title: Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice.
abstract: OBJECTIVE
  In obesity, chronic low-grade inflammation and overproduction of reactive oxygen species (ROS) in fat contribute to the development of metabolic syndrome. Suppression of inflammation and ROS production in fat may attenuate the metabolic syndrome. Activation of mineralocorticoid receptor (MR) promotes inflammation in heart, kidney, and vasculature via ROS generation. However, the significance of MR in fat remains elusive. Here we investigated whether MR blockade attenuates obesity-related insulin resistance and improves adipocyte dysfunction.
  
  
  RESULTS
  Obese ob/ob and db/db mice were treated with eplerenone, a MR antagonist, for 3 weeks. 3T3-L1 adipocytes were treated with aldosterone or H2O2, with and without eplerenone or MR-siRNA. High levels of MR mRNA were detected in adipose tissue of obese ob/ob and db/db mice. Eplerenone treatment significantly reduced insulin resistance, suppressed macrophage infiltration and ROS production in adipose tissues, and corrected the mRNA levels of obesity-related genes in obese mice. In 3T3-L1 adipocytes, aldosterone and H2O2 increased intracellular ROS levels and MR blockade inhibited such increases. H2O2 and aldosterone resulted in dysregulation of mRNAs of various genes related to ROS and cytokines, whereas MR blockade corrected such changes.
  
  
  CONCLUSIONS
  MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Hirata
authors.forename: Norikazu
authors.initials: N
authors.lastname: Maeda
authors.forename: Aki
authors.initials: A
authors.lastname: Hiuge
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hibuse
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Takuya
authors.initials: T
authors.lastname: Okada
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.forename: Iichiro
authors.initials: I
authors.lastname: Shimomura
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000077545:Eplerenone; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D000451:Mineralocorticoid Receptor Antagonists; D019255:NADPH Oxidases / Q000235:genetics; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000502:physiology; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000077545:Eplerenone; D019255:NADPH Oxidases