Obesity is a risk factor for various endocrine diseases including metabolic syndrome, cancer, and infertility, and its increasing incidence in society poses a major health concern. INPP4B is a tumor suppressor in breast cancer and a metabolic regulator that was shown to protect male mice from obesity and type 2 diabetes. Despite the wide expression pattern of INPP4B, its role in normal physiology is not fully described. It is also not known whether loss of INPP4B plays a role in obesity-associated increase in breast cancer initiation and progression or whether it alters tumor metabolism. In this dissertation, I showed that INPP4B loss affects the metabolic health of female mice, mammary gland development, and ERBB2- driven tumorigenesis in females. I found that Inpp4b-/- females develop high-fat diet (HFD) induced obesity, hyperglycemia, nonalcoholic fatty liver disease (NAFLD), and adipose tissue inflammation. I determined that NAFLD is due to increased hepatic lipid synthesis, while hyperglycemia is caused by insulin resistance, increased gluconeogenesis, and reduction in hypothalamic FGF21/FGFR1 signaling. Increased de novo lipogenesis in liver, decreased fat combustion in adipose tissue, and hypothalamic leptin resistance contributed to diet- induced obesity and inflammation of visceral adipose tissue. In mammary glands, I showed that INPP4B stimulates ductal branching by stabilizing progesterone receptor levels and inducing its transcriptional activity. The mammary glands of Inpp4b- knockout females on an HFD have elevation of AKT and p53 levels, as well as dysregulated leptin signaling and inflammation. In ERBB2 driven mammary gland tumorigenesis, both INPP4B loss of function and HFD accelerate tumor incidence and progression by reducing p53 expression and activity and increasing lipid synthesis. I also found that INPP4B plays an important role in male reproductive function. Inpp4b-/- males exhibit smaller testis and fewer sperm due to reduced rates of meiosis and increased apoptosis. In men, the expression of INPP4B is highest in post-meiotic germ cells and it declines significantly in testes of infertile men that lack mature sperm. Thus, INPP4B emerges as a new regulator of metabolic and reproductive health as well as in obesity-induced tumorigenesis.
