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.

Obesity is caused by imbalanced energy intake and expenditure. Excessive energy intake and storage in adipose tissues are associated with many diseases. Several studies have demonstrated that vascular growth endothelial factor B (VEGFB) deficiency induces obese phenotypes. However, the 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-Vegfb₁₆₇ ^tg/+and aP2-Vegfb₁₈₆^tg/+) were generated and their biologic roles were investigated. On regular chow, adipose-specific VEGFB₁₈₆ is negatively associated with white adipose tissues (WATs) and positively regulates brown adipose tissues (BATs). VEGFB₁₈₆ upregulates energy metabolism and metabolism-associated genes. In contrast, VEGFB₁₆₇ has a nominal role in adipose development and function. On high-fat diet, VEGFB₁₈₆ expression can reverse the phenotypes of VEGFB deletion. VEGFB₁₈₆ overexpression upregulates BAT-associated genes and downregulates WAT-associated genes. VEGFB₁₈₆ and VEGFB₁₆₇ have very distinct roles in the 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.

Excessive fat accumulation causes obesity and many diseases. Previous study demonstrates VEGFB universal knockout induces obese phenotypes including expansion of white adipose tissue, whitening of brown adipose tissue, increase of fat accumulation and reduction in energy consumption. However, roles of VEGFB in adipose tissues are not clear. In this study, we have generated a mouse model with adipose-specific VEGFB repression using CRISPR/dCas9 system (Vegfb ^AdipoDown ) and investigated the roles of VEGFB in adipose development and energy metabolism. VEGFB repression induced significant changes in adipose tissue structure and function. Vegfb ^AdipoDown mice have larger body sizes, larger volume of white adipose tissues than its wild type littermates. Adipose-specific VEGFB repression induced morphological and functional transformation of adipose tissues toward white adipose for energy storage. Metabolic processes are broadly changed in Vegfb ^AdipoDown adipose tissues including carbohydrate metabolism, lipid metabolism, nucleotide metabolism and amino acid metabolism. We have demonstrated that adipose VEGFB repression can recapitulate most of the phenotypes of the whole body VEGFB knockout mouse. Intriguingly, approximately 50% VEGFB repression in adipose tissues can almost completely mimic the effects of universal Vegfb deletion, suggesting adipose VEGFB is a major regulator of energy metabolism and may be important in prevention and treatment of obesity.