The Role of Thermogenesis in Antipsychotic Drug‐induced Weight Gain

Stefanidis, Aneta; Verty, Aaron N A; Allen, Andrew M.; Owens, Neil Craig; Cowley, Michael A.; Oldfield, Brian J.

doi:10.1038/oby.2008.468

Cited by 96 publications

(78 citation statements)

References 52 publications

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“…These results both confirmed that decreased energy expenditure and increased food intake/feeding efficiency contributed to increased weight gain induced by chronic olanzapine treatment [65,180].…”

Section: The Mechanisms Underlying Betahistine In Reducing Antipsychosupporting

confidence: 75%

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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 Mechanisms Underlying Betahistine In Reducing Antipsychosupporting

confidence: 75%

“…Additionally, it was also revealed that the expression of BAT UCP 1 and PGC-1α protein levels (biomarkers of thermogenesis) is reduced by chronic olanzapine treatment [65,180].…”

Section: The Mechanisms Underlying Betahistine In Reducing Antipsychomentioning

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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“…16,[47][48][49][50] Interestingly, the decrease in body temperature was followed by a much longer-lasting increase in temperature, which continued into the following light phase. Reactive hyperthermia was previously also reported after OLA was discontinued in rats that had been treated continuously for 18 days.…”

Section: Discussionmentioning

confidence: 99%

The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature

et al. 2011

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Objective: Significant weight gain is a problematic side effect of treatment with the antipsychotic drug olanzapine (OLA). Previous studies in rats suggest that one of the contributing factors is an impairment in satiation that results in increased food intake. However, the mechanisms underlying this impairment in satiation remain largely unclear. Methods and results: In this study, we determined the effect of OLA on levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide-1, peptide YY and amylin in male rats that had received a fixed amount of food. OLA did not affect the secretion of any of these hormones, except for ghrelin levels, which were increased compared with controls. Furthermore, when ghrelin levels were determined in rats just before they received their meal, OLA caused a significant increase in ghrelin levels compared with controls, whereas OLA failed to affect baseline ghrelin levels. Next, we investigated the effect of OLA on the efficacy of CCK to reduce meal size. With coadministration, OLA pretreatment counteracted the reduction in meal size by CCK, although there was no significant interaction between the treatments. Finally, telemetry measurements revealed that acute OLA treatment causes a temporary decrease in both locomotor activity and body core temperature. Conclusion: Taken together, this study shows that acute injection of OLA selectively increases meal-related ghrelin secretion and this may partially underlie the impairment in satiation by OLA.

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“…[96] Interestingly, a number of studies found that olanzapine (1-8mg/kg/day) causes dramatic increase of daily food intake particularly during short-term treatment (<2 weeks) in rats. [96][97][98][99] During long-term treatment, the olanzapine treatment group showed no significant difference in food intake from week 3-5, but maintained a higher body weight compared to the vehicle-treated control rats. [96][97]99] In addition, pair-fed rats which were given the same amount of food did not increase weight gain during short-term olanzapine treatment (6mg/kg/day, oral, 5days).…”

Section: Does Ampk-cpt1 Signaling Play a Different Role In The Three mentioning

confidence: 99%

“…[96][97][98][99] During long-term treatment, the olanzapine treatment group showed no significant difference in food intake from week 3-5, but maintained a higher body weight compared to the vehicle-treated control rats. [96][97]99] In addition, pair-fed rats which were given the same amount of food did not increase weight gain during short-term olanzapine treatment (6mg/kg/day, oral, 5days). [86] Patients treated with SGAs exert significantly decreased energy expenditure especially after chronic treatment (6-12 months).…”

Section: Does Ampk-cpt1 Signaling Play a Different Role In The Three mentioning

confidence: 99%

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

Deng

Huang

2013

CNS Drugs

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Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGAinduced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGAinduced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short-and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK-carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity.

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The Role of Thermogenesis in Antipsychotic Drug‐induced Weight Gain

Cited by 96 publications

References 52 publications

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

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

The acute effects of olanzapine on ghrelin secretion, CCK sensitivity, meal size, locomotor activity and body temperature

The Role of Hypothalamic H1 Receptor Antagonism in Antipsychotic-Induced Weight Gain

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