AMP-Activated Protein Kinase (AMPK) and Energy-Sensing in the Brain

5'-adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved cellular and organismal energy integrator that responds to numerous stimuli with the overall intention to facilitate energy conservation and enhance energy balance while also affecting cellular survival and behaviors. AMPK has been appreciated for many years to function in peripheral organs that contribute to the generation or disposition of cellular energy, while its role in the brain has been only recently elucidated. While acknowledged to respond to organismal energy balance, we now recognize that energy balance within neurons also affects the brain's response to these peripheral signals. In this review, we discuss AMPK's regulation and its ever-expanding role as a neuronal energy integrator at both the cellular and systems levels.

[1]  AMP kinase–mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis , 2010, The Journal of cell biology.

[2]  Michael D. Schneider,et al.  A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway , 2006, Proceedings of the National Academy of Sciences.

[3]  D. Hardie,et al.  Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase* , 2005, Journal of Biological Chemistry.

[4]  C. Culmsee,et al.  AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation , 2001, Journal of Molecular Neuroscience.

[5]  Eng H. Lo,et al.  The Science of Stroke: Mechanisms in Search of Treatments , 2010, Neuron.

[6]  Peter Schjerling,et al.  Knockout of the α2 but Not α1 5′-AMP-activated Protein Kinase Isoform Abolishes 5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranosidebut Not Contraction-induced Glucose Uptake in Skeletal Muscle* , 2004, Journal of Biological Chemistry.

[7]  M. Garcia-Gil,et al.  5′-aminoimidazole-4-carboxamide riboside induces apoptosis in human neuroblastoma cells , 2003, Neuroscience.

[8]  G. Ronnett,et al.  Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass. , 2004, American journal of physiology. Endocrinology and metabolism.

[9]  B. Viollet,et al.  The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity. , 2003, The Journal of clinical investigation.

[10]  L. McCullough,et al.  Effects of AMP-Activated Protein Kinase in Cerebral Ischemia , 2010, Journal of Cerebral Blood Flow and Metabolism.

[11]  M. Korbonits,et al.  The Orexigenic Effect of Ghrelin Is Mediated through Central Activation of the Endogenous Cannabinoid System , 2008, PloS one.

[12]  Linda M Arseneau,et al.  Extracellular glucose in rat ventromedial hypothalamus during acute and recurrent hypoglycemia. , 2003, Diabetes.

[13]  Kohjiro Ueki,et al.  Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. , 2007, Cell metabolism.

[14]  C. Townsend,et al.  Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. , 2000, Science.

[15]  B. Kemp,et al.  Whole Body Deletion of AMP-activated Protein Kinase β2 Reduces Muscle AMPK Activity and Exercise Capacity* , 2010, The Journal of Biological Chemistry.

[16]  R. Huganir,et al.  C75, a Fatty Acid Synthase Inhibitor, Modulates AMP-activated Protein Kinase to Alter Neuronal Energy Metabolism* , 2004, Journal of Biological Chemistry.

[17]  Ricardo Lage,et al.  Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance , 2010, Nature Medicine.

[18]  Jun Li,et al.  Adenosine monophosphate activated protein kinase inhibition is protective in both sexes after experimental stroke , 2010, Neuroscience Letters.

[19]  G. Ronnett,et al.  C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase* , 2004, Journal of Biological Chemistry.

[20]  J. Park,et al.  Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. , 2005, Diabetes.

[21]  B. Kemp,et al.  β-Subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK) , 2010, Proceedings of the National Academy of Sciences.

[22]  D. Hardie AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. , 2011, Genes & development.

[23]  A. Vidal-Puig,et al.  Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance , 2011, Reviews in Endocrine and Metabolic Disorders.

[24]  R. Sherwin,et al.  Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. , 2004, Diabetes.

[25]  A. Means,et al.  Chutes and Ladders: the search for protein kinases that act on AMPK. , 2006, Trends in biochemical sciences.

[26]  David Carling,et al.  AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure. , 2011, The Biochemical journal.

[27]  Louise Lantier,et al.  AMPK: Lessons from transgenic and knockout animals. , 2009, Frontiers in bioscience.

[28]  S. Gamblin,et al.  AMP-activated protein kinase: nature's energy sensor. , 2011, Nature chemical biology.

[29]  A. Hevener,et al.  AMPK β1 Deletion Reduces Appetite, Preventing Obesity and Hepatic Insulin Resistance* , 2009, The Journal of Biological Chemistry.

[30]  A. Salminen,et al.  AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network , 2012, Ageing Research Reviews.

[31]  Ricardo Lage,et al.  Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. , 2008, Cell metabolism.

[32]  N. Fujii,et al.  Cloning and characterization of mouse 5'-AMP-activated protein kinase γ3 subunit , 2004 .

[33]  N. Fujii,et al.  Cloning and characterization of mouse 5'-AMP-activated protein kinase gamma3 subunit. , 2004, American journal of physiology. Cell physiology.

[34]  G. Ronnett,et al.  Physiological oxygen level is critical for modeling neuronal metabolism in vitro , 2012, Journal of neuroscience research.

[35]  D. Hardie,et al.  Edinburgh Research Explorer The glycogen-binding domain on the AMPK beta subunit allows the kinase to act as a glycogen sensor , 2008 .

[36]  B. Viollet,et al.  AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress , 2011, Proceedings of the National Academy of Sciences.

[37]  S. Ohta,et al.  Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death. , 2008, Toxicology and applied pharmacology.

[38]  M. Birnbaum,et al.  Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake , 2007, Proceedings of the National Academy of Sciences.

[39]  R. Shaw,et al.  The AMPK signalling pathway coordinates cell growth, autophagy and metabolism , 2011, Nature Cell Biology.

[40]  G. Barsh,et al.  AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. , 2007, The Journal of clinical investigation.

[41]  D. Dickson,et al.  Nuclear translocation of AMPK-α1 potentiates striatal neurodegeneration in Huntington’s disease , 2011, The Journal of cell biology.

[42]  Simon C Watkins,et al.  Starving Neurons Show Sex Difference in Autophagy* , 2009, Journal of Biological Chemistry.

[43]  L. McCullough,et al.  Pharmacological Inhibition of AMP-activated Protein Kinase Provides Neuroprotection in Stroke* , 2005, Journal of Biological Chemistry.

[44]  M. Febbraio,et al.  Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice. , 2006, Endocrinology.

[45]  清水 裕史 Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via adenosine monophosphate-activated protein kinase signaling in the arcuate nucleus of rats , 2009 .

[46]  M. Birnbaum,et al.  AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus , 2004, Nature.

[47]  B. Viollet,et al.  Knockout of the alpha2 but not alpha1 5'-AMP-activated protein kinase isoform abolishes 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranosidebut not contraction-induced glucose uptake in skeletal muscle. , 2004, The Journal of biological chemistry.

[48]  J. Milbrandt,et al.  AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development. , 2009, Developmental cell.

[49]  I. Kang,et al.  5-Aminoimidazole-4-carboxamide-ribonucleoside enhances oxidative stress-induced apoptosis through activation of nuclear factor-κB in mouse Neuro 2a neuroblastoma cells , 2004, Neuroscience Letters.

[50]  G. Velasco,et al.  The AMP‐activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes , 2001, FEBS letters.

[51]  S. Gamblin,et al.  AMP-activated protein kinase: also regulated by ADP? , 2011, Trends in biochemical sciences.

[52]  D. Spencer,et al.  Striking Differences in Glucose and Lactate Levels between Brain Extracellular Fluid and Plasma in Conscious Human Subjects: Effects of Hyperglycemia and Hypoglycemia , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[53]  J. Simon,et al.  AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism* , 2010, The Journal of Biological Chemistry.

[54]  Steven J. Greco,et al.  Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells. , 2009, Biochemical and biophysical research communications.

[55]  D. Judge AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization , 2011 .

[56]  M. Carlson,et al.  Mammalian TAK1 Activates Snf1 Protein Kinase in Yeast and Phosphorylates AMP-activated Protein Kinase in Vitro* , 2006, Journal of Biological Chemistry.

[57]  B. Kemp,et al.  AMPK Is a Direct Adenylate Charge-Regulated Protein Kinase , 2011, Science.

[58]  B. Kemp,et al.  Cellular Distribution and Developmental Expression of AMP‐Activated Protein Kinase Isoforms in Mouse Central Nervous System , 1999, Journal of neurochemistry.

[59]  B. Viollet,et al.  AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1 , 2011, Nature Cell Biology.

[60]  A. Roopra,et al.  Metabolic Regulation of Neuronal Plasticity by the Energy Sensor AMPK , 2010, PloS one.

[61]  G. Ronnett,et al.  Physiological glucose is critical for optimized neuronal viability and AMPK responsiveness in vitro , 2008, Journal of Neuroscience Methods.

[62]  I. Singh,et al.  Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. , 2010, Biochemical and biophysical research communications.

[63]  K. Nakao,et al.  Central melanocortin signaling restores skeletal muscle AMP-activated protein kinase phosphorylation in mice fed a high-fat diet. , 2007, Cell metabolism.

[64]  K-U. Lee,et al.  Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats , 2005, Diabetologia.

[65]  Seth Love,et al.  Apoptosis and brain ischaemia , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[66]  Jun Li,et al.  Neuroprotective Effects of Adenosine Monophosphate-Activated Protein Kinase Inhibition and Gene Deletion in Stroke , 2007, Stroke.

[67]  I. Silver,et al.  Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[68]  L. McCullough,et al.  Effects of Metformin in Experimental Stroke , 2010, Stroke.

[69]  C. Townsend,et al.  Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. , 2002, American journal of physiology. Endocrinology and metabolism.

[70]  D. Choi,et al.  Apoptosis and Necrosis in Cerebrovascular Disease , 1999, Annals of the New York Academy of Sciences.

[71]  Hyunju Chung,et al.  Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. , 2008, Endocrine journal.

[72]  D. Dickson,et al.  AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies , 2011, Acta Neuropathologica.

[73]  B. Viollet,et al.  Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy , 2011, Science.

[74]  D. Carling,et al.  AMP-activated Protein Kinase Plays a Role in the Control of Food Intake* , 2004, Journal of Biological Chemistry.

[75]  Kun Xu,et al.  A Pharmacological Activator of AMP-Activated Protein Kinase Protects Hypoxic Neurons in a Concentration-Dependent Manner , 2010, Neurochemical Research.