Oxytocin receptor (OXTR) is a G-protein-coupled receptor and known for regulation of maternal and social behaviors. Null mutation (Oxtr−/−) leads to defects in lactation due to impaired milk ejection and maternal nurturing. Overexpression of OXTR has never been studied. To define the functions of OXTR overexpression, a transgenic mouse model that overexpresses mouse Oxtr under β-actin promoter was developed ( ++ Oxtr). ++ Oxtr mice displayed advanced development and maturation of mammary gland, including ductal distention, enhanced secretory differentiation and early milk production at non-pregnancy and early pregnancy. However, ++ Oxtr dams failed to produce adequate amount of milk and led to lethality of newborns due to early involution of mammary gland in lactation. Mammary gland transplantation results indicated the abnormal mammary gland development was mainly from hormonal changes in ++ Oxtr mice but not from OXTR overexpression in mammary gland. Elevated OXTR expression increased prolactin-induced phosphorylation and nuclear localization of STAT5 (p-STAT5), and decreased progesterone level, leading to early milk production in non-pregnant and early pregnant females, whereas low prolactin and STAT5 activation in lactation led to insufficient milk production. Progesterone treatment reversed the OXTR-induced accelerated mammary gland development by inhibition of prolactin/p-STAT5 pathway. Prolactin administration rescued lactation deficiency through STAT5 activation. Progesterone plays a negative role in OXTR-regulated prolactin/p-STAT5 pathways. The study provides evidence that OXTR overexpression induces abnormal mammary gland development through progesterone and prolactin-regulated p-STAT5 pathway.
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- Author: Honghong Jin x
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Dan Li, Yan Ji, Chunlan Zhao, Yapeng Yao, Anlan Yang, Honghong Jin, Yang Chen, Mingjun San, Jing Zhang, Mingjiao Zhang, Luqing Zhang, Xuechao Feng, and Yaowu Zheng
Yang Chen, Xin Li, Jing Zhang, Mingjiao Zhang, Salah Adlat, Xiaodan Lu, Dan Li, Honghong Jin, Chenhao Wang, Zin Mar Oo, Farooq Hayel, Quangang Chen, Xufeng Han, Renjin Chen, Xuechao Feng, Luqing Zhang, and Yaowu Zheng
Obesity is caused by imbalanced energy intake and expenditure. The excessive energy intake and storage in adipose tissues is associated with many diseases. Several studies have demonstrated that VEGFB deficiency induces obese phenotypes. However, roles of VEGFB isoforms VEGFB167 and VEGFB186 in adipose tissue development and function are still not clear. In this study, genetic mouse models of adipose-specific VEGFB167 and VEGFB186 overexpression (aP2-Vegfb167tg/+ and aP2-Vegfb186tg/+) were generated and their biologic roles were investigated. On regular chow, adipose-specific VEGFB186 is negatively associated with white adipose tissues (WAT) and positively regulates brown adipose tissues (BAT). VEGFB186 up-regulates energy metabolism and metabolism-associated genes. In contrast, VEGFB167 has nominal roles in adipose development and function. On high fat diet, VEGFB186 expression can reverse the phenotypes of VEGFB deletion. VEGFB186 overexpression up-regulates BAT-associated genes and down-regulates WAT-associated genes. VEGFB186 and VEGFB167 have very distinct roles in regulation of adipose development and energy metabolism. As a key regulator of adipose tissue development and energy metabolism, VEGFB186 may be a target for obesity prevention and treatment.
