimately lead to diabetic cardiomyopathy. However, little is known about the early biochemical changes that cause cardiac metabolic dysregulation and dysfunction. We used a dietary model of fructose‐induced T2DM (10% fructose in drinking water for 6 weeks) to study cardiac fatty acid metabolism in early T2DM and related signaling events in order to better understand mechanisms of disease. In early type‐2 diabetic hearts, flux through the fatty acid oxidation pathway was increased as a result of increased cellular uptake (CD36), mitochondrial uptake (CPT1B), as well as increased β‐hydroxyacyl‐CoA dehydrogenase and medium‐chain acyl‐CoA dehydrogenase activities, despite reduced mitochondrial mass. Long‐chain acyl‐CoA dehydrogenase activity was slightly decreased, resulting in the accumulation of long‐chain acylcarnitine species. Cardiac function and overall mitochondrial respiration were unaffected. However, evidence of oxidative stress and subtle changes in cardiolipin content and composition were found in early type‐2 diabetic mitochondria. Finally, we observed decreased activity of SIRT1, a pivotal regulator of fatty acid metabolism, despite increased protein levels. This indicates that the heart is no longer capable of further increasing its capacity for fatty acid oxidation. Along with increased oxidative stress, this may represent one of the earliest signs of dysfunction that will ultimately lead to inflammation and remodeling in the diabetic heart.

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“…This process is blunted in insulin-resistant humans and animals in association with other abnormalities in fuel metabolism ( [132][133][134]. With respect to mitochondrial metabolism, genetic and diet-induced obesity and type 2 diabetes in rodents is associated impaired mitochondrial function [135][136][137].…”

Section: Heartmentioning

confidence: 99%

Mitochondrial Metabolism and Insulin Action

Turner¹

2013

Type 2 Diabetes

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Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding

Cited by 150 publications

References 47 publications

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

Mitochondrial Metabolism and Insulin Action

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