title: Hypothalamic AMP-activated protein kinase regulates glucose production.
abstract: OBJECTIVE
  The fuel sensor AMP-activated protein kinase (AMPK) in the hypothalamus regulates energy homeostasis by sensing nutritional and hormonal signals. However, the role of hypothalamic AMPK in glucose production regulation remains to be elucidated. We hypothesize that bidirectional changes in hypothalamic AMPK activity alter glucose production.
  
  
  METHODS
  To introduce bidirectional changes in hypothalamic AMPK activity in vivo, we first knocked down hypothalamic AMPK activity in male Sprague-Dawley rats by either injecting an adenovirus expressing the dominant-negative form of AMPK (Ad-DN AMPKα2 [D(157)A]) or infusing AMPK inhibitor compound C directly into the mediobasal hypothalamus. Next, we independently activated hypothalamic AMPK by delivering either an adenovirus expressing the constitutive active form of AMPK (Ad-CA AMPKα1(312) [T172D]) or the AMPK activator AICAR. The pancreatic (basal insulin)-euglycemic clamp technique in combination with the tracer-dilution methodology was used to assess the impact of alternations in hypothalamic AMPK activity on changes in glucose kinetics in vivo.
  
  
  RESULTS
  Injection of Ad-DN AMPK into the hypothalamus knocked down hypothalamic AMPK activity and led to a significant suppression of glucose production with no changes in peripheral glucose uptake during the clamps. In parallel, hypothalamic infusion of AMPK inhibitor compound C lowered glucose production as well. Conversely, molecular and pharmacological activation of hypothalamic AMPK negated the ability of hypothalamic nutrients to lower glucose production.
  
  
  CONCLUSIONS
  These data indicate that changes in hypothalamic AMPK activity are sufficient and necessary for hypothalamic nutrient-sensing mechanisms to alter glucose production in vivo.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Canada.
authors.forename: Clair S
authors.initials: CS
authors.lastname: Yang
authors.forename: Carol K L
authors.initials: CK
authors.lastname: Lam
authors.forename: Madhu
authors.initials: M
authors.lastname: Chari
authors.forename: Grace W C
authors.initials: GW
authors.lastname: Cheung
authors.forename: Andrea
authors.initials: A
authors.lastname: Kokorovic
authors.forename: Sun
authors.initials: S
authors.lastname: Gao
authors.forename: Isabelle
authors.initials: I
authors.lastname: Leclerc
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000096:biosynthesis*; D006019:Glycolysis / Q000187:drug effects; D006706:Homeostasis; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology*; D007328:Insulin / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D005934:Glucagon; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose