Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions

Abstract

Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.

Physiological and pathophysiological roles of adiponectin and adiponectin receptors in the integrated regulation of metabolic and cardiovascular diseases

“…16 We confirmed that AdipoR1 or R2 knockout mice showed abrogation of AdipoR1 or R2 protein, respectively. In wild-type mice, adiponectin binds specifically to hepatocytes, whereas targeted disruption of both AdipoR1 and R2 completely abrogated adiponectin-specific binding to hepatocytes.…”

“…These data indicated that AdipoR1 and R2 serve as the major AdipoRs in vivo. 16 AdipoR1 knockout mice and double knockout mice exhibited insulin resistance and impaired glucose tolerance, whereas AdipoR2 knockout mice exhibited insulin resistance without glucose intolerance. These data indicated that AdipoR1 and R2 play physiologically important roles in the regulation of insulin sensitivity and glucose metabolism in vivo.…”

Undernutrition during suckling in rats elevates plasma adiponectin and its receptor in skeletal muscle regardless of diet composition: a protective effect?

“…36 Fatty acids are critical determinants of insulin resistance and we investigated the expression of CPT-1, which contributes to the utilization of energy and fatty-acid metabolism by increasing mitochondrial lipid oxidation. 11 CPT-1 expression was elevated in rats from ULs, regardless of their diet after weaning, suggesting that there may be some long-term effects of early undernourishment on fatty-acid oxidation and metabolism.…”

Lack of direct effect of adiponectin on vascular smooth muscle cell BKCa channels or Ca2+ signaling in the regulation of small artery pressure-induced constriction

“…2010; Yamauchi et al. 2007, 2002). Fesus and colleagues were the first group to show a vasodilation to adiponectin, demonstrating a robust effect of adiponectin at healthy human serum concentrations (3  μ g/mL) on wire mounted rat or mouse aorta or mouse mesenteric arteries preconstricted with serotonin (Fesus et al.…”