Adiponectin receptors in revascularization and metabolic dysfunction
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Abstract
Adipose-derived secreted factors termed adipokines affect both metabolic and cardiovascular function. Previous studies have shown that ablation of the adipokine adiponectin leads to endothelial and metabolic dysfunction, whereas its overexpression is protective. However, the receptor(s) mediating the protective effects of adiponectin on the vasculature are not known. The goal of this study was to elucidate the role of three adiponectin receptors: T-cadherin, AdipoR1, and AdipoR2, in the revascularization response to chronic ischemia and the metabolic adaptation to diet-induced obesity.
T-cadherin is a membrane protein which localizes adiponectin to the vascular endothelium. In a model of peripheral artery disease, T-cadherin-deficient mice phenocopy adiponectin-deficient mice such that both strains display impaired blood flow recovery compared to wild-type controls. Adiponectin delivery rescued the impaired revascularization phenotype in adiponectin-deficient mice, but not in T-cadherin-deficient mice. In cultured endothelial cells, T-cadherin deficiency prevented the ability of adiponectin to promote cellular migration and proliferation. These data highlight a previously unrecognized role for T-cadherin in limb revascularization, and show that it is essential for mediating the vascular actions of adiponectin.
AdipoR1- and AdipoR2-deficient mice were also subjected to hind limb ischemia surgery to determine their role in vascular function. Blood flow recovery in AdipoR1-deficient mice was similar to wild-type; however, revascularization in AdipoR2-deficient mice was severely attenuated. Adiponectin administration enhanced the recovery of wild-type but not AdipoR2-deficient mice. These data show for the first time that AdipoR2 is functionally important in an in vivo model of vascular disease and that its expression is essential for the revascularization actions of adiponectin.
Since adiponectin also plays an important role in metabolic disease, T-cadherin, AdipoR1- and AdipoR2-deficient mice were evaluated in a model of diet-induced obesity. No differences in metabolic function were detected at baseline between wild-type and any of these knockout strains. On a high-calorie diet, T-cadherin-deficient mice developed glucose intolerance despite an attenuated weight gain. Strikingly, AdipoR1-deficiency resulted in severe metabolic dysfunction and increased body weight, whereas, AdipoR2-deficiency was protective against diet-induced weight gain and metabolic perturbations. These studies show that T-cadherin, AdipoR1 and AdipoR2 have important yet divergent roles in mouse models of vascular and metabolic disease.
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Thesis (Ph.D.)--Boston University