Astrocytic TrkB in diet-induced obesity

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 DESCRIPTION (provided by applicant): In rodent diet-induced obesity (DIO) models, long-term exposure to high-fat diets (HFD) increases the expression of proinflammatory genes, such as the genes encoding IL-1β, IL-6, TNFα, SOCS3 and IKKβ, in the hypothalamus. HFD feeding also induces reactive gliosis, as evidenced by an increase in both number and size of microglia and astrocytes, and neuronal loss in the mediobasal hypothalamus (MBH). The inflammatory response and gliosis in the MBH occur within 3 days of HFD exposure, which is much faster than the inflammatory response in peripheral tissues that takes more than 4 weeks of HFD feeding. Some studies suggest that saturated fatty acids derived from a HFD recruits and activates microglia in the MBH, which in turn orchestrate hypothalamic inflammation by releasing cytokines such as TNFα. However, it remains unknown whether hypothalamic microgliosis is sufficient to cause obesity and whether astrogliosis also play any role in the pathogenesis of DIO. Brain-derived neurotrophic factor (BDNF) is among the 18 genes that have been associated with human obesity in genome-wide association studies. Furthermore, BDNF and its receptor TrkB, along with leptin/leptin receptor and alpha melanocyte-stimulating hormone/melanocortin-4 receptor, are among a few ligand-receptor pairs whose signaling deficiencies lead to severe obesity in human individuals. In addition to the full-length TrkB receptor tyrosine kinase (TrkB-FL), the TrkB gene also produces truncated TrkB (TrkB-T) that misses the tyrosine kinase domain. We propose to test the hypothesis that HFD induces astrocytic TrkB-T expression, which leads to astrogliosis, down-regulation of neuronal BDNF-to-TrkB-FL signaling, and subsequent obesity. We will test this hypothesis by examining energy balance, hypothalamic inflammation, and hypothalamic gliosis in astrocyte-specific TrkB-T knockout mice fed a high-fat diet. If this exploratory research project demonstrates that this hypothesis is correct, we will provide evidence to indicate an important role for astrogliosis and TrkB-T in the pathogenesis of DIO. Future studies on the regulation of TrkB-T gene expression could provide targets for developing treatments for the common form of obesity.