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

Abstract

Inhibitors of insulin-PI3K signaling potently induce insulin secretion in-vivo, demonstrating that insulin secretion is governed by feedback control. Resolving the mechanism of this feedback is necessary to understand hyperinsulinemia and insulin resistance and to develop optimal PI3K-targeted therapies. Adipose tissue-specific knockout mice for the insulin receptor, or AKT1 and AKT2, are severely lipodystrophic. Thereby, the role of adipocyte insulin signaling in the feedback control of insulin secretion remains unknown. To investigate insulin-PI3K signaling in the adipocyte in vivo, we generated adipocyte-specific PI3Ka knockout mice (PI3KaAdQ). PI3KaAdQ mice and PI3KaF/F control mice showed similar adiposity, indicating compensation from another PI3K activity. PI3Kb-selective inhibitors dumped AKT phosphorylation, specifically in the adipocytes of PI3KaAdQ mice. The PI3Kb-selective inhibitor GSK2636771 markedly increased serum FFA and insulin secretion in PI3KaAdQ mice but not in PI3KaF/F mice, demonstrating that insulin secretion is governed by adipocyte PI3K, a phenomenon that we name the adipoincretin effect. The adipoincretin effect can be induced in mice fasted overnight with decreasing glycemia. The effects of adipocyte-specific PI3K inhibition on insulin secretion and serum FFA could be partly dissociated by cotreating PI3KaAdQ mice with GSK2636771 and the lipolysis inhibitor nicotinic acid. The adipoincretin effect was associated with reduced plasma branched-chain amino acids, reduced serum leptin, and increased 3-hydroxybutyrylcarnitine. These results demonstrate that baseline insulin secretion and lipolysis are coregulated by adipocyte PI3K signaling to control adipostasis during fasting through an adipoincretin effect.