Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats

Zhang, Qingsheng; He, Meng Xiao; Deng, Chao; Wang, Hongqin; Lian, Jiamei; Huang, Xu‐Feng

doi:10.1017/s1461145713001697

Cited by 50 publications

(75 citation statements)

References 66 publications

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“…It has also been reported that the NPY level was upregulated in short (7 days) and mid-term (15 days) olanzapine treatment in rats [129]. Ak and colleagues also reported that the plasma NPY level was attenuated in first attack psychotic male patients treated with olanzapine [100], while quetiapine increased the NPY level in cerebrospinal fluid from schizophrenia patients [130]; these changes in NPY level were associated with SGA-induced weight gain.…”

Section: The Role Of Npy and Agrp In Sga-induced Weight Gainmentioning

confidence: 91%

“…In terms of the effect of SGAs on expression of POMC and CART, it was shown that olanzapine treatment resulted in attenuation of POMC but not CART expression in the hypothalamus of rats [98,65,160,128,129]. Ak and colleagues also reported that the plasma POMC level was elevated in first attack psychotic male patients treated with olanzapine, but no changes in plasma CART level were observed [100].…”

Section: The Role Of Pomc and Cart In Sga-induced Weight Gainmentioning

confidence: 99%

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Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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Second generation antipsychotic drugs (SGAs) cause substantial body weight gain/obesity and other metabolic side-effects such as dyslipidaemia. Their antagonistic affinity to the histaminergic H1 receptor (H1R) has been identified as one of the main contributors to weight gain/obesity side-effects. The effects and mechanisms of betahistine (a histaminergic H1R agonist and H3 receptor antagonist) have been investigated for ameliorating SGA-induced weight gain/obesity in both animal models and clinical trials. It has been demonstrated that co-treatment with betahistine is effective in reducing weight gain, associated with olanzapine in drug-naïve patients with schizophrenia, as well as in the animal models of both drug-naïve rats and rats with chronic, repeated exposure to olanzapine. Betahistine co-treatment can reduce food intake and increase the effect of thermogenesis in brown adipose tissue by modulating hypothalamic H1R-NPY-AMPKα (NPY: neuropeptide Y; AMPKα: AMP-activated protein kinase α) pathways, and ameliorate olanzapineinduced dyslipidaemia through modulation of AMPKα-SREBP-1-PPARα-dependent pathways (SREBP-1: Sterol regulatory element binding protein 1; PPARα: Peroxisome proliferator-activated receptor-α) in the liver. Although reduced locomotor activity was observed from antipsychotic treatment in rats, betahistine did not affect locomotor activity. Importantly, betahistine co-treatment did not influence the effects of antipsychotics on serotonergic receptors in the key brain regions for antipsychotic therapeutic efficacy. However, betahistine co-treatment reverses the upregulated dopamine D2 binding caused by chronic olanzapine administration, which may be beneficial in reducing D2 supersensitivity often observed in chronic antipsychotic treatment. Therefore, these results provide solid evidence supporting further clinical trials in treating antipsychotics-induced weight gain using betahistine in patients with schizophrenia and other mental disorders.

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Section: The Role Of Npy and Agrp In Sga-induced Weight Gainmentioning

confidence: 91%

Section: The Role Of Pomc and Cart In Sga-induced Weight Gainmentioning

confidence: 99%

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Lian

Huang

Pai

et al. 2016

Pharmacological Research

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“…Using the adult female rat model for antipsychotic-induced weight gain, it has been repeatedly revealed that olanzapine elevated the expression of appetite stimulating neuropeptides in the hypothalamus, including neuropeptide Y (NPY) and agouti-related peptide (AgRP), while decreasing appetite inhibiting neuropeptides such as proopiomelanocortin (POMC) [25,[27][28][29]. On the other hand, H 1 R is independent of POMC regulation [30], but links to NPY expression [31].…”

Section: Introductionmentioning

confidence: 99%

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Lian

Santis

et al. 2015

Pharmacological Research

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. (2015). Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways. Pharmacological Research,[95][96] Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: the role of histaminergic and NPY pathways AbstractSecond generation antipsychotic drugs (SGAs) such as risperidone are increasingly prescribed (mostly for offlabel use) to children and adolescents for treating various mental disorders. SGAs cause serious weight gain/ obesity and other metabolic side-effects. This study aimed to establish an animal model of risperidoneinduced weight gain in female juvenile rats, and to investigate the effects of risperidone on the expression of hypothalamic histaminergic H1 receptors (H1R) and neuropeptides, and their association with weight gain. Female Sprague Dawley rats were treated orally with risperidone (0.3 mg/kg, 3 times/day) or vehicle (control) starting from postnatal day (PD) 23 (±1 day) for 3 weeks (a period corresponding to the childhoodadolescent period in humans). In the female juvenile rats, risperidone treatment increased food intake and body weight gain, which started to appear after 12 days' treatment. Risperidone also significantly decreased the locomotor activity of the female rats. Consistently, risperidone significantly elevated mRNA expression of hypothalamic H1R, neuropeptide Y (NPY), and agouti-related peptide (AgRP) compared to controls, and H1R and NPY levels were correlated with risperidone enhanced weight gain and food intake in the female juvenile rats. However, risperidone did not affect hypothalamic proopiomelanocortin (POMC) and cocaineand amphetamine-regulated transcript (CART) mRNA expression. Therefore, these results suggested that risperidone elevated appetite and body weight gain in juveniles via regulation of the hypothalamic H1R, NPY and AgRP pathways, as well as by reducing activity.

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“…Indeed, the plasma ghrelin level is reported to be elevated acutely but decreases during chronic treatment with olanzapine (36). It has also shown in rats that olanzapine leads to hyperphagia and weight gain by upregulating ghrelin signaling pathway (37). Taken together, it is suggested that the blockade of 5-HT 2B and 5-HT 2C receptors followed by stimulation of ghrelin release may contribute at least in part to the olanzapine-induced improvement of the control of nausea in patients receiving cisplatin-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Control of Nausea Based on Risk Analysis in Patients with Esophageal and Gastric Cancer Who Received Cisplatin-based Chemotherapy

Fujii

Iihara

Kajikawa

et al. 2017

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Cisplatin is commonly used for esophageal and gastric cancer, however, the agent has high emetic risk, classified as highly emetic chemotherapy. Ohtsu et al. demonstrated in patients with advanced gastric cancer that 5-fluorouracil (5-FU) plus cisplatin led to a significantly higher tumor response rate and longer median progression-free survival but not overall survival as compared with 5-FU alone (1). Koizumi et al. also reported in phase 3 study comparing the effect of S-1 alone and its combination with cisplatin in patients with advanced gastric cancer that the combination was superior to S-1 alone in prolonging median progression-free survival (HR: 0.57; p<0.0001) as well as median overall survival (HR: 0.77; p=0.04) but led to more severe adverse drug reactions, including nausea and vomiting (2). Thus, oral fluoropyrimidine and cisplatin combination chemotherapy is currently used as the first-line treatment option for unresectable advanced gastric cancer. On the other hand, Bang et al. reported in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric or gastro-oesophageal junction cancer that addition of trastuzumab (monoclonal antibody to HER2) to chemotherapy led to ignificantly longer median overall survival than chemotherapy alone (3). Thus, oral fluoropyrimidine, cisplatin and trastuzumab combination chemotherapy is currently regarded as the standard chemotherapy for HER2-positive gastric cancer.On the other hand, cisplatin with 5-FU regimen is recommended as neoadjuvant chemotherapy for stage II/III thoracic esophageal cancer and unresectable progressive recurrent esophageal cancer (4, 5).Cisplatin is classified as chemotherapy with high emetic risk (HEC) in several guidelines for prevention of chemotherapy-induced nausea and vomiting (CINV) (6-9). 6831

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Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats

Cited by 50 publications

References 66 publications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

Risperidone-induced weight gain and reduced locomotor activity in juvenile female rats: The role of histaminergic and NPY pathways

Control of Nausea Based on Risk Analysis in Patients with Esophageal and Gastric Cancer Who Received Cisplatin-based Chemotherapy

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