title: Beta-adrenoceptors, but not alpha-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1.
abstract: OBJECTIVE
  Brown adipocytes provide a potentially important model system for understanding AMP-activated protein kinase (AMPK) regulation, where adrenergic stimulation leads to mitochondrial uncoupling through uncoupling protein-1 (UCP1) activity. AMPK is a sensor of energy homeostasis and has been implicated in glucose and lipid metabolism in several insulin-sensitive tissues. The aim of this study was to characterise the potential role of AMPK in adrenergically mediated glucose uptake and to find out whether UCP1 is involved in the adrenergic activation of AMPK.
  
  
  METHODS
  We used primary brown adipocytes differentiated in culture and measured AMPK phosphorylation and glucose uptake following adrenergic activation.
  
  
  RESULTS
  Treatment of adipocytes with noradrenaline (norepinephrine) caused phosphorylation of AMPK via beta-adrenoceptors and not alpha(1)- or alpha(2)-adrenoceptors. This effect was not beta(3)-adrenoceptor specific, since responses remained intact in adipocytes from beta(3)-adrenoceptor knock-out mice. These effects were also mimicked by forskolin and cAMP analogues. Treatment of cells with adenine 8-beta-D-arabinofuranoside, an AMPK inhibitor, partially blocked beta-adrenoceptor-mediated increases in glucose uptake. Brown adipocytes are characterised by the production of UCP1, which can uncouple the mitochondria. Using adipocytes from Ucp1(+/+) and Ucp1(-/-) mice, we showed that noradrenaline-mediated phosphorylation of AMPK does not require the presence or activity of UCP1.
  
  
  CONCLUSIONS
  These results suggest a pathway where increases in cAMP mediated by beta-adrenoceptors leads to activation of AMPK in brown adipocytes, which contributes in part to beta-adrenoceptor-mediated increases in glucose uptake, an effect independent of the presence or function of UCP1.
authors.affiliation: Department of Physiology, The Wenner-Gren Institute, Arrhenius Laboratory F3, Stockholm University, Sweden.
authors.forename: D S
authors.initials: DS
authors.lastname: Hutchinson
authors.forename: E
authors.initials: E
authors.lastname: Chernogubova
authors.forename: O S
authors.initials: OS
authors.lastname: Dallner
authors.forename: B
authors.initials: B
authors.lastname: Cannon
authors.forename: T
authors.initials: T
authors.lastname: Bengtsson
mesh_terms: D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives; D005260:Female; D005947:Glucose / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D000316:Adrenergic alpha-Agonists; D002352:Carrier Proteins; D007328:Insulin; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005576:Colforsin; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D009638:Norepinephrine