期刊
FASEB JOURNAL
卷 33, 期 12, 页码 14010-14021出版社
WILEY
DOI: 10.1096/fj.201901820R
关键词
olanzapine; A769662; liver; glucose; lipids
资金
- Canadian Institutes of Health Research (CIHR)
- Ontario Graduate Scholarship
- Dairy Farmers of Ontario Doctoral Research Assistantship
- Natural Sciences and Engineering Research Council of Canada (NSERC) Postgraduate Scholarship
- Australian Research Council [DP170101196]
- NHMRC [APP1085460]
- University of Guelph
Olanzapine (OLZ) is a second-generation antipsychotic that is used to treat schizophrenia but also causes acute hyperglycemia. This study aimed to determine if the ablation of AMPK beta 1-containing complexes potentiates acute OLZ-induced metabolic dysfunction and if the activation of AMPK beta 1 suppresses these effects. Female AMPK beta 1(-/-) or wild-type (WT) control mice were treated with OLZ, and changes in blood glucose, serum and liver metabolites, whole-body fuel oxidation, and pyruvate-induced increases in blood glucose were measured. Additionally, WT mice were cotreated with OLZ and A769662, a specific AMPK beta 1 activator, and we determined if cotreatment protected against acute, OLZ-induced metabolic dysfunction. OLZ-induced increases in blood glucose were exacerbated in AMPK beta 1 mice compared with WT mice, and this was paralleled by greater OLZ-induced increases in markers of liver glucose production, such as pyruvate tolerance, serum glucagon, and glucagon responsiveness. Cotreatment with A769662 attenuated OLZ-induced increases in blood glucose, serum nonesterified fatty acid, and glycerol. Furthermore, this effect was absent in AMPK beta 1(-/-) mice, consistent with A769662's specificity for the AMPK beta 1 subunit. Reductions in AMPK activity potentiate the effects of acute OLZ treatment on blood glucose, whereas specifically targeting AMPK beta 1-containing complexes is sufficient to protect against OLZ-induced hyperglycemia.
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