Depression is a severe and common mental disorder and often coexists with metabolic disorders such as diabetes. Therefore, the identification and characterization of therapeutic targets that are potentially beneficial for the treatment of both depression and diabetes would be of great clinical significance. Adiponectin, a hormone secreted almost exclusively by white adipose tissue, is well recognized as an anti-diabetic adipokine. We have demonstrated that adiponectin insufficiency increases susceptibility to depression-like symptoms. By contrast, administration of exogenous adiponectin to the brain produces antidepressant-like effects in normal weight mice and in obese diabetic mice, suggesting a critical role for adiponectin in depressive-like behaviors. The goal of this project i to define the molecular and cellular mechanisms of adiponectin actions on depressive behaviors. Adiponectin receptors, AdipoR1 and AidpoR2, display distinct expression patterns in the hippocampus and medial prefrontal cortex (mPFC), two key brain regions implicated in depression and the therapeutic actions of antidepressants. Central injection of adiponectin induces neuronal activation and stimulates p38MAPK, an upstream activator of the inhibitory phosphorylation site of GSK-3b. Moreover, adiponectin has been shown to stimulate hippocampal neurogenesis in vitro. Based upon these findings, we hypothesize that adiponectin regulates depressive behaviors in a brain-region, receptor-specific manner through distinct molecular and cellular mechanisms. We propose to determine the region-specific roles of AdipoR1 and AdipoR2 in the development of depressive-like behaviors and in mediating the antidepressant-like effect of adiponectin, identify the signaling cascade that mediates actions of adiponectin on depressive-like behaviors, and determine whether neurogenesis contributes to the behavioral effect of adiponectin. These studies will provide novel insights into adipokine regulation of mood-related behaviors and lead to the development of novel therapies for depression.
Depression is a highly prevalent mood disorder and is often associated with other medical conditions. Individuals with diabetes are at significantly greater risk for developing depression. Therefore, it is of clinical significance to identify novel therapeutic targets with beneficial effects on both depression and diabetes. The studies proposed in this project will enhance our understanding of the pathogenesis of depression and provide a potential novel treatment strategy for depression, especially for treating depression comorbid with diabetes.
|Guo, M; Li, C; Lei, Y et al. (2017) Role of the adipose PPAR?-adiponectin axis in susceptibility to stress and depression/anxiety-related behaviors. Mol Psychiatry 22:1056-1068|
|Zhang, D; Wang, X; Wang, B et al. (2017) Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors. Mol Psychiatry 22:1044-1055|
|Zhang, Di; Wang, Xuezhen; Lu, Xin-Yun (2016) Adiponectin Exerts Neurotrophic Effects on Dendritic Arborization, Spinogenesis, and Neurogenesis of the Dentate Gyrus of Male Mice. Endocrinology 157:2853-69|
|Carrier, Nicole; Wang, Xuezhen; Sun, Linshan et al. (2015) Sex-Specific and Estrous Cycle-Dependent Antidepressant-Like Effects and Hippocampal Akt Signaling of Leptin. Endocrinology 156:3695-705|
|Wang, X; Zhang, D; Lu, X-Y (2015) Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin. Mol Psychiatry 20:509-19|
|Guo, M; Lu, X-Y (2014) Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates. Transl Psychiatry 4:e486|
|Guo, Ming; Huang, Tung-Yi; Garza, Jacob C et al. (2013) Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours. Int J Neuropsychopharmacol 16:857-67|