Dominant Role of PI3K p110α over p110β in Insulin and β-Adrenergic Receptor Signalling

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.

Targeting PI3K/AKT signaling pathway in obesity

“…Selective knock-out of the PI3Kγ isoform in mice have been reported to prevent HFD-induced obesity and to elevate insulin sensitivity compared to wild-type animals [93,97]. Additionally, long-term tissue-specific inactivation of PI3Kα in the adipose tissue depot results in predominantly beneficial metabolic effects as it correlates with enhanced β-adrenergic signaling (browning of WAT) in obesity [17,25,107]. Even though fact that the mechanistic studies on PI3K inhibition to target obesity are controversial, they provide solid indicators that fine-tuning in PI3K/AKT signaling that is tissue-and context-specific worth exploration as therapeutic approach.…”

“…The early stages of obesity involve adipocyte hyperplasia, thus modulation in adipogenic transformation is a key approach in obesity management at this point [3,25]. The licorice (Glycyrrhiza glabra L.) root is widely exploited in the food industry as a natural flavor and sweetener.…”

“…Localization of the p110γ and p110δ isoforms is primarily restricted to immune cells [23], whereas p110α and p110β are ubiquitousthough they also exhibit isoform-specific cell-type-and context-dependent requirements [22,24]. Among class I PI3K isoforms p110α is the primary insulin responsive kinase in adipocytes and myotubes [17,25]. Simultaneously, the class I PI3Ks are the most exhaustedly investigated PI3Ks as drug targets in respect to metabolic regulation [17,24,26,27] and so the current review PI3K will refer to class I, unless stated otherwise.…”

Development and safety of PI3K inhibitors in cancer

“…In vitro, targeting p110γ with IPI-549 can reshape the tumour immune microenvironment and overcome resistance to checkpoint blockade therapy in myeloid cells (De Henau et al 2016 ). In vivo, IPI-549 remodels the suppressive tumour microenvironment alike by inhibiting p110γ in both murine pancreatic cancer and melanoma models (Zhang et al 2019 ). Furthermore, the codelivery of IPI-549 and silibinin to breast tumours can act synergistically (Jiang et al 2020 ).…”