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

Abstract

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.

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

“…Moreover, deprivation of food predominantly led to activation of H 1 R expression in the hypothalamic Arc [13,55]. It was confirmed that Intracerebroventricular (ICV) injection of the H 1 R agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) inhibited food intake [56].…”

“…Therefore, it is extremely important to prevent and treat weight gain/obesity induced by SGAs. It has been suggested that the histamine H 1 R, its downstream pathways and associated neuropeptide are involved in the SGA-induced weight gain/obesity side-effects [6,12,13]. It has been reported that betahistine acts as modulator for the histaminergic system through its H 1 R-agonsitic and H 3 R-antagonsitic properties in the brain [167,203].…”

“…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].…”

“…Additionally, administration of olanzapine by acute ICV infusion increased hypothalamic pAMPK expression [98,99]. Therefore, besides H 1 R itself, its downstream AMPK signals are also valuable targets for treating SGA-induced weight gain/obesity side-effects [12,13] (summarized in Figure 1). …”

Effects of olanzapine and betahistine co-treatment on serotonin transporter, 5-HT2A and dopamine D2 receptor binding density

“…The binding affinities of olanzapine to these neurotransmitter receptors are ranked in the following order: H 1 R>5-HT 2 R>D 2 R>αR and M 1 R (Uchida et al, 2007). Since a number of studies have shown that H 1 R plays a key role in olanzapine induced weight gain/obesity (Kim et al, 2007, Han et al, 2008a, He et al, 2013, H 1 R could be a therapeutic target for controlling olanzapine-induced weight gain side-effects. Recently we found in a rat model that olanzapine-induced weight gain can be partially reduced (-45%) by co-treatment with betahistine (an H 1 R agonist and H 3 R antagonist) .…”