Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance

Qi, Dake; Ding, An; Kewalramani, Girish; Qi, Yadan; Pulinilkunnil, Thomas; Abrahani, Ashraf; Al-Atar, Usama; Ghosh, Sanjoy; Wambolt, Richard B.; Allard, Michael F.; Innis, Sheila M.; Rodrigues, Brian

doi:10.1152/ajpendo.00083.2006

Cited by 25 publications

(32 citation statements)

References 43 publications

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“…One possible explanation for this interaction evidenced here could be a positive regulation of AMPK expression or activity in response to glucocorticoid administration. Such an outcome has been reported in hepatic (53) and cardiac (41) tissue, although the authors of the former study cite unpublished data that this effect was not observed in skeletal muscle. Our results examining native AMPK␣ expression and activity (Figs.…”

Section: Discussionmentioning

confidence: 54%

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C₂C₁₂ cells

Krawiec

Nystrom

Frost

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

117

106

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hypothesis of the present study was that exposure of differentiated muscle cells to agonists of the AMP-activated protein kinase (AMPK) would increase the mRNA content of the muscle-specific ubiquitin ligases muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). C 2C12 cells were incubated with incremental doses of 5-aminoimidazol-4-carboximide ribonucleoside (AICAR) or metformin for 24 h. Both MAFbx and MuRF1 mRNA increased dose dependently in response to these AMPK activators. AICAR, metformin, and 2-deoxy-D-glucose produced time-dependent alterations in ubiquitin ligase expression, typified by a biphasic pattern of expression marked by an acute repression followed by a sustained induction. AMPK-activating treatments in conjunction with dexamethasone produced a pronounced synergistic effect on ligase mRNA expression at later time points. This cooperative response occurred in the absence of a dexamethasone-dependent increase in AMPK expression or activity, as determined by immunoblotting for phosphorylation and expression of AMPK␣ and its downstream target acetyl-CoA carboxylase (ACC). These responses elicited by AMPK activation singly or in combination with dexamethasone did not extend to the mRNA expression of the UBR box family E3s UBR1/E3␣I and UBR2/E3␣II. Treatment with the AMPK inhibitor compound C prevented increases in MAFbx and MuRF1 mRNA in response to serum deprivation, as well as AICAR and dexamethasone treatment individually or jointly. Stimulation of AMPK activity in vivo via AICAR injection increased both MAFbx and MuRF1 mRNA in murine skeletal muscle. These data suggest that activation of AMPK in skeletal muscle results in a specific upregulation of MAFbx and MuRF1, responses that are reminiscent of the proposed atrophic transcriptional program executed under various conditions of skeletal muscle wasting. Therefore, AMPK may be a critical component of the intercalated network of signaling pathways governing skeletal muscle atrophy, where its input acts to modify anti-and proatrophic signals to influence gene expression in reaction to catabolic perturbations.atrogin-1; proteolysis; 2-deoxyglucose FOR PROPER GROWTH AND SURVIVAL, all organisms require means of responding to diverse inputs originating from a discontinuous environmental milieu. Failure to both properly integrate these signals and accordingly adjust metabolism within favorable physiological limits may ultimately result in maladaptation, disease, and death. One critical component of this control system in mammalian systems is the AMP-activated protein kinase (AMPK). AMPK functions as a heterotrimer (consisting of a catalytic ␣-subunit and regulatory ␤-and ␥-subunits), which senses alterations in the AMP-to-ATP ratio within cells (15,25,35). In response to energy-depleting stressors (which consequently increase cellular AMP concentrations), AMPK acts to balance energy consumption with production by suppressing ATP-expensive processes and activating ATP-repleting ones. Regulation of its activity is achieved in an elegant fashion...

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Section: Discussionmentioning

confidence: 54%

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C₂C₁₂ cells

Krawiec

Nystrom

Frost

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

117

106

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“…These include phosphorylation of AMPK, p38 MAPK, and HSP25 that cause actin cytoskeleton rearrangement, facilitating LPL translocation to the myocyte cell surface. Transfer of the enzyme from the myocyte cell surface to the coronary lumen would be expected to increase LPL-derived FA provision to the heart, likely compromising glucose utilization (36).…”

Section: Discussionmentioning

confidence: 99%

“…The gradual decline in AMPK activation is likely a consequence of the excessive amount of cardiac LPL-derived FA. Cardiac LPL is a major determinant of plasma TG (28), and the increase in cardiac luminal LPL is associated with a decline in circulating TG and an increase in cardiac FA (palmitic and oleic acid) and TG levels (36). High FA or TG, through their formation of ceramide, has been shown to activate protein phosphatase 2A, leading to dephosphorylation of AMPK (46).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, using an acute dexamethasone (DEX) model, our laboratory has reported that glucocorticoid treatment leads to amplification in coronary LPL (both LPL activity and LPL protein) (37). The resulting clearance of plasma TG increases FA delivery to the heart, augments FA (but decreases glucose) oxidation (37,36), and ensures continuous ATP generation to maintain normal heart function. Under these conditions, an increase in oxygen demand and generation of reactive oxygen species could lead to the cardiac damage seen following chronic glucocorticoid use.…”

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confidence: 99%

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Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases

Kewalramani

Puthanveetil²,

Kim³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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(LPL), an enzyme that hydrolyzes lipoproteins to FA. We examined the mechanisms by which DEX augments cardiac LPL. DEX was injected in rats, and hearts were removed, or isolated cardiomyocytes were incubated with DEX (0 -8 h), for measurement of LPL activity and Western blotting. Acute DEX induced whole body insulin resistance, likely an outcome of a decrease in insulin signaling in skeletal muscle, but not cardiac tissue. The increase in luminal LPL activity after DEX was preceded by rapid nongenomic alterations, which included phosphorylation of AMPK and p38 MAPK, that led to phosphorylation of heat shock protein (HSP)25 and actin cytoskeleton rearrangement, facilitating LPL translocation to the myocyte cell surface. Unlike its effects in vivo, although DEX activated AMPK and p38 MAPK in cardiomyocytes, there was no phosphorylation of HSP25, nor was there any evidence of F-actin polymerization or an augmentation of LPL activity up to 8 h after DEX. Combining DEX with insulin appreciably enhanced cardiomyocyte LPL activity, which closely mirrored a robust elevation in phosphorylation of HSP25 and F-actin polymerization. Silencing of p38 MAPK, inhibition of PI 3-kinase, or preincubation with cytochalasin D prevented the increases in LPL activity. Our data suggest that, following DEX, it is a novel, rapid, nongenomic phosphorylation of stress kinases that, together with insulin, facilitates LPL translocation to the myocyte cell surface.

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“…Acute glucocorticoid treatment results in the stimulation of cardiac AMPK (Qi et al 2006, Puthanveetil et al 2008. However, with chronic glucocorticoid treatment, we have found reduced cardiac AMPK activity in both rats and mice.…”

Section: Korbonits 2009)mentioning

confidence: 58%

CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus

Scerif¹,

Füzesi²,

Thomas³

et al. 2013

Journal of Endocrinology

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AMP-activated protein kinase (AMPK), a regulator of cellular and systemic energy homeostasis, can be influenced by several hormones. Tissue-specific alteration of AMPK activity by glucocorticoids may explain the increase in appetite, the accumulation of lipids in adipose tissues, and the detrimental cardiac effects of Cushing's syndrome. Endocannabinoids are known to mediate the effects of various hormones and to influence AMPK activity. Cannabinoids have central orexigenic and direct peripheral metabolic effects via the cannabinoid receptor type 1 (CB1). In our preliminary experiments, WT mice received implants of a corticosterone-containing pellet to establish a mouse model of Cushing's syndrome. Subsequently, WT and Cb1 (Cnr1)-knockout (CB1-KO) littermates were treated with corticosterone and AMPK activity in the hypothalamus, various adipose tissues, liver and cardiac tissue was measured. Corticosterone-treated CB1-KO mice showed a lack of weight gain and of increase in hypothalamic and hepatic AMPK activity. In adipose tissues, baseline AMPK activity was higher in CB1-KO mice, but a glucocorticoid-induced drop was observed, similar to that observed in WT mice. Cardiac AMPK levels were reduced in CB1-KO mice, but while WT mice showed significantly reduced AMPK activity following glucocorticoid treatment, CB1-KO mice showed a paradoxical increase. Our findings indicate the importance of the CB1 receptor in the central orexigenic effect of glucocorticoid-induced activation of hypothalamic AMPK activity. In the periphery adipose tissues, changes may occur independently of the CB1 receptor, but the receptor appears to alter the responsiveness of the liver and myocardial tissues to glucocorticoids. In conclusion, our data suggest that an intact cannabinoid pathway is required for the full metabolic effects of chronic glucocorticoid excess.

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Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance

Abstract: . Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance.

Cited by 25 publications

References 43 publications

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C₂C₁₂ cells

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C₂C₁₂ cells

Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases

CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus

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Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance

Abstract: . Altered cardiac fatty acid composition and utilization following dexamethasone-induced insulin resistance.

Cited by 25 publications

References 43 publications

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C2C12 cells

Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases

CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus

Contact Info

Product

Resources

About

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C₂C₁₂ cells

AMP-activated protein kinase agonists increase mRNA content of the muscle-specific ubiquitin ligases MAFbx and MuRF1 in C₂C₁₂ cells