Abstract
Attribution of specific roles to the two ubiquitously expressed PI 3-kinase (PI3K) isoforms p110α and p110β in biological functions they have been implicated, such as in insulin signalling, has been challenging. While p110α has been demonstrated to be the principal isoform activated downstream of the insulin receptor, several studies have provided evidence for a role of p110β. Here we have used isoform-selective inhibitors to estimate the relative contribution of each of these isoforms in insulin signalling in adipocytes, which are a cell type with essential roles in regulation of metabolism at the systemic level. Consistent with previous genetic and pharmacological studies, we found that p110α is the principal isoform activated downstream of the insulin receptor under physiological conditions. p110α interaction with Ras enhanced the strength of p110α activation by insulin. However, this interaction did not account for the selectivity for p110α over p110β in insulin signalling. We also demonstrate that p110α is the principal isoform activated downstream of the β-adrenergic receptor (β-AR), another important signalling pathway in metabolic regulation, through a mechanism involving activation of the cAMP effector molecule EPAC1. This study offers further insights in the role of PI3K isoforms in the regulation of energy metabolism with implications for the therapeutic application of selective inhibitors of these isoforms.
Highlights
Consistent with a previous study which demonstrated that functional Ras is required for maximal p110α activation by insulin [6], we show that embryonic fibroblasts from mice with p110α-Ras binding domain (RBD)
In the present study we have revisited the question of the relative contribution of each of the ubiquitously expressed PI 3-kinase (PI3K) isoforms, p110α and p110β, in the insulin signalling pathway and we have assessed the potential involvement of p110β in the β-adrenergic receptor (β-AR)
With regards to the relative contribution of each of the two isoforms to insulin receptor signalling, our experiments with the use of isoform-selective p110α and p110β inhibitors presented here are consistent with the previous reports that p110α is the principal isoform activated downstream of the insulin receptor [2,3]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. We have sought to dissect the molecular mechanism of PI3K activation by β-AR For this purpose, we have used murine brown adipocytes from wild-type or adipose tissue-specific p110α deleted mice as well as 3T3-L1 adipocytes in conjunction with treatment with p110α- and p110β-selective inhibitors. We show that p110β has no substantial contribution to β-AR stimulation of Akt and that the cAMP-activated guanine nucleotide exchange factor (GEF) EPAC1 is a key mediator in the mechanism of p110α activation by β-AR These studies further clarify the roles of the ubiquitously expressed PI3K isoforms in key metabolic pathways and add important information in light of the ongoing efforts for therapeutic application of PI3K isoform-selective inhibitors
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