JAK-STAT signaling and myocardial glucose metabolism

Abstract

JAK-STAT signaling occurs in virtually every tissue of the body, and so does glucose metabolism. In this review, we summarize the regulation of glucose metabolism in the myocardium and ponder whether JAK-STAT signaling participates in this regulation. Despite a paucity of data directly pertaining to cardiac myocytes, we conclude that JAK-STAT signaling may contribute to the development of insulin resistance in the myocardium in response to various hormones and cytokines.

Keywords: JAK; Janus kinase; SOCS; STAT; cardiac myocytes; glucose metabolism; insulin; insulin resistance; myocardium; signal transducer and activator of transcription; suppressor of cytokine signaling.

Figure 1.

Principal points of regulation of glucose metabolism in cardiac myocytes. Glucose enters cardiac myocytes by facilitated diffusion through GLUT (mostly GLUT4) transporters and to a minor extent by cotransport with sodium through SGLT1. Glycolysis yields pyruvate, which is converted to acetyl-CoA to undergo mitochondrial oxidation in the Krebs cycle. Principal points of regulation are transmembrane transport, regulated by translocation of GLUT4, the PFK-1 reaction, which is stimulated by F2,6BP, and activity of the pyruvate dehydrogenase complex, regulated by phosphorylation by PDH kinases or dephosphorylation by PDH phosphatases. See text for details. Abbreviations: AMPK, AMP-activated protein kinase; F1,6BP, fructose-1,6-bisphosphate; F2,6BP, fructose-2,6-bisphosphate; F6P, fructose-6-phosphate; GLUT1 or 4, facilitative glucose transporters; Ins, insulin; IRα/β, insulin receptor, subunit α, respectively β; PDC, pyruvate dehydrogenase complex; PDK1-4, pyruvate dehydrogenase kinase 1 to 4; PDPC1-2, pyruvate dehydrogenase phosphatase 1 or 2; PFK-1, 6-phosphofructo-1-kinase; PFK-2, 6-phosphofructo-2-kinase; SGLT1, sodium-glucose cotransporter 1; WISK, wortmannin-sensitive and insulin-stimulated protein kinase.

Figure 2.

Interference of JAK-STAT signaling with insulin signaling and glucose transport in cardiac myocytes. Top: Normal insulin signaling leading to Akt activation and translocation of GLUT4. Right: activation of JAK-STAT signaling by Ang II, LIF, and CT-1 leading to SOCS3 overexpression and GLUT4 repression. Left: disruption of insulin signaling by SOCS3, with dissociation and degradation of IRS-1. Bottom: sequestration of IRS-1 by JAK2 activated by the ligand-bound AGTR1. See text for details. Abbreviations: Ang II, angiotensin II; AGTR1, angiotensin receptor type 1; CT-1, cardiotrophin-1; gp130, glycoprotein 130; IRS-1, insulin receptor substrate 1; LIF, leukemia inhibitory factor; LIFR, LIF receptor; mTORC2, mammalian target of rapamycin complex 2; PDPK1, phosphoinositide-dependent protein kinase 1; PI3Kα, phosphoinositide 3-kinase α; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; pY, phosphotyrosine; SOCS3, suppressor of cytokine signaling 3.