Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice.
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.
Hirata
Ayumu
A
Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan.
Maeda
Norikazu
N
Hiuge
Aki
A
Hibuse
Toshiyuki
T
Fujita
Koichi
K
Okada
Takuya
T
Kihara
Shinji
S
Funahashi
Tohru
T
Shimomura
Iichiro
I
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
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