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.

Download full-text


Available from: Rubén Nogueiras,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Psychopharmacology 04/2014; 231(20). DOI:10.1007/s00213-014-3540-3 · 3.88 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    The International Journal of Neuropsychopharmacology 10/2013; 17(01):1-18. DOI:10.1017/S146114571300093X · 4.01 Impact Factor
  • Source
    • "On one hand, patient studies report an increase in insulin levels after chronic or sub-chronic treatment (Ou et al., 2012; Melkersson et al. 2011, 2000) and no changes after acute administration (Kopf et al., 2012). On the other hand, animal studies showed that Olan-induced glucose dysregulation can be associated with increased (Boyda et al., 2012a; Smith et al., 2011), decreased (Weston-Green et al., 2012) and even unaltered insulin levels (Ferno et al., 2011) with no relation with the duration of the treatment. However, Boyda et al. showed that chronic treatment with Olan leads to a desensitization of the insulin response to an acute challenge with the same drug (Boyda et al., 2012b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Atypical antipsychotic drugs such as Olanzapine (Olan) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. It has been shown that peripheral injections of Olan activate neurons in the lateral hypothalamus/perifornical area and that a large part of these neurons are orexin (Ox) A-positive. We investigated further the possible involvement of the central Ox system in the metabolic side-effects of Olan by comparing the hyperglycaemic effects of an intragastric (IG) Olan infusion between animals treated intracerebroventricularly (ICV) with an Ox-1 receptor antagonist (SB-408124) or vehicle. As observed in previous studies IG Olan caused an increase in blood glucose, endogenous glucose production and plasma glucagon levels. ICV pre-treatment with the Ox-1 receptor antagonist did not affect the Olan-induced hyperglycemia or increased plasma glucagon concentrations, but the increased endogenous glucose production was blunted by the ICV SB-408124 treatment. From these results we conclude that the metabolic side-effects of Olan are partly mediated by the hypothalamic Ox system.
    Brain research 07/2013; 1527. DOI:10.1016/j.brainres.2013.06.034 · 2.84 Impact Factor
Show more