Adipocyte Lipid Chaperone aP2 Is a Secreted Adipokine Regulating Hepatic Glucose Production

Abstract

Proper control of hepatic glucose production is central to whole body glucose homeostasis and its disruption plays a major role in diabetes. Here we demonstrate that, although established as an intracellular lipid chaperone, aP2 is in fact actively secreted from adipocytes to regulate liver glucose metabolism. Fasting and lipolysisrelated signals regulate secretion of aP2 from adipocytes, and circulating aP2 levels are markedly elevated in mouse and human obesity. Recombinant aP2 stimulates glucose production and gluconeogenic activity in primary hepatocytes in vitro and in lean mice in vivo. In contrast, neutralization of secreted aP2 reduces glucose production and corrects the diabetic phenotype of obese mice. Hyperinsulinemiceuglycemic and pancreatic clamp studies demonstrated actions of aP2 in liver upon aP2 administration or neutralization. We conclude that aP2 is a novel adipokine linking adipocytes to hepatic glucose production and that neutralizing secreted aP2 may represent an effective therapeutic strategy for diabetes.

Ectopic Fatty Acid–Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury

“…FABP4 is secreted from adipocytes under regulation by the catecholamine‐induced lipolytic signal pathway, although FABP4 lacks an N‐terminal secretory signal sequence 7, 12, 13. The present study showed that secretion of FABP4 from endothelial cells was slightly, but significantly, enhanced by stimulation of isoproterenol, similar to that in the case of adipocytes.…”

“…FABP4 was secreted from HCAECs in a time‐dependent manner (Figure 2I), and the secretion of FABP4 was slightly, but significantly, enhanced in the presence of isoproterenol for 12 and 24 hours, which is known to increase secretion of FABP4 from adipocytes 12, 13. Secretion of FABP4 in the CM of Ad‐FABP4–transfected HCAECs was significantly greater than that in the CM of Ad‐Control–transfected HCAECs (Figure 2J).…”

“…Similarly, we demonstrated in the present study that treatment of vascular smooth muscle cells and vascular endothelial cells with recombinant FABP4 induced vascular inflammation, proliferative and migratory responses, and endothelial dysfunction. Recent studies have also demonstrated that neutralization of secreted FABP4 with an antibody to FABP4 could be a feasible approach for treatment of insulin resistance and type 2 diabetes mellitus 12, 41. In the present study, we revealed inhibitory effects of FABP4 neutralization using an antibody to FABP4 on proliferation, migration, and inflammatory response in vascular smooth muscle cells and on inflammatory response and endothelial dysfunction in vascular endothelial cells in vitro.…”

“…It has recently been reported that FABP4 is secreted from adipocytes in association with lipolysis via a nonclassical secretion pathway,12, 13 although there are no typical secretory signal peptides in the sequence of FABP4 5. FABP4 has also been shown to be secreted from macrophages,14 although the predominant contributors of circulating FABP4 are adipocytes rather than macrophages 12.…”

“…FABP4 has also been shown to be secreted from macrophages,14 although the predominant contributors of circulating FABP4 are adipocytes rather than macrophages 12. Previous studies demonstrated that circulating FABP4 acts as an adipokine, an adipocyte‐derived bioactive molecule, for the development of insulin resistance and atherosclerosis 12, 14. Furthermore, elevation of the circulating FABP4 level is associated with obesity, insulin resistance, hypertension, cardiac dysfunction, dyslipidemia, and atherosclerosis 15, 16, 17, 18, 19, 20, 21.…”