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Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice
Ayumu Hirata1, Norikazu Maeda, Aki Hiuge
1Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2-B5 Yamada-oka, Suita, Osaka 565-0871, Japan.
Aims:
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.
Methods And 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.
Conclusion:
MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.
Insights
Mineralocorticoid receptor (MR) blockade reduces fat reactive oxygen species (ROS) and inflammation, improving insulin resistance in obesity. This suggests MR antagonism as a potential therapeutic strategy for metabolic syndrome.
Area of Science:
- Endocrinology
- Metabolic Syndrome Research
- Adipocyte Biology
Background:
- Obesity is linked to chronic inflammation and reactive oxygen species (ROS) in adipose tissue, contributing to metabolic syndrome.
- Mineralocorticoid receptor (MR) activation promotes inflammation and ROS in various organs, but its role in adipose tissue is unclear.
Purpose of the Study:
- To investigate if MR blockade can reduce obesity-related insulin resistance and improve adipocyte dysfunction.
- To explore the role of MR in fat tissue's inflammatory and oxidative stress pathways.
Main Methods:
- Obese mice (ob/ob and db/db) were treated with eplerenone, an MR antagonist.
- 3T3-L1 adipocytes were treated with aldosterone or H2O2, with and without MR blockade (eplerenone or MR-siRNA).
- Gene expression, ROS levels, and macrophage infiltration were analyzed.
Main Results:
- MR mRNA was elevated in adipose tissue of obese mice.
- Eplerenone treatment reduced insulin resistance, macrophage infiltration, and ROS production in obese mice.
- MR blockade in adipocytes prevented ROS increases and corrected gene expression related to ROS and cytokines.
Conclusions:
- MR blockade attenuates obesity-related insulin resistance.
- This effect is partly mediated by reducing ROS production and inflammation in adipose tissue.
- MR antagonism may offer a therapeutic approach for metabolic dysfunction in obesity.
