Liraglutide stimulates the beta-catenin signaling cascade in mouse epididymal fat tissue
JOURNAL OF MOLECULAR ENDOCRINOLOGY(2022)
Abstract
Although canonical Wnt signaling pathway activation was shown to negatively regulate adipogenesis, recent investigations suggest that Wnt pathway effectors TCF7L2 and beta-catenin (beta-cat) in adipose tissues are also involved in energy homeostasis during adulthood. In assessing the metabolic beneficial effect of GLP-1-based diabetes drugs in high-fat diet (HFD)-challenged mice, we observed that liraglutide treatment affected the expression of a battery of adipose tissue-specific genes, including those that encode adiponectin and leptin, mainly in epididymal white adipose tissue (eWAT). Fourteen-week HFD challenge repressed TCF7L2 and beta-cat S675 phosphorylation in eWAT, while such repression was reversed by liraglutide treatment (150 mu g/kg body weight daily) during weeks 10-14. In Glp1r(-/-) mice, liraglutide failed in stimulating TCF7L2 or beta-cat in eWAT. We detected Glp1r expression in mouse eWAT and its level is enriched in its stromal vascular fraction (SVF). Mouse eWAT-SVF showed reduced expression of Tcf7l2 and its Tcf7l2 level could not be stimulated by liraglutide treatment; while following adipogenic differentiation, rat eWAT-SVF showed elevated Tcf7l2 expression. Direct in vitro liraglutide treatment in eWAT-SVF stimulated CREB S133, beta-cat S675 phosphorylation, and cellular cAMP level. Thus, cAMP/beta-cat signaling cascade can be stimulated by liraglutide in eWAT via GLP-1R expressed in eWAT-SVF.
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Key words
beta-catenin, eWAT, GLP-1R, liraglutide, SVF, TCF7L2
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