INPP4B protects from metabolic syndrome and associated disorders

A high fat diet and obesity have been linked to the development of metabolic dysfunction and the promotion of multiple cancers. The causative cellular signals are multifactorial and not yet completely understood. In this report, we show that Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B) signaling protects mice from diet-induced metabolic dysfunction. INPP4B suppresses AKT and PKC signaling in the liver thereby improving insulin sensitivity. INPP4B loss results in the proteolytic cleavage and activation of a key regulator in de novo lipogenesis and lipid storage, SREBP1. In mice fed with the high fat diet, SREBP1 increases expression and activity of PPARG and other lipogenic pathways, leading to obesity and non-alcoholic fatty liver disease (NAFLD). Inpp4b(-/-) male mice have reduced energy expenditure and respiratory exchange ratio leading to increased adiposity and insulin resistance. When treated with high fat diet, Inpp4b(-/-) males develop type II diabetes and inflammation of adipose tissue and prostate. In turn, inflammation drives the development of high-grade prostatic intraepithelial neoplasia (PIN). Thus, INPP4B plays a crucial role in maintenance of overall metabolic health and protects from prostate neoplasms associated with metabolic dysfunction. Characterizing mice lacking Inositol Polyphosphate-4-Phosphatase Type II B (INPP4B), Zhang et al. discovered that SREBP1 signaling is activated in livers of Inpp4b(-/-) males leading to development of NAFLD and insulin resistance. When fed high fat diet, Inpp4b(-/-) males develop type II diabetes, inflammation of adipose tissue, and prostate neoplasia. These findings provide insights into INPP4B protective role from metabolic syndrome.

Automated summary

Research has shown that INPP4B signaling can protect mice from diet-induced metabolic dysfunction and help prevent multiple cancers associated with this condition.