Open AccessEndothelium‐specific CYP 2J2 overexpression attenuates age‐related insulin resistance
Author(s) -
Yang Yan,
Dong Ruolan,
Chen Zhihui,
Hu Danli,
Fu Menglu,
Tang Ying,
Wang Dao Wen,
Xu Xizhen,
Tu Ling
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12718
Subject(s) - chemistry , medicine , endocrinology , insulin resistance , cytochrome p450 , skeletal muscle , epoxygenase , adipose tissue , endothelium , inflammation , insulin , enzyme , biochemistry , biology
Summary Ample evidences demonstrate that cytochrome P450 epoxygenase‐derived epoxyeicosatrienoic acids ( EET s) exert diverse biological activities, which include potent vasodilatory, anti‐inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium‐specific CYP 2J2 overexpression on age‐related insulin resistance and metabolic dysfunction. Endothelium‐specific targeting of the human CYP epoxygenase, CYP 2J2, transgenic mice (Tie2‐ CYP 2J2‐Tr mice) was utilized. The effects of endothelium‐specific CYP 2J2 overexpression on aging‐associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2‐ CYP 2J2‐Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in aged skeletal muscle, adipose tissue, and liver were observed in aged adult male mice, and moreover, these effects were partly inhibited in 16‐month‐old CYP 2J2‐Tr mice. In addition, CYP 2J2 overexpression‐mediated insulin sensitization in aged mice was associated with the amelioration of inflammatory state. Notably, the aging‐associated increases in fat mass and adipocyte size were only observed in 16‐month‐old wild‐type mice, and CYP 2J2 overexpression markedly prevented the increase in fat mass and adipocyte size in aged Tie2‐ CYP 2J2‐Tr mice, which was associated with increased energy expenditure and decreased lipogenic genes expression. Furthermore, these antiaging phenotypes of Tie2‐ CYP 2J2‐Tr mice were also associated with increased muscle blood flow, enhanced active‐phase locomotor activity, and improved mitochondrial dysfunction in skeletal muscle. Collectively, our findings indicated that endothelium‐specific CYP 2J2 overexpression alleviated age‐related insulin resistance and metabolic dysfunction, which highlighted CYP epoxygenase‐ EET system as a potential target for combating aging‐related metabolic disorders.