title: AMPK regulates circadian rhythms in a tissue- and isoform-specific manner.
abstract: BACKGROUND
  AMP protein kinase (AMPK) plays an important role in food intake and energy metabolism, which are synchronized to the light-dark cycle. In vitro, AMPK affects the circadian rhythm by regulating at least two clock components, CKIα and CRY1, via direct phosphorylation. However, it is not known whether the catalytic activity of AMPK actually regulates circadian rhythm in vivo.
  
  
  RESULTS
  THE CATALYTIC SUBUNIT OF AMPK HAS TWO ISOFORMS: α1 and α2. We investigate the circadian rhythm of behavior, physiology and gene expression in AMPKα1-/- and AMPKα2-/- mice. We found that both α1-/- and α2-/- mice are able to maintain a circadian rhythm of activity in dark-dark (DD) cycle, but α1-/- mice have a shorter circadian period whereas α2-/- mice showed a tendency toward a slightly longer circadian period. Furthermore, the circadian rhythm of body temperature was dampened in α1-/- mice, but not in α2-/- mice. The circadian pattern of core clock gene expression was severely disrupted in fat in α1-/- mice, but it was severely disrupted in the heart and skeletal muscle of α2-/- mice. Interestingly, other genes that showed circadian pattern of expression were dysreguated in both α1-/- and α2-/- mice. The circadian rhythm of nicotinamide phosphoryl-transferase (NAMPT) activity, which converts nicotinamide (NAM) to NAD+, is an important regulator of the circadian clock. We found that the NAMPT rhythm was absent in AMPK-deficient tissues and cells.
  
  
  CONCLUSIONS
  This study demonstrates that the catalytic activity of AMPK regulates circadian rhythm of behavior, energy metabolism and gene expression in isoform- and tissue-specific manners.
authors.affiliation: Laboratory of Obesity and Aging Research, Genetics and Developmental Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jee-Hyun
authors.initials: JH
authors.lastname: Um
authors.forename: Julie S
authors.initials: JS
authors.lastname: Pendergast
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Springer
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Brown
authors.forename: Myung K
authors.initials: MK
authors.lastname: Kim
authors.forename: Shin
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Jay H
authors.initials: JH
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001831:Body Temperature; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002153:Calorimetry, Indirect; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D004435:Eating / Q000235:genetics / Q000502:physiology; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D007527:Isoenzymes; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases