Regulation of Beta-catenin by GLP-1 in the Hypothalamus

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 824-833-GI Regulatory Peptides
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-825
Hayden John Leonard McEwen*1, Emmanuelle Cognard2, Sharon Rachel Ladyman1, Peter Robin Shepherd2 and David R. Grattan1
1University of Otago, Dunedin, New Zealand, 2University of Auckland, Auckland, New Zealand
Polymorphisms near the TCF7L2 gene resulting in its overexpression are strongly linked with susceptibility to type-2 diabetes, but the mechanisms involved are poorly understood. Given that TCF7L2 interacts functionally with beta-catenin, we have sought to understand how levels of beta-catenin might be involved in regulating processes controlling glucose metabolism.  These studies have shown that beta-catenin levels are regulated by glucose in pancreatic beta-cells and provided evidence for a role for beta-catenin in regulating insulin secretion downstream of cAMP (Cognard et. al. Biochem. J. vol 449 p803-811, 2012). Here we investigate whether beta-catenin is also regulated in key regions in the hypothalamus involved in regulation of metabolism. During fast/refeeding experiments in male Sprague-dawley rats, beta-catenin protein accumulated in neurons in regions of the hypothalamus associated with metabolism, within 1 hour. Expression of mRNA from genes known to associate with beta-catenin/TCF7L2 signaling also increased during this period. Given the time frame of these changes, GLP-1, an early acting metabolic hormone released during feeding, was investigated further as a candidate responsible for the observed changes. Exendin4, a GLP-1 analogue increased the total levels of beta-catenin and it’s associated gene transcripts in metabolic hypothalamic regions, similar to feeding. Exendin4 also increased levels of stabilizing phosphorylation at serine 552 and 675 on beta-catenin as well as dephosphorylation at serine 33, 37 and threonine 41, sites known to destabilize the molecule when phosphorylated. Analysis of various protein kinase pathways known to interact with these sites suggested that this effect was occurring through activation of protein kinase A. Using the hypothalamic cell line GT1-7, inhibition of protein kinase A reversed the stabilizing effects of exendin4 on beta-catenin through the decrease in serine 552 and 675 phosphorylation. The data indicates the beta-catenin is being regulated by GLP-1 in regions of the hypothalamus that regulate metabolism. Given that beta-catenin is known to regulate synaptic secretory vesicles we hypothesize that the alterations in beta-catenin may be a mechanism to regulate the strength of signals emanating from hypothalamic neurons.

(1) Cognard et. al. Biochem. J. vol 449 p803-811, 2012

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