Antipsychotic drugs relieve symptoms of schizophrenia as well as manic-depressive illness. The first generation drugs, however, were ineffective in many patients and failed to alleviate features such as emotional withdrawal reflecting the negative symptoms of schizophrenia. A new generation, atypical antipsychotic drugs (AAPDs), help non-responders, ameliorate negative symptoms, have fewer side-effects and so have emerged as some of the most widely used of all drugs. However, their use has been hampered by adverse metabolic side effects including severe weight gain elicited by some of those agents, sometimes doubling patient weights and with no clear cut explanation. We have found that the drugs that cause weight gain potently and selectively activate the enzyme AMP-kinase (AMPK) in the hypothalamic area of the brain in discrete nuclei which regulate eating behavior. This activation occurs secondary to the drugs' blocking the histamine H1 receptor for histamine, which, besides its roles in allergy, is a neurotransmitter in the feeding centers of the hypothalamus. Our preliminary studies indicate that inositol polyphosphate multikinase (IPMK), which utilizes one of the downstream molecules (inositol 1,4,5-triphosphate) produced upon histamine H1 receptor activation, is required for AMPK regulation. Also, the expression level of IPMK in the hypothalamus is modulated by energy balance. These intriguing observations led us to hypothesize that IPMK is the main mediator between histamine H1 receptor and AMPK regulation in the hypothalamus. Hence, in this proposal we will investigate the novel role of IPMK on AMPK modulation and energy homeostasis. We will characterize the molecular mechanism by which IPMK regulates AMPK modulation in the hypothalamus (Aim1). Moreover, we will investigate the posttranslational modification of IPMK, which can lead to a change of eating behavior via AMPK modulation (Aim 2). Finally, the contribution of IPMK in energy homeostasis and AAPDs-mediated weight gain in animal model will be investigated utilizing ipmkloxP/loxP mice (Aim3). Together, these studies will unveil not only the molecular basis of AAPD-mediated weight gain but also a novel signaling mechanism by which appetite is regulated in the hypothalamus. Accordingly, more efficient and effective strategies could be developed to manage the patients experiencing APPD-related metabolic side effects. PUBLIC HEALTH RELEVANCE: The use of second generation antipsychotic drugs greatly improved the treatment of psychosis such as schizophrenia but its unexpected metabolic side effects such as weight gain hampered their use. These side effects have a significant effect on their health implication as well as patient's low self-esteem and, consequently on low compliance. Hence, it is upmost importance to identify the molecular mechanism of how AAPDs lead to an excessive weight gain.