奥氮平治疗引发摄食行为异常及代谢紊乱的中枢调控机制

Olanzapine (OLZ) is one of the first-line antipsychotics but its chronic administration is often associated with severe metabolic side-effects characterized with obesity and even diabetes. So far the mechanisms of olanzapine-induced metabolic abnormalities are largely unknown. We have recently identified that OLZ administration for two months in human patients and animal models significantly upregulates plasma MIF (macrophage migration inhibitory factor) level which may contribute to the incidence of peripheral tissue insulin resistance. More interestingly, OLZ also increases MIF expression in hypothalamus that is associated with hyperphagia and obesity. It is however unclear how MIF in hypothalamus controls feeding behaviors and downstream signaling pathways following OLZ administration. Thus, our current study will investigate these mechanisms through utilizing positional brain injection and mini osmotic pump techniques and newly created hypothalamus-specific MIF knockout mice. We will perform our proposed experiments in cell-, organ- or animal-based models. Eventually, we will actively investigate the pharmacologic effects of ISO-1, an established MIF inhibitor in the treatment of olanzapine induced metabolic abnormalities. We believe that our work will not only bring mechanistic insights into the neurological basis of OLZ-induced behavioral changes, but also provide theoretic guidance and solid foundation for better design and continuous improvement of clinic anti-psychiatric treatments.

奥氮平（OLZ）是治疗精神疾病的一线用药，但服药后多数患者出现以肥胖为主要临床症状的代谢紊乱，甚至糖尿病。其机理不清。我们最新数据表明OLZ可能通过上调促炎症因子巨噬细胞迁移抑制因子（MIF）促进外周胰岛素抵抗，从而导致代谢紊乱；OLZ也可以诱发下丘脑区MIF水平增高，导致摄食增加。此发现为国际首次。然而这种OLZ诱导的下丘脑区MIF上调是否及如何调节摄食行为、参与OLZ诱发代谢紊乱的中枢行为尚不清楚。本研究拟采用下丘脑条件性MIF基因敲除小鼠及脑立体定位注射、微渗透泵等方法，首先从细胞、离体器官和在体动物三个层面研究下丘脑MIF调节摄食行为及对OLZ诱导代谢紊乱的中枢调控机制，并进一步探索利用MIF抑制剂ISO-1克服OLZ引发代谢紊乱的可能性。如获资助，本研究将有利于深入探讨OLZ诱发代谢紊乱的中枢调控机制，并为改善精神疾病临床药物治疗提供强有力的理论指导和实验依据。

奥氮平（OLZ）是治疗精神疾病的一线用药，但服药后多数患者出现以肥胖为主要临床症状的代谢紊乱，甚至糖尿病。其机理不清。我们最新数据表明OLZ可能通过上调促炎症因子巨噬细胞迁移抑制因子（MIF）促进外周胰岛素抵抗，从而导致代谢紊乱；OLZ也可以诱发下丘脑区MIF水平增高，导致摄食增加。此发现为国际首次。然而这种OLZ诱导的下丘脑区MIF上调是否及如何调节摄食行为、参与OLZ诱发代谢紊乱的中枢行为尚不清楚。本研究拟采用下丘脑条件性MIF基因敲除小鼠及脑立体定位注射、微渗透泵等方法，首先从细胞、离体器官和在体动物三个层面研究下丘脑MIF调节摄食行为及对OLZ诱导代谢紊乱的中枢调控机制，并进一步探索利用MIF抑制剂ISO-1克服OLZ引发代谢紊乱的可能性。如获资助，本研究将有利于深入探讨OLZ诱发代谢紊乱的中枢调控机制，并为改善精神疾病临床药物治疗提供强有力的理论指导和实验依据。