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- Title
Activation of AMP-Activated Protein Kinase (AMPK) by Neuroglucopenia in Hypothalamus Is not Mediated by Ca[sup 2+]/Calmodulin-Dependent Protein Kinase Kinase (CaMKK).
- Authors
Kawashima, Junji; Alquier, Thierry; Peroni, Odile D.; Kahn, Barbara B.
- Abstract
AMPK is a critical regulator of energy balance at both the cellular and whole-body levels. Recently, several upstream kinases that activate AMPK (AMPKK) have been identified including CaMKK which is highly expressed in neurons. CaMKK modulates AMPK activity in some cultured cells. In brain slices ex vivo CaMKK activity is necessary for activation of AMPK in response to KC1 but not phenformin. Hypoglycemia activates AMPK activity in hypothalamus and this is important for the counter-regulatory hormone response. Since hypoglycemia increases calcium flux in neurons we aimed to determine whether neuroglucopenia-induced AMPK activation is mediated by CaMKK. We detected CaMKKbeta protein in multiple hypothalamic nuclei and hindbrain. To induce neuroglucopenia, we incubated rat brain slices with 2-deoxy-glucose (2DG, 10 mM) for 15 min. Control slices were incubated with glucose (10mM) or with KC1 (30 mM). Preincubation with STO609 (25 uM), a CaMKK inhibitor, blocked alphal- and alpha2-AMPK activation induced by KC1 but not by 2DG in hypothalamus dissected from these brain slices. To determine whether the biologic responses to neuroglucopenia are mediated by CaMKK, we tested whether STO609 would block the effects of 2DG injected into the lateral ventricle in rats. We studied 3 groups, 1) saline injection alone; 2) saline before 2DG (40 umol) and 3) STO609 (50 nmol) before 2DG. 60 min after injection, glycemia in saline-2DG group was higher than in saline-only group (225 ± 20 vs. 112 ± 2 mg/dl). In STO609-2DG group (233 ± 11 mg/dl), glycemia was not different from saline-2DG group. Food intake from 1 to 2 hrs after 2DG injection was increased in saline-2DG (4.4 ± 0.7 g) and STO609-2DG (5.7 ± 0.5 g) groups compared to saline-only control group (1.1 ± 0.4 g). Preliminary data suggest that STO609 injection intracerebroventricularly in rats did not block the activation of alpha1- and alpha2-AMPK in arcuate and dorsomedial/ventromedial hypothalamus induced by 2DG. In summary, STO609 does not inhibit activation of AMPK by neuroglucopenia in vivo or ex vivo, or the biologic effects of neuroglucopenia. In conclusion, even though neuroglucopenia has been shown to stimulate calcium flux, activation of AMPK by neuroglucopenia is not mediated by CaMKK in hypothalamus. ADA-Funded Research
- Publication
Diabetes, 2007, Vol 56, pA514
- ISSN
0012-1797
- Publication type
Academic Journal