The time-dependent role of brain histaminergic system and associated AMPK signaling in olanzapine-induced obesity

Treatment with second generation antipsychotics (SGAs), particularly clozapine and olanzapine, is associated with severe obesity side-effects. Histamine H1 receptor (H1R) antagonism has been identified as a main cause of SGA-induced obesity, but its molecular mechanisms remain unclear. The hypothalamus and brainstem dorsal vagal complex (DVC) are well-documented in the regulation of food intake and body weight. Using an established olanzapine-induced obesity rat model, this study investigated the role of brain histaminergic system and its associated AMP-activated protein kinase (AMPK) signaling in the hypothalamus and DVC at different stages (early acceleration, middle new equilibrium, and late heavy weight maintenance) of olanzapine-induced obesity. Together, the findings reveal that the time-dependent alterations of HDC, H1R and H3R induced by olanzapine may largely contribtue to the progressive development of obesity. Olanzapine activated the hypothalamic and DVC AMPK signaling via the H1R blockade, leading to hyperphagia and weight gain. With prolonged treatment, the H1R blockade contributed to weight gain via mechanisms other than AMPK, possibly by decreasing energy expenditure. A pharmacological treatment targeting the H1R– AMPK signaling may be an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.