DEsire - DEP-1 as potential modulator of cerebral insulin resistance and emotional behavior

点击翻译按钮获取中文摘要

More than 650 million people worldwide are overweight and 400 million suffer from diabetes. Insulin resistance, a condition described by an inadequate response to insulin, characterizes obesity and diabetes. Importantly, insulin resistance, often triggered by diet-induced obesity, not only manifests in peripheral tissues but also in the brain. Therefore, diabetes and insulin resistance are associated with altered brain function, cognition impairment and mood disorders. A serious category of mood change involves depression. Obese patients are at an increased risk of depression. Vice versa, depressed patients develop diabetes more often. The insulin and IGF-1 receptor (IR, IGF-1R), both receptor tyrosine kinases, play a relevant role in modulating neuronal functions. These receptors are expressed throughout the brain in areas affecting metabolism, cognition and mood. We could show that in mice an IR deficiency in the brain results in depressive-like behavior and anxiety.Tyrosine phosphorylation and thus the function of both receptors is negatively regulated by protein tyrosine phosphatases (PTPs). Increased expression of PTPs is present in both mice with insulin resistance and in mice characterized by depressive-like behavior. We were able to show that the reduction of the PTP density-enhanced phosphatase-1 (DEP-1) protects against diet-induced insulin resistance. Unpublished own data show that decreased expression of DEP-1 in neuronal cells enhances insulin-mediated tyrosine phosphorylation of the IR and IGF-1R. In addition, brains of obese, insulin-resistant mice show increased expression of DEP-1. Also, diabetic patients are characterized by increased DEP-1 gene expression and genetic variations of the DEP-1 gene locus associate with altered sleep patterns and nightmares. Therefore, we hypothesize that DEP-1 is a hitherto unidentified modulator of cerebral insulin resistance that affects both metabolism and emotional behavior.DEP-1 will be postnatally deleted in brain structures implicated in insulin and dopamine signaling in order to investigate the function of DEP-1 on metabolism and emotional behavior over time in lean and high fat diet-fed mice. For this, CamKIIα Cre mice are bred with DEP-1lox/lox mice. Moreover, using N2a dopaminergic neurons, we characterize the interaction of IR and IGF-1R with DEP-1, including the impact of DEP-1 on synaptic plasticity. Applying a proximity ligation assay the spatial brain distribution of IR/IGF-1R, DEP-1 and their interaction in vivo will be assessed. Finally, we analyze the metabolic regulation of PTP activity in different brain areas of the dopaminergic system by tyrosine dephosphorylation assays.The overall goal is in the characterization of DEP-1 as hitherto unrecognized potential modulator of cerebral insulin resistance and emotional behavior.