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Mechanisms of Adiponectin Action: Implication of Adiponectin Receptor Agonism in Diabetic Kidney Disease

机译:脂联素作用机制:脂联素受体激动在糖尿病肾病中的意义

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摘要

Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.
机译:脂联素是一种由脂肪细胞分泌的脂肪因子,通过其抗炎,抗纤维化和抗氧化作用,在糖尿病和代谢综合征的环境中发挥有利作用。它通过诱导AMP激活的蛋白激酶(AMPK)磷酸化并通过脂联素受体(AdipoR)1和AdipoR2分别增加过氧化物酶体增殖物激活的受体(PPAR)-α的表达来介导脂肪酸代谢,进而激活PPARγ共激活子1 alpha。 (PGC-1α),增加酰基辅酶A氧化酶的磷酸化,并上调参与能量消耗的解偶联蛋白。此外,脂联素独立于AMPK,可有效刺激与其两个受体相关的神经酰胺酶活性,并增强神经酰胺分解代谢和抗凋亡代谢产物鞘氨醇1磷酸酯(S1P)的形成。具有胰岛素抵抗,2型糖尿病和心血管疾病风险的肥胖患者中循环脂联素水平低,以及蛋白尿状态的脂联素表达增加,表明脂联素在减轻明显的糖尿病形成过程中进一步减轻肾脏损伤方面具有保护性和补偿性作用肾脏疾病(DKD)。我们建议将口服活性合成脂联素受体激动剂AdipoRon作为恢复DKD而不引起全身不良反应的有希望的药物。此处揭示了其通过增强AMPK /PPARα途径和通过AdipoRs的神经酰胺酶活性而对脂质毒性和氧化应激的肾脏保护作用。

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