Journal
PLOS ONE
Volume 6, Issue 6, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0020571
Keywords
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Categories
Funding
- Research Council of Norway
- Norwegian Council for Mental Health
- Extrastiftelsen Helse og Rehabilitering
- Helse Vest RHF
- Dr. Einar Martens Fund
- European Community [245009, 223713, 018734]
- Xunta de Galicia [ML: 10PXIB208164PR, RN: 2010/14]
- Fondo Investigationes Sanitarias [ML: PS09/01880]
- Ministerio de Educacion y Ciencia [CD: BFU2008-02001, ML: RyC-2007-00211, RN: RyC-2008-02219, SAF2009-07049]
- Medical Research Council
- Welcome Trust
- MRC [G0802051] Funding Source: UKRI
- Medical Research Council [G0802051] Funding Source: researchfish
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The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.
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