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 PI3Kalpha knockout mice (PI3K alphaAdQ). PI3Kalpha AdQ mice and PI3Kalpha F/F control mice showed similar adiposity, indicating compensation from another PI3K activity. PI3Kbeta-selective inhibitors dumped AKT phosphorylation, specifically in the adipocytes of PI3K alpha AdQ mice. The PI3Kbeta-selective inhibitor GSK2636771 markedly increased serum FFA and insulin secretion in PI3Kalpha AdQ mice but not in PI3KalphaF/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 PI3Kalpha AdQ 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.

The Complex Interplay of Insulin Resistance and Metabolic Inflammation in Transition Dairy Cows

“…As described in Figure 2 , under normal physiological conditions, insulin binds to the insulin receptor located on the cellular membrane of insulin-sensitive tissues, primarily including muscle, AT, and the liver [ 16 , 79 ]. This interaction gives rise to a series of events that involve insulin receptor substrate signaling, ultimately leading to an increase in cellular glucose uptake and the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway [ 80 ]. This process can increase the expression of the gene that is responsible for encoding the glucose transporter-4 (Glut4), promoting the translocation and integration of these components into the cell membrane, thereby facilitating the transportation of sugar into the cells ( Figure 2 ).…”

Neuro-Vulnerability in Energy Metabolism Regulation: A Comprehensive Narrative Review

“…Insulin also functions as an adipostatic signal in the brain and reaches the brain via saturable transport. Glucose stimulates insulin production in the pancreas through body fat levels [ 110 ]. Thus, when obesity is present and insulin resistance is established, the pancreas secretes more insulin and excess insulin results in increased fat storage in the adipocytes [ 111 ].…”

An adipocentric perspective of pancreatic lipotoxicity in diabetes pathogenesis

“…In fact, stimulation of β3-adrenergic receptor in the AT induces insulin secretion while reducing blood glucose levels ( Grujic et al 1997 ). Similarly, a preprint recently demonstrated that acute AT-specific inhibition of PI3K activity leads to an increased insulin secretion without increasing glycaemia ( Becattini et al 2023 ). Both models are associated with increased FFA levels.…”