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Diabetes. 2018 Jun;67(6):1113-1127. doi: 10.2337/db17-1032. Epub 2018 Apr 4.

Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression of SREBF1-Mediated Lipogenic Pathway.

Author information

1
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
2
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan fukuhara@endmet.med.osaka-u.ac.jp.
3
Department of Adipose Management, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
4
Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Abstract

Recent studies have emphasized the association of adipose oxidative stress (Fat reactive oxygen species [ROS]) with the pathogenesis of metabolic disorders in obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivo remain unclear because no mouse model has been available in which oxidative stress is manipulated by targeting adipocytes. In this research, we generated two models of Fat ROS-manipulated mice and evaluated the metabolic features in diet-induced obesity. Fat ROS-eliminated mice, in which Cat and Sod1 were overexpressed in adipocytes, exhibited adipose expansion with decreased ectopic lipid accumulation and improved insulin sensitivity. Conversely, Fat ROS-augmented mice, in which glutathione was depleted specifically in adipocytes, exhibited restricted adipose expansion associated with increased ectopic lipid accumulation and deteriorated insulin sensitivity. In the white adipose tissues of these mice, macrophage polarization, tissue fibrosis, and de novo lipogenesis were significantly changed. In vitro approaches identified KDM1A-mediated attenuation of sterol-regulatory element-binding transcription factor 1 (SREBF1) transcriptional activities as the underlying mechanism for the suppression of de novo lipogenesis by oxidative stress. Thus, our study uncovered the novel roles of Fat ROS in healthy adipose expansion, ectopic lipid accumulation, and insulin resistance, providing the possibility for the adipocyte-targeting antioxidant therapy.

PMID:
29618580
DOI:
10.2337/db17-1032
[Indexed for MEDLINE]
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