The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

Abstract

Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome. ABSTRACTBased on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGAinduced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium.Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/ agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome.

Decreased 5‐HT2cR and GHSR1a interaction in antipsychotic drug‐induced obesity

“…This result is also observed in the preclinical rat model, as plasma ghrelin is increased after 8 d of olanzapine treatment, but declines to normal levels after 16 d, despite the continued progression of hyperphagia and weight gain in these rats . Therefore, drug effects on ghrelin secretion, both directly from its origin in the stomach or indirectly via vagal efferent commands from the brain , cannot be the only mechanism by which SGAs increase hypothalamic ghrelin signalling and stimulate obesity. We recently reported that olanzapine increases hypothalamic GHSR1a protein (18–28%) and mRNA (64–92%) expression, independent of treatment duration .…”

“…The GHSR1a stimulates several signalling pathways ; however, research has highlighted an important role for the 5′ AMP‐activated protein kinase (AMPK) pathway in ghrelin‐induced food intake via NPY and AgRP up‐regulation. For example, ghrelin increases hypothalamic AMPK in rodents in vivo and in NPY neurons in vitro , GHSR1a knock‐out mice do not exhibit ghrelin‐induced hypothalamic AMPK activation or hyperphagia, while AMPK inhibition decreases ghrelin‐stimulated food intake .…”

Olanzapine reduced brown adipose tissue thermogenesis and locomotor activity in female rats

“…While second-generation antipsychotics (SGAs) have been widely prescribed as the primary treatment for patients with schizophrenia and other psychiatric diseases, excessive body weight gain associated with the use of SGAs, in particular olanzapine and clozapine, has attracted increasing concerns from patients, clinicians, and medical researchers (Zhang et al , 2013a). This weight gain side-effect of SGAs, along with other metabolic side-effects, could lead to increased morbidity and mortality, and poor compliance to the antipsychotic drug for patients (Deng, 2013).…”

Association Study of 60 Candidate Genes with Antipsychotic-induced Weight Gain in Schizophrenia Patients

“…It mediates the perception of hunger or appetite for meal initiation via receptors in the hypothalamus [15,16]. Clinical and animal data indicated that antipsychotic treatments modulate circulating ghrelin levels, and some studies have suggested that altered ghrelin signaling might contribute to an increase in food intake and weight gain during antipsychotic treatment [17,18]. However, there has been no pharmacogenetic study reporting an association between the ghrelin gene, GHRL and AIWG.…”