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Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation.

Fernø J, Varela L, Skrede S, Vázquez MJ, Nogueiras R, Diéguez C, Vidal-Puig A, Steen VM, López M - PLoS ONE (2011)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway. johan.ferno@uib.no

ABSTRACT
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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Effect of subchronic olanzapine administration on phosphorylation of hypothalamic AMPK and ACC.Western blot analysis of hypothalamic pAMPK and pACC from rats following an over night fast after 5 consecutive days of administration by gavage (b.i.d) with a) olanzapine (ad libitum fed) or b) olanzapine (pair-fed), relative to control rats. Calculations are based on results from 6 rats for each treatment group, run in duplicate. Representative images for the calculated difference were selected. Each lane (pACC, pAMPK and β-actin) always represents results on the same gel from the same rat. * P≤0.05 vs. vehicle. ** P≤0.01 vs. vehicle. *** P≤0.001 vs. vehicle.
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pone-0020571-g004: Effect of subchronic olanzapine administration on phosphorylation of hypothalamic AMPK and ACC.Western blot analysis of hypothalamic pAMPK and pACC from rats following an over night fast after 5 consecutive days of administration by gavage (b.i.d) with a) olanzapine (ad libitum fed) or b) olanzapine (pair-fed), relative to control rats. Calculations are based on results from 6 rats for each treatment group, run in duplicate. Representative images for the calculated difference were selected. Each lane (pACC, pAMPK and β-actin) always represents results on the same gel from the same rat. * P≤0.05 vs. vehicle. ** P≤0.01 vs. vehicle. *** P≤0.001 vs. vehicle.

Mentions: In the subchronic setting, hypothalamic pAMPK levels were measured after 5 days of olanzapine exposure. Interestingly, we found that pAMPK levels in the hypothalamus of olanzapine-treated, ad libitum-fed rats were significantly reduced (42±3%, P<0.0001) relative to vehicle-treated controls (Figure 4a). Accordingly, olanzapine reduced the levels of phosphorylated acetyl-CoA carboxylase (pACC; 70±9%, P<0.05) in ad libitum-fed rats. No significant changes were observed in pair-fed rats, neither for pAMPK nor for pACC (Figure 4b).


Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation.

Fernø J, Varela L, Skrede S, Vázquez MJ, Nogueiras R, Diéguez C, Vidal-Puig A, Steen VM, López M - PLoS ONE (2011)

Effect of subchronic olanzapine administration on phosphorylation of hypothalamic AMPK and ACC.Western blot analysis of hypothalamic pAMPK and pACC from rats following an over night fast after 5 consecutive days of administration by gavage (b.i.d) with a) olanzapine (ad libitum fed) or b) olanzapine (pair-fed), relative to control rats. Calculations are based on results from 6 rats for each treatment group, run in duplicate. Representative images for the calculated difference were selected. Each lane (pACC, pAMPK and β-actin) always represents results on the same gel from the same rat. * P≤0.05 vs. vehicle. ** P≤0.01 vs. vehicle. *** P≤0.001 vs. vehicle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3113797&req=5

pone-0020571-g004: Effect of subchronic olanzapine administration on phosphorylation of hypothalamic AMPK and ACC.Western blot analysis of hypothalamic pAMPK and pACC from rats following an over night fast after 5 consecutive days of administration by gavage (b.i.d) with a) olanzapine (ad libitum fed) or b) olanzapine (pair-fed), relative to control rats. Calculations are based on results from 6 rats for each treatment group, run in duplicate. Representative images for the calculated difference were selected. Each lane (pACC, pAMPK and β-actin) always represents results on the same gel from the same rat. * P≤0.05 vs. vehicle. ** P≤0.01 vs. vehicle. *** P≤0.001 vs. vehicle.
Mentions: In the subchronic setting, hypothalamic pAMPK levels were measured after 5 days of olanzapine exposure. Interestingly, we found that pAMPK levels in the hypothalamus of olanzapine-treated, ad libitum-fed rats were significantly reduced (42±3%, P<0.0001) relative to vehicle-treated controls (Figure 4a). Accordingly, olanzapine reduced the levels of phosphorylated acetyl-CoA carboxylase (pACC; 70±9%, P<0.05) in ad libitum-fed rats. No significant changes were observed in pair-fed rats, neither for pAMPK nor for pACC (Figure 4b).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway. johan.ferno@uib.no

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus