title: Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity.
abstract: OBJECTIVE
  Obesity-related insulin resistance is associated with accumulation of bioactive lipids in skeletal muscle. The AMP-activated protein kinase (AMPK) regulates lipid oxidation in muscle by inhibiting acetyl-CoA carboxylase-2 (ACC2) and increasing mitochondrial biogenesis. We investigated whether reduced levels of muscle AMPK promote lipid accumulation and insulin resistance during high-fat feeding.
  
  
  METHODS
  Male C57/BL6 wild-type mice and transgenic littermates overexpressing an alpha2AMPK kinase-dead (KD) in muscle were fed control or high-fat diet. Whole-body glucose homeostasis was assessed by glucose and insulin tolerance tests, and by measuring fasting and fed serum insulin and glucose. Insulin action in muscle was determined by measuring 2-deoxy-[(3)H]glucose uptake and Akt phosphorylation in incubated soleus and extensor digitorum longus muscles. Muscle triacylglycerol, diacylglycerol and ceramide content was measured by thin-layer chromatography. Mitochondrial proteins were measured by immunoblotting.
  
  
  RESULTS
  KD mice had reduced skeletal muscle alpha2AMPK activity (50% in gastrocnemius and >80% in soleus and extensor digitorum longus) and ACC2 Ser228 phosphorylation (90% in gastrocnemius). High-fat feeding increased body mass and adiposity, and impaired insulin and glucose tolerance; however, there were no differences between wild-type and KD littermates. High-fat feeding impaired insulin-stimulated muscle glucose uptake and Akt-phosphorylation, while increasing muscle triacylglycerol, diacylglycerol (p = 0.07) and ceramide, but these effects were not exacerbated in KD mice. In response to high-fat feeding, mitochondrial proteins were increased to similar levels in wild-type and KD muscles.
  
  
  CONCLUSIONS
  Obesity-induced lipid accumulation and insulin resistance were not exacerbated in AMPK KD mice, suggesting that reduced levels of muscle alpha2AMPK do not promote insulin resistance in the early phase of obesity-related diabetes.
authors.affiliation: St Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, VIC, Australia. sbjorgensen@ifi.ku.dk
authors.forename: S
authors.initials: S
authors.lastname: Beck Jørgensen
authors.forename: H M
authors.initials: HM
authors.lastname: O'Neill
authors.forename: K
authors.initials: K
authors.lastname: Hewitt
authors.forename: B E
authors.initials: BE
authors.lastname: Kemp
authors.forename: G R
authors.initials: GR
authors.lastname: Steinberg
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D003847:Deoxyglucose / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D007700:Kinetics; D015227:Lipid Peroxidation / Q000502:physiology; D008055:Lipids / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012016:Reference Values; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D008055:Lipids; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D003847:Deoxyglucose; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide
references.citation: Diabetes. 2008 Nov;57(11):2958-66
references.pmid: 18728234
references.citation: J Physiol. 2008 Dec 1;586(23):5819-31
references.pmid: 18845612
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15983-7
references.pmid: 12444247
references.citation: Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E57-66
references.pmid: 19435854
references.citation: Am J Physiol. 1999 Dec;277(6):E1130-41
references.pmid: 10600804
references.citation: Diabetes. 2009 Apr;58(4):829-39
references.pmid: 19136654
references.citation: Science. 2001 Aug 31;293(5535):1673-7
references.pmid: 11533494
references.citation: Diabetes. 2007 Aug;56(8):2085-92
references.pmid: 17519422
references.citation: Diabetes. 2003 May;52(5):1066-72
references.pmid: 12716734
references.citation: Diabetes. 2001 May;50(5):921-7
references.pmid: 11334434
references.citation: Nature. 2006 Dec 14;444(7121):860-7
references.pmid: 17167474
references.citation: Science. 2001 Mar 30;291(5513):2613-6
references.pmid: 11283375
references.citation: Eur J Biochem. 1990 Jan 12;187(1):183-90
references.pmid: 1967580
references.citation: Nat Med. 2006 May;12(5):541-8
references.pmid: 16604088
references.citation: Obes Res. 2004 Aug;12(8):1264-70
references.pmid: 15340109
references.citation: J Biol Chem. 1999 Aug 20;274(34):24202-10
references.pmid: 10446195
references.citation: J Clin Invest. 1994 Dec;94(6):2349-56
references.pmid: 7989591
references.citation: Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E331-9
references.pmid: 16954334
references.citation: J Clin Endocrinol Metab. 2004 Sep;89(9):4575-80
references.pmid: 15356065
references.citation: Am J Physiol Endocrinol Metab. 2000 Nov;279(5):E1202-6
references.pmid: 11052978
references.citation: Diabetes. 2001 May;50(5):1076-82
references.pmid: 11334411
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7815-20
references.pmid: 18509063
references.citation: Diabetes. 2002 Oct;51(10):2886-94
references.pmid: 12351423
references.citation: J Clin Invest. 2004 Sep;114(6):823-7
references.pmid: 15372106
references.citation: Diabetes. 2006 Aug;55(8):2277-85
references.pmid: 16873691
references.citation: Diabetes. 2002 May;51(5):1477-84
references.pmid: 11978645
references.citation: Diabetes. 2005 Jan;54(1):8-14
references.pmid: 15616005
references.citation: Am J Physiol. 1997 Dec;273(6):E1107-12
references.pmid: 9435525
references.citation: Diabetologia. 2007 Apr;50(4):790-6
references.pmid: 17334651
references.citation: Diabetes. 2007 May;56(5):1376-81
references.pmid: 17287462
references.citation: J Biol Chem. 1990 Oct 5;265(28):16880-5
references.pmid: 2211599
references.citation: Diabetes. 2001 Jan;50(1):123-30
references.pmid: 11147777
references.citation: Diabetes. 2001 Oct;50(10):2210-8
references.pmid: 11574400
references.citation: Physiol Rev. 2007 Apr;87(2):507-20
references.pmid: 17429039
references.citation: J Biol Chem. 2004 Sep 10;279(37):38441-7
references.pmid: 15247217
references.citation: Cell Metab. 2007 Mar;5(3):167-79
references.pmid: 17339025
references.citation: FASEB J. 2005 Jul;19(9):1146-8
references.pmid: 15878932
references.citation: Nature. 2002 Nov 21;420(6913):333-6
references.pmid: 12447443
references.citation: J Biol Chem. 2002 Dec 27;277(52):50230-6
references.pmid: 12006582
references.citation: Diabetes. 2009 Mar;58(3):550-8
references.pmid: 19073774
references.citation: Am J Physiol. 1999 Jan;276(1):E1-E18
references.pmid: 9886945
references.citation: Am J Physiol Endocrinol Metab. 2002 Jul;283(1):E187-92
references.pmid: 12067860
references.citation: FASEB J. 1999 Nov;13(14):2051-60
references.pmid: 10544188
references.citation: Mol Cell. 2001 May;7(5):1085-94
references.pmid: 11389854
references.citation: Cell Metab. 2005 Jan;1(1):15-25
references.pmid: 16054041
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Cell Metab. 2006 Dec;4(6):465-74
references.pmid: 17141630
references.citation: J Biol Chem. 2004 Jan 9;279(2):1070-9
references.pmid: 14573616
references.citation: Diabetes. 2007 Mar;56(3):836-48
references.pmid: 17327455