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Τετάρτη 7 Φεβρουαρίου 2018

A novel role of the corticotropin-releasing hormone (CRH) regulating peptide, teneurin-1 C-terminal associated peptide (TCAP-1), on glucose uptake into the brain

Abstract

Teneurin C-terminal associated peptide (TCAP) is an ancient paracrine signaling agent that evolved via lateral gene transfer from prokaryotes into an early metazoan ancestor. Although it bears structural similarity to corticotropin-releasing hormone (CRH), it inhibits the in vivo actions of CRH. The TCAPs are highly expressed in neurons where they induce rapid cytoskeletal rearrangement and are neuroprotective. Because these processes are highly energy dependent, this suggests that TCAP has the potential to regulate glucose uptake as glucose is the primary energy substrate in brain, and neurons require a steady supply to meet the high metabolic demands of neuronal communication. Therefore, the objective of this study was to assess the effect of TCAP-mediated glucose uptake in the brain and in neuronal cell models. TCAP-mediated 18F-deoxyglucose (FDG) uptake into brain tissue was assessed in male wild type Wistar rats by functional positron emission tomography (fPET). TCAP-1 increased FDG uptake by over 40% into cortical regions of the brain, demonstrating that TCAP-1 can significantly enhance glucose supply. Importantly, a single nanomolar injection of TCAP-1 increased brain glucose after 3 days and decreased blood glucose after one week. This is corroborated by decreased serum concentration of insulin and increased serum concentration of glucagon. In immortalized hypothalamic neurons, TCAP-1 increased ATP production and enhanced glucose uptake by increasing glucose transporter recruitment to the plasma membrane likely via AKT and MEK/ERK phosphorylation events. Together this data demonstrates that TCAP-1 increases glucose metabolism in neurons, and may represent a peptide signaling agent that regulated glucose uptake before insulin and related peptides.

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