Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes

Ruderman, Neil B.; Cacicedo, José M.; Itani, Samar I.; Yagihashi, Norito; Saha, Asish K.; Ye, J.M.; Chen, K.; Zou, Ming‐Hui; Carling, David; Boden, Guenther; Cohen, Richard A.; Keaney, John F.; Kraegen, Edward W.; Ido, Yasuo

doi:10.1042/bst0310202

Cited by 126 publications

(76 citation statements)

References 48 publications

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“…Second, pancreatic beta cell damage in the ZDF rat has been related to ceramide-induced apoptosis [39], and AICAR, by activating AMPK, has been shown to inhibit apoptosis in human umbilical vein endothelial cells [43] and astrocytes [44] incubated with palmitate or a high concentration of glucose. Furthermore, in some of these studies AICAR was shown to inhibit de novo ceramide synthesis and decrease the activity of serine palmitoyl transferase, the first committed enzyme in the de novo ceramide synthesis pathway [44,45]. Third, in endothelial cells incubated with an elevated concentration of glucose or NEFA, AICAR, and, where studied, expression of a constitutively active AMPK, inhibited oxidative stress, mitochondrial damage and the activation of NFκβ and caspase-3 [44,45].…”

Section: Discussionmentioning

confidence: 97%

“…Furthermore, in some of these studies AICAR was shown to inhibit de novo ceramide synthesis and decrease the activity of serine palmitoyl transferase, the first committed enzyme in the de novo ceramide synthesis pathway [44,45]. Third, in endothelial cells incubated with an elevated concentration of glucose or NEFA, AICAR, and, where studied, expression of a constitutively active AMPK, inhibited oxidative stress, mitochondrial damage and the activation of NFκβ and caspase-3 [44,45]. All of these effects could have contributed to the observed actions of AICAR administration on the islets.…”

Section: Discussionmentioning

confidence: 99%

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Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

et al. 2004

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Aims/hypothesis. Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator. Methods. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat. Results. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetesprone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle. Conclusions/interpretation. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

et al. 2004

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“…The high molecular weight and hexameric isoforms of ACRP30 also activate NF-B (3). On the other hand, recent studies by Ido and his coworkers (41,42) have shown that AMPK activation by AICAR or expression of a constitutively active AMPK can inhibit NF-B-mediated gene expression in both cultured human umbilical vein endothelial cells and COS7 cells. Thus, the interaction of gACRP30 and the various oligomeric forms of ACRP30 in regulating NF-B activity, and in turn its relevance to their biological actions, clearly requires further study.…”

Section: Discussionmentioning

confidence: 99%

Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation

Tomàs

Tsao

Saha

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

885

598

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gACRP30, the globular subunit of adipocyte complement-related protein of 30 kDa (ACRP30), improves insulin sensitivity and increases fatty acid oxidation. The mechanism by which gACRP30 exerts these effects is unknown. Here, we examined if gACRP30 activates AMP-activated protein kinase (AMPK), an enzyme that has been shown to increase muscle fatty acid oxidation and insulin sensitivity. Incubation of rat extensor digitorum longus (EDL), a predominantly fast twitch muscle, with gACRP30 (2.5 g͞ml) for 30 min led to 2-fold increases in AMPK activity and phosphorylation of both AMPK on Thr-172 and acetyl CoA carboxylase (ACC) on Ser-79. Accordingly, concentration of malonyl CoA was diminished by 30%. In addition, gACRP30 caused a 1.5-fold increase in 2-deoxyglucose uptake. Similar changes in malonyl CoA and ACC were observed in soleus muscle incubated with gACRP30 (2.5 g͞ml), although no significant changes in AMPK activity or 2-deoxyglucose uptake were detected. When EDL was incubated with full-length hexameric ACRP30 (10 g͞ml), AMPK activity and ACC phosphorylation were not altered. Administration of gACRP30 (75 g) to C57 BL͞6J mice in vivo led to increased AMPK activity and ACC phosphorylation and decreased malonyl CoA concentration in gastrocnemius muscle within 15-30 min. Both in vivo and in vitro, activation of AMPK was the first effect of gACRP30 and was transient, whereas alterations in malonyl CoA and ACC occurred later and were more sustained. Thus, gACRP30 most likely exerts its actions on muscle fatty acid oxidation by inactivating ACC via activation of AMPK and perhaps other signal transduction proteins.diabetes ͉ insulin sensitivity ͉ obesity ͉ malonyl CoA

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“…AMPK plays an important role in regulating the energy balance in the myocardium; the activation of AMPK during ischemia-reperfusion can reduce ischemia-induced necrosis and apoptosis (23,39). The increase in the cellular AMP-to-ATP ratio is a major regulator of AMPK activity (23,38), but adiponectin has also been reported to activate AMPK (21,38). Most of the beneficial effects of adiponectin are reportedly mediated by AMPK-associated signaling (21).…”

Section: Effect Of Cr On Myocardial Ischemia-reperfusion Injury and Ipcmentioning

confidence: 99%

Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

Shinmura

Tamaki

Bolli

2008

American Journal of Physiology-Heart and Circulatory Physiology

116

114

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Ischemic tolerance decreases with aging, and the cardioprotective effect of ischemic preconditioning (IPC) is impaired in middle-aged animals. We have demonstrated that short-term caloric restriction (CR) improves myocardial ischemic tolerance in young and old animals via the activation of adiponectin-AMP-activated protein kinase (AMPK)-mediated signaling. However, it is unknown whether prolonged CR confers cardioprotection in a similar manner. Furthermore, little is known regarding the myocardial expression of silent information regulator 1 (Sirt1; which reportedly mediates various aspects of the CR response) with prolonged CR. Thus, 6-mo-old male Fischer-344 rats were randomly divided into ad libitum (AL) and CR groups. Six months later, isolated perfused hearts were subjected to 25 min of global ischemia followed by 120 min of reperfusion with or without IPC. CR improved the recovery of left ventricular function and reduced infarct size after ischemiareperfusion and restored the IPC effect. Serum adiponectin levels increased, but myocardial levels of total and phosphorylated AMPK did not change with prolonged CR. Total levels of Sirt1 did not change with CR; however, in the nuclear fraction, CR significantly increased Sirt1 and decreased acetyl-histone H3. Eleven rats from each group were given N-nitro-L-arginine methyl ester in their drinking water for 4 wk before death. In these hearts, chronic inhibition of nitric oxide synthase prevented the increase in nuclear Sirt1 content by CR and abrogated CR-induced cardioprotection. These results demonstrate that 1) prolonged CR improves myocardial ischemic tolerance and restores the IPC effect in middle-aged rats and 2) CR-induced cardioprotection is associated with a nitric oxidedependent increase in nuclear Sirt1 content. aging; myocardial ischemia; nutrition; preconditioning; reperfusion injury; silent information regulator 1

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Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes

Cited by 126 publications

References 48 publications

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: Acetyl–CoA carboxylase inhibition and AMP-activated protein kinase activation

Impact of 6-mo caloric restriction on myocardial ischemic tolerance: possible involvement of nitric oxide-dependent increase in nuclear Sirt1

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