title: Ca2+/calmodulin-dependent protein kinase kinase is not involved in hypothalamic AMP-activated protein kinase activation by neuroglucopenia.
abstract: Hypoglycemia and neuroglucopenia stimulate AMP-activated protein kinase (AMPK) activity in the hypothalamus and this plays an important role in the counterregulatory responses, i.e. increased food intake and secretion of glucagon, corticosterone and catecholamines. Several upstream kinases that activate AMPK have been identified including Ca(2+)/Calmodulin-dependent protein kinase kinase (CaMKK), which is highly expressed in neurons. However, the involvement of CaMKK in neuroglucopenia-induced activation of AMPK in the hypothalamus has not been tested. To determine whether neuroglucopenia-induced AMPK activation is mediated by CaMKK, we tested whether STO-609 (STO), a CaMKK inhibitor, would block the effects of 2-deoxy-D-glucose (2DG)-induced neuroglucopenia both ex vivo on brain sections and in vivo. Preincubation of rat brain sections with STO blocked KCl-induced α1 and α2-AMPK activation but did not affect AMPK activation by 2DG in the medio-basal hypothalamus. To confirm these findings in vivo, STO was pre-administrated intracerebroventricularly (ICV) in rats 30 min before 2DG ICV injection (40 µmol) to induce neuroglucopenia. 2DG-induced neuroglucopenia lead to a significant increase in glycemia and food intake compared to saline-injected control rats. ICV pre-administration of STO (5, 20 or 50 nmol) did not affect 2DG-induced hyperglycemia and food intake. Importantly, activation of hypothalamic α1 and α2-AMPK by 2DG was not affected by ICV pre-administration of STO. In conclusion, activation of hypothalamic AMPK by 2DG-induced neuroglucopenia is not mediated by CaMKK.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Junji
authors.initials: J
authors.lastname: Kawashima
authors.forename: Thierry
authors.initials: T
authors.lastname: Alquier
authors.forename: Youki
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Odile D
authors.initials: OD
authors.lastname: Peroni
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites / Q000009:adverse effects / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D003847:Deoxyglucose / Q000009:adverse effects / Q000494:pharmacology; D007003:Hypoglycemia / Q000139:chemically induced / Q000201:enzymology*; D007031:Hypothalamus / Q000201:enzymology*; D008297:Male; D053644:Naphthalimides / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000963:Antimetabolites; D001562:Benzimidazoles; D053644:Naphthalimides; D009419:Nerve Tissue Proteins; C458525:STO 609; D003847:Deoxyglucose; C543928:Prkaa2 protein, rat; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat