Redox-dependent and ligand-independenttrans-activation of insulin receptor by globular adiponectin

Abstract

Adiponectin/ACRP30 is an adipose tissue-derived hormone with antiatherogenic, antidiabetic, and insulin-sensitizing properties. Although the metabolic effects of adiponectin on glucose and lipid metabolism are well known, the signaling pathways triggered by adiponectin receptors remain to be elucidated. We report evidence that in hepatic cells, adiponectin stimulation produces a transient burst of reactive oxygen species (ROS) through activation of the small GTPase Rac1 and 5-lypoxigenase. Furthermore, adiponectin-induced oxidants cause the oxidation/inhibition of protein-tyrosine phosphatase (PTP) 1B, one of the major phosphotyrosine phosphatases involved in the control of insulin receptor phosphorylation. Adiponectin causes increased association of PTP1B to insulin receptor and the oxidation/ inhibition of the phosphatase, ultimately provoking the ligand-independent trans-phosphorylation of insulin receptor. We also report evidence that redox signaling plays a key role in both mitogen-activated protein kinase activation and hepatic glucose consumption induced by adiponectin. A diponectin/ACRP30 is an abundant adipocytederived circulating plasma protein with insulinsensitizing metabolic effects and vascular protective properties. 1 Adiponectin is composed of 2 structurally distinct domains, an N-terminal collagen-like domain and a C-terminal globular domain. Both the full-length and the globular form of the hormone have been observed in mammalian plasma. 2 Furthermore, adiponectin molecules can associate in the plasma to form trimers, hexamers, and high molecular weight forms whose biological activities are poorly understood. 3 Studies in humans and monkeys show that plasma adiponectin level significantly correlates with insulin sensitivity in the whole body. 4,5 Moreover, the hormone treatment improves diabetes in mice. 6 These findings identify adiponectin as an insulinsensitizing hormone and indicate that its reduced production might be related to the pathophysiology of insulin resistance. The physiological effects of adiponectin on glucose and lipid metabolism in the liver and in skeletal muscle are mediated by 2 receptors (AdipoR1 and AdipoR2) that have been identified recently. 7 These receptors contain 7-transmembrane domains but are structurally and functionally distinct from G-protein-coupled receptors. However, the signaling pathways responsible for the metabolic effects of adiponectin have been only partially elucidated. An involvement of AMP kinase (AMPK) activation has been indicated for both full-length and globular adiponectin (gAd) in muscle and only for the fulllength hormone in the liver, suggesting different organ targeting of the 2 adiponectin forms. 7 In muscle, AMPK activation has been correlated to fatty acid oxidation and

Adiponectin resistance and vascular dysfunction in the hyperlipidemic state

“…The regulation of these adipocytokines (already established to be related to obesity and diabetes) by APN suggest a molecular link between obesity and skeletal muscle IR. Recently, Fiaschi and colleagues reported the ability of APN in trans-activation of insulin receptor [67] . More specifically, APN stimulation produces a transient burst of reactive oxygen species (ROS), and causes the oxidation/inhibition of protein-tyrosine phosphatase (PTP) 1B in hepatic cells.…”

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…Indeed, gAd provokes a ligand-independent trans-phosphorylation of insulin receptor that occurs through the production of reactive oxygen species. The oxidants generated following gAd stimulation are important second messengers for glucose oxidation and glycogen production in hepatic cells [38]. Recent data report the involvement of a cross-talk between adiponectin and fibroblast growth factor 21 (FGF21) in the insulin-sensitizing effect of adiponectin.…”

Globular adiponectin induces differentiation and fusion of skeletal muscle cells

“…Recently, we reported that in hepatic cells the metabolic effects of globular adiponectin (gAd) are linked to a transient burst of reactive oxygen species (ROS). This oxidant producwww.cell-research.com | Cell Research Tania Fiaschi et al 585 npg tion leads to a ligand-independent trans-activation of the insulin receptor and mediates the intracellular signalling and metabolic effects of the gAd in liver [9]. In muscle, gAd has been correlated to fatty acid oxidation, glucose uptake and lactate production [10].…”