Plenary Lecture Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

College of Life Sciences, University of Dundee, Dundee, UK.
Proceedings of The Nutrition Society (Impact Factor: 5.27). 11/2010; 70(1):92-9. DOI: 10.1017/S0029665110003915
Source: PubMed


The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP:ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.

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Available from: David G Hardie, Feb 24, 2014
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    • "VWR decreased liver Scd1 expression in HOM wheel-runners compared to sedentary HOM controls (Figure 7H). The central melanocortin system regulates leptininduced skeletal muscle AMPK activation and GLUT4 translocation [54] [55], resulting in decreased skeletal muscle glucose uptake during MC4R deficiency [56]. Because impaired substrate utilization can decrease exercise capacity, we measured protein levels of GLUT4 and HXK2, important regulators of increased muscle glucose utilization during exercise [57], in triceps muscle after 5 wk of VWR. "
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    • "In addition to serving as a sensor of energy balance, AMPK is a regulator of the functional phenotypes of microglia/macrophages (Sag et al., 2008; Lu et al., 2010). In response to microenvironment signals, microglia/macrophages are highly plastic and assume different functional phenotypes that critically influence the damage and tissue repair that occurs following injury (O'Neill and Hardie, 2013; Mantovani et al., 2013; David and Kroner, 2011). For example , the brain-resident microglia and peripheral macrophages that infiltrate the ischemic brain following cerebral ischemia transiently assume M2 phenotype and subsequently assume long-term M1 phenotype (Hu et al., 2012). "
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    ABSTRACT: Acute AMPK activation exacerbates ischemic brain damage experimentally. Paradoxically, the clinical use of an AMPK activator metformin reduces the incidence of stroke. We investigated whether post-stroke chronic metformin treatment promotes functional recovery and tissue repair via an M2-polarization mechanism following experimental stroke. Mice were randomly divided to receive metformin or vehicle daily beginning at 24 h after middle cerebral artery occlusion (MCAO). Neurological deficits were monitored for 30 days following MCAO. To characterize the polarization of the microglia and infiltrating macrophages, the expression of the M1 and M2 signature genes was analyzed with qPCR, ELISA and immunohistochemistry. Post-MCAO angiogenesis and neurogenesis were examined immunohistochemically. An in vitro angiogenesis model was employed to examine whether metformin promoted angiogenesis in a M2 polarization-dependent manner. Post-stroke chronic metformin treatment had no impact on acute infarction but enhanced cerebral AMPK activation, promoted functional recovery and skewed the microglia/macrophages toward an M2 phenotype following MCAO. Metformin also significantly increased angiogenesis and neurogenesis in the ischemic brain. Consistently, metformin-induced M2 polarization of BV2 microglial cells depended on AMPK activation in vitro. Furthermore, treatment of brain endothelial cells with conditioned media collected from metformin-polarized BV2 cells promoted angiogenesis in vitro. In conclusion, post-stroke chronic metformin treatment improved functional recovery following MCAO via AMPK-dependent M2 polarization. Modulation of microglia/macrophage polarization represents a novel therapeutic strategy for stroke.
    Brain Behavior and Immunity 08/2014; 40. DOI:10.1016/j.bbi.2014.03.003 · 5.89 Impact Factor
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    • "In the early stages of type 2 diabetes, significant decreasing of glycogen synthesis in muscle is the distinguishing characteristic for the insulin resistance [1]. Glycogen biosynthesis and consumption involves several signaling pathways, such as Adenosine 5’-monophosphate-activated protein kinase (AMPK) [2], Phosphoinositide 3-kinases (PI3K) [3], Wnt/β-catenin [4], Mitogen-activated protein kinase (MAPK) [5]. Further, AMPK and PI3K directly regulate glycogen synthase (GYS) to control glycogen metabolism and glucose storage. "
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    ABSTRACT: Background Tangzhiqing fomula (TZQ-F), the mixture of Red Paeony root, Mulberry leaf, Lotus leaf, Danshen root and Hawthorn leaf, regulates the abnormal glucose and lipids in prediabetic patients. In this study, we focus on the mechanism of TZQ-F and its fractions on glucose metabolism. Methods After orally administration of TZQ-F for 4 weeks in KK-Ay mice, we dissected out the liver and muscle, and employed PCR and western blotting to screening the PI3K/AKT pathway. The following PI3K/AKT signaling pathway were performed in L-6 myotube and HepG2 cells. Results In the liver of KK-Ay mice, no significance was observed on PI3K, AKT and their phosphorylation between TZQ-F and controls , while, in the muscle, up-regulation of PI3K, AKT, Glycogen synthase (GYS) and their phosphorylation type, as well as GluT4, was deteced in TZQ-F. In HepG2 cells, TZQ-F increased IRS-2 by 10 folds, without interrupting AKT, IRS-1 and GluT4. In L-6 myotube cells, TZQ-F and its fractions treatment significantly increased IRS-1 and AKT at mRNA level. Conclusion TZQ-F prevents pre-diabetes through increasing effect on IRS-1-dependent PI3K/AKT signaling pathway in muscle.
    BMC Complementary and Alternative Medicine 06/2014; 14(1):198. DOI:10.1186/1472-6882-14-198 · 2.02 Impact Factor
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