Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats

Abstract

Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.

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

“…In hypothalamic tissue slices, the level of pAMPK can be enhanced markedly by olanzapine, which indicates that the weight gain/obesity side-effects associated with olanzapine is mediated by activation of hypothalamic AMPK linked to blockade of the histaminergic H 1 R [63]. Further in vivo studies in a rat model showed that the pAMPK level was upregulated by olanzapine administration correlated with changes in weight gain [56,64,65]. Additionally, administration of olanzapine by acute ICV infusion increased hypothalamic pAMPK expression [98,99].…”

“…It was confirmed that Intracerebroventricular (ICV) injection of the H 1 R agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) inhibited food intake [56]. [57,58,14,59].…”

“…Several animal studies found that olanzapine could modulate histaminergic neurotransmission for the regulation of food intake and weight gain in rats [62,56,63]. Olanzapine treatment upregulated mRNA expression and protein levels of hypothalamic H 1 R, which was correlated with hyperphagia and weight gain induced by olanzapine [56,64,65]. Similarly, clinical studies demonstrated patients treated with antipsychotics showed a significant correlation between the genetic variants of H 1 R (rs346074 -rs346070), BMI (body mass index) and obesity [66,67].…”

“…In particular, H 1 R blockade is recognised as a predominant target for SGA-induced weight gain compared with other receptors [4,60,61]. Several animal studies found that olanzapine could modulate histaminergic neurotransmission for the regulation of food intake and weight gain in rats [62,56,63]. Olanzapine treatment upregulated mRNA expression and protein levels of hypothalamic H 1 R, which was correlated with hyperphagia and weight gain induced by olanzapine [56,64,65].…”

“…Since histamine cannot pass the blood-brain barrier, direct peripheral H 1 R antagonism by SGA treatment may also contribute to the obesity side-effects [13,56,64]. The H 1 R antagonistic affinity of SGAs is significantly correlated not only with increased body weight and adiposity, but also with insulin-resistance in schizophrenia patients [68,60,69].…”