Differential effects of C1q/tumor necrosis factor-related proteins on cardiomyocyte glucose metabolism

Background: The adipose tissue-derived cytokine adiponectin plays a major role in glucose metabolism. A family of adiponectin paralogs, designated as C1q/tumor necrosis factor-alpha-related proteins (CTRPs) and comprising 15 members, has recently been discovered. While independent CTRP receptors have not been identified so far, the adiponectin receptor AdipoR1 has been suggested to be involved in CTRP signaling. However, there are no data on CTRP effects on glucose metabolism in cardiomyocytes available so far.

Results: Glucose uptake and translocation of the insulin-dependent glucose transporter GLUT-4 was significantly stimulated by CTRP2, CTRP7, CTRP9 and CTRP13 but not by the other CTRPs. CTRP2, CTRP7, CTRP12 and CTRP15 induced a significant upregulation of GLUT-1 mRNA, while GLUT-4 was upregulated by CTRP2, CTRP7, CTRP9 and CTRP13. All investigated CTRPs except CTRP1 and CTRP6 induced an increase in phosphofructokinase mRNA expression. Hexokinase was upregulated by CTRP6, CTRP10 and CTRP12, pyruvate kinase was upregulated by CTRP7. CTRP2, CTRP7, CTRP 9 and CTRP13 resulted in an activation of AMPK, p44/42 MAPK and Akt in cardiomyocytes. Inhibition of AMPK by adenine 9-β-D-arabinofuranoside resulted in a blunted glucose uptake and GLUT-4 translocation in response to these CTRPs. Knockdown of AdipoR1 but not of AdipoR2 blocked the CTRP-induced AMPK-phosphorylation and glucose uptake. In addition, CTRP3 and CTRP13 induced an AMPK-independent tyrosine phosphorylation of IRS-1.

Conclusion: The adiponectin paralogs CTRP2, CTRP7, CTRP9 and CTRP13 enhance glucose uptake and GLUT4 translocation in cardiomyocytes through an AdipoR1 and AMPK-dependent signaling pathway. CTRPs may provide a therapeutic target in metabolic diseases such as diabetes and obesity.