GSE134466
INPP4B protects from metabolic disease and obesity associated prostate neoplasia.
A high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers in mice and men. The causative cellular signals are multifactorial and not completely understood. Previous studies have shown that metabolic dysfunction leads to activation of the AKT and PKC pathways. Both signaling pathways are inhibited by the dual specificity phosphatase, INPP4B, which dephosphorylates PI(3,4)P2, an activator of AKT, and PI(4,5)P2, an activator of the PLC/PKC pathway. We established that INPP4B signaling protects mice from metabolic dysfunction. Inpp4b-/- male mice had accelerated activation of SREBF1 in liver which, along with the high fat diet, caused increased expression and activity of PPARG and other lipogenic pathways leading  non-alcoholic fatty liver disease (NAFLD), type II diabetes, expansion and inflammation of WAT, and systemic and localized prostate inflammation that drives the development of high-grade prostatic intraepithelial neoplasia (PIN). Overall design: WT and Inpp4b-/- males were fed with either LFD (LabDiet 5V75, St. Louis, MO) or HFD (TestDiet 58R3, St. Louis, MO). The HFD consisted of 59.4% fat, 25.7% carbohydrate, and 14.9% protein (total 22.8 kJ/g), whereas the regular chow contained 12.9% fat, 63.8% carbohydrate, and 23.2% protein (total 13.6 kJ/g). All LFD WT, LFD Inpp4b-/-, HFD WT, and HFD Inpp4b-/- mice were euthanized and dissected at 12 weeks and their tissues where collected for analysis. RNA was purified  from HFD WT (N=4) and HFD Inpp4b-/- (N = 4) and submitted to Novogene for RNA sequencing.