We previously demonstrated that oral supplementation with antioxidants induced hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis, attested by hypercorticoidism, through an up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal. This study analyzed the role of peroxisome proliferator-activated receptor (PPAR)-γ on HPA axis hyperactivity induced by N-acetyl-cysteine (NAC). Male Swiss-Webster mice were orally treated with NAC for 1, 3, 5, 10, 15, or 18 consecutive days. The PPAR-γ agonist rosiglitazone and/or antagonist GW9662 were daily-injected i.p. for 5 consecutive days, starting concomitantly with NAC treatment. Rosiglitazone treatment inhibited NAC-induced adrenal hypertrophy and hypercorticoidism. Rosiglitazone also significantly reversed the NAC-induced increase in the MC2R expression in adrenal, but not steroidogenic acute regulatory protein (StAR). NAC treatment reduces the expression of PPARγ in the adrenals, but rosiglitazone did not restore the expression of this cytoprotective gene. In addition, GW9662 blocked the ability of rosiglitazone to decrease plasma corticosterone levels in NAC-treated mice. In conclusion, our findings showed that antioxidant supplementation induced a state of hypercorticoidism through down-regulation of PPARγ expression in the adrenals, in a mechanism probably related to a down-regulation of ACTH receptor expression.

我们之前证明，通过上调肾上腺中促肾上腺皮质激素 (ACTH) 受体 (MC2R)，口服抗氧化剂可诱导下丘脑-垂体-肾上腺 (HPA) 轴的过度活跃，这由高皮质激素证明。本研究分析了过氧化物酶体增殖物激活受体 (PPAR)-γ 在 N-乙酰半胱氨酸 (NAC) 诱导的 HPA 轴过度活跃中的作用。雄性 Swiss-Webster 小鼠连续 1、3、5、10、15 或 18 天口服 NAC。PPAR-γ激动剂罗格列酮和/或拮抗剂GW9662连续5天每天腹腔注射，同时开始与NAC治疗。罗格列酮治疗可抑制 NAC 诱导的肾上腺肥大和高皮质激素。罗格列酮还显着逆转了 NAC 诱导的肾上腺中 MC2R 表达的增加，但不是类固醇急性调节蛋白 (StAR)。NAC 治疗降低了肾上腺中 PPARγ 的表达，但罗格列酮并未恢复该细胞保护基因的表达。此外，GW9662 阻断了罗格列酮降低 NAC 治疗小鼠血浆皮质酮水平的能力。总之，我们的研究结果表明，抗氧化剂补充剂通过下调肾上腺中 PPARγ 的表达来诱导高皮质激素状态，其机制可能与 ACTH 受体表达的下调有关。GW9662 阻断了罗格列酮降低 NAC 治疗小鼠血浆皮质酮水平的能力。总之，我们的研究结果表明，抗氧化剂补充剂通过下调肾上腺中 PPARγ 的表达来诱导高皮质激素状态，其机制可能与 ACTH 受体表达的下调有关。GW9662 阻断了罗格列酮降低 NAC 治疗小鼠血浆皮质酮水平的能力。总之，我们的研究结果表明，抗氧化剂补充剂通过下调肾上腺中 PPARγ 的表达来诱导高皮质激素状态，其机制可能与 ACTH 受体表达的下调有关。