Olanzapine-Induced Hyperphagia and Weight Gain Associate with Orexigenic Hypothalamic Neuropeptide Signaling without Concomitant AMPK Phosphorylation

Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
PLoS ONE (Impact Factor: 3.23). 06/2011; 6(6):e20571. DOI: 10.1371/journal.pone.0020571
Source: PubMed


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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    • "Ser 491 phosphorylation of AMPKα2 was recently identified as a novel mechanism of AMPK inhibition, accounting for leptin-induced weight loss (Dagon et al. 2012). The abovementioned studies (Kim et al. 2004; Kim et al. 2007) only examined acute effects of ALA or AAPDs on AMPK activity; another study (Ferno et al. 2011) examined subchronic changes in AMPK activity by olanzapine but measured only Thr 172 phosphorylation levels as an indicator of AMPK activity. Fig. 4 Effects of α-lipoic acid on the phosphorylation of hypothalamic AMPK in female mice treated with olanzapine for 10 days. "
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    ABSTRACT: Alpha-lipoic acid (ALA) was shown to suppress atypical antipsychotic drug (AAPD)-induced weight gain. However, its mode of action has remained unidentified. We aimed to identify mechanisms underlying anti-obesity effects of ALA in mice treated with olanzapine. We compared body weight and food intake among vehicle-, olanzapine-, and olanzapine plus ALA-treated mice, and measured hypothalamic AMP-activated protein kinase (AMPK) activity by detecting levels of Thr(172) and Ser(485/491) phosphorylation, which indicate activation and inhibition of AMPK, respectively. Body weights were increased by olanzapine in parallel with increased levels of Thr(172) phosphorylation of hypothalamic AMPK. Initially increased rate of weight gain was diminished as Thr(172) phosphorylation levels were decreased to control levels after 10 days of olanzapine treatment. ALA successfully not only prevented olanzapine-induced weight gain but also induced additional weight loss even relative to control levels throughout the treatment period. During the initial stage, ALA's action was indicated by both suppression of olanzapine-induced Thr(172) phosphorylation and an increase in Ser(485/491) phosphorylation levels. However, in the later stage when no more increases in Thr(172) phosphorylation and weight gain by olanzapine were observed, ALA's action was only indicated by increased levels of Ser(485/491) phosphorylation. Our data suggest that anti-obesity effects of ALA may be related to modulation of both Ser(485/491) phosphorylation and Thr(172) phosphorylation of hypothalamic AMPK, while olanzapine-induced weight gain may be only associated with increase in Thr(172) phosphorylation. This might be an important mechanistic clue for the future development of anti-obesity drugs beyond control of AAPD-induced weight gain.
    Full-text · Article · Apr 2014 · Psychopharmacology
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    • "Sub-chronic olanzapine treatment has been shown to result in down regulation of pro-opiomelanocortin expression in the rat hypothalamus (Ferno et al. 2011). However, Davoodi et al. (2009) reported that female rats treated with olanzapine gained body weight and exhibited increased food intake, but showed no difference in POMC mRNA expression compared to controls. "
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    ABSTRACT: Objectives. The use of second-generation antipsychotic medications may result in substantial weight gain in a subset of schizophrenia patients. Distinct populations of neurons expressed in the hypothalamus, including the cocaine- and amphetamine-regulated transcript (CART), the polypeptide pro-opiomelanocortin (POMC) and the agouti-related protein (AGRP), have regulatory roles in weight control and energy homeostasis. Thus, we investigated the potential role of CART, POMC and AGRP genetic variants in antipsychotic-induced weight gain (AIWG). Methods. Five CART single nucleotide polymorphisms (SNPs) (rs10515115, rs3763153, rs3857384, rs11575893, rs16871471), three POMC SNPs (rs6713532, rs1047521, rs3754860) and one AGRP SNP (rs1338993), were genotyped in 218 patients treated with antipsychotics for chronic schizophrenia and evaluated for AIWG. We compared weight change (%) across genotypic groups using analysis of covariance. Results. None of the SNPs in POMC, CART, AGRP were significantly associated with AIWG in the refined samples stratified by ethnicity and medication treatment. Conclusions. In this exploratory study, we observed that POMC, CART and AGRP gene variants are not a major contributor to AIWG. However larger samples are required to completely rule out their effect on AIWG.
    Full-text · Article · Feb 2014 · The World Journal of Biological Psychiatry
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    • "Furthermore, feeding efficiency (grams of weight gained/grams of food consumed ) was significantly increased by olanzapine and was positively correlated with total white fat mass, suggesting that the increase in adiposity was (in part) due to reduced energy expenditure (Pouzet et al., 2003; Arjona et al., 2004; Huang et al., 2006; Wallingford et al., 2008; Weston-Green et al., 2011). However, body weight gain in females was also positively correlated with total food intake (Huang et al., 2006; Han et al., 2008; Weston-Green et al., 2011,) and two studies failed to observe weight gain in pair-fed olanzapine-treated (female) rats (Davoodi et al., 2009; Ferno et al., 2011), suggesting that weight-gain depended solely on hyperphagia . Unfortunately, these studies assessed only body weight in the pair-fed group, and it cannot be excluded that adiposity levels increased in the absence of weight gain, as they did in the study by Chintoh et al. (2008). "
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    ABSTRACT: The second-generation antipsychotic drug olanzapine has become a widely prescribed drug in the treatment of schizophrenia and bipolar disorder. Unfortunately, its therapeutic benefits are partly outweighed by significant weight gain and other metabolic side effects, which increase the risk for diabetes and cardiovascular disease. Because olanzapine remains superior to other antipsychotic drugs that show less weight gain liability, insight into the mechanisms responsible for olanzapine-induced weight gain is crucial if it is to be effectively addressed. Over the past few decades, several groups have investigated the effects of olanzapine on energy balance using rat models. Unfortunately, results from different studies have not always been consistent and it remains to be determined which paradigms should be used in order to model olanzapine-induced weight gain most accurately. This review summarizes the effects of olanzapine on energy balance observed in different rat models and discusses some of the factors that appear to contribute to the inconsistencies in observed effects. In addition it compares the effects reported in rats with clinical findings to determine the predictive validity of different paradigms.
    Full-text · Article · Oct 2013 · The International Journal of Neuropsychopharmacology
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