Adipocyte PI3K links adipostasis with basal insulin secretion through an adipoincretin effect

Abstract

Insulin secretion is governed by insulin-PI3K signaling. Resolving the mechanism of this feedback is necessary to understand how insulin operates. Mice lacking the insulin receptor, or AKT1 and AKT2 in adipocytes, are severely lipoatrophic. Thus, the role of adipocyte insulin-PI3K signaling in the control of insulin secretion remains unknown. Using adipocyte- specific PI3K knockout mice (PI3KAdQ) and a panel of isoform-selective PI3K inhibitors, we have found that PI3K and PI3K{beta} activities are functionally redundant in adipocyte insulin signaling. PI3K{beta}-selective inhibitors had no effect on adipocyte AKT phosphorylation in control mice but blunted AKT phosphorylation specifically in adipocytes of PI3KAdQ mice, demonstrating adipocyte-selective inhibition of PI3K signaling. Adipocyte-selective PI3K inhibition increased serum FFA and potently induced insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect was dissociated from blood glucose and blood glucose counterregulatory response. The contribution of lipolysis, lipid, and amino acid metabolism, and selected adipokines to the adipoincretin effect has been investigated. We conclude that basal insulin secretion is chiefly controlled by adipocyte PI3K signaling through the adipoincretin effect. This phenomenon reveals an essential role for adipocyte insulin-PI3K signaling in linking the rates of adipose tissue lipolysis with baseline insulin secretion during fasting.