Impact of obesity-induced dysregulation of renin-angiotensin-aldosterone system in the hypothalamus on the homeostasis of energy metabolism.

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Angiotensin2(AT2) stimulates ROS production in peripheral tissues and promotes insulin resistance. We have indicated that aldosterone also induces insulin resistance through ROS production independent of AT2. To demonstrate the in vivo impact of MRA, we administrated mineralocorticoid antagonist(MRA) to the mice model of metabolic syndrome accompanied with steatohepatitis(NASH model). Administration of MRA effectively ameliorated systemic insulin resistance, dyslipidemia, and abnormal histological change in the liver. Diabetic models of both high-fat diet(HFD)-fed mice and db/db mice showed elevated expressions of proinflammatory cytokines in the hypothalamus. However, systemic administration of MRA did not affect these inflammatory changes in the hypothalamus. In bone marrow derived macrophage(BMDM), pretreatment of H2O2 or NAC, a ROS scavenger did not affect LPS-induced TNFαproduction. In addition, pretreatment with MRA, but not ARB effectively ameliorated the enhanced production.