INPP4B protects from metabolic syndrome and associated disorders

Abstract

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.

LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer

“…2 E, right, Table S1 2 and Methods), among which five events ( L1-MCM3 , L1-PHF20 , L1-INPP4B , L1-SLC44A5 , L1-SUGCT ) are overlapped with those detected in LUSC suggesting their common and unified role in carcinogenesis of NSCLC. Interestingly, 2 genes ( INPP4B and SUGCT ) are associated with metabolic pathways or disorders [ 27 , 28 ]. MCM3 and INPP4B has been reported before to be related to cancer [ 29 , 30 ], while other three might be potential candidates for further study.…”

Phosphoinositides as membrane organizers

“…Such information seems crucial as membrane traffic and contacts between organelles need to be adapted to cellular nutrient status (for example, to regulate metabolic flux of lipids or fatty acids). Conversely, many phosphoinositide kinases and phosphatases and their effectors are known to change their subcellular localization and/or activity in response to external and internal metabolic cues, identifying them as prime candidates for the metabolic rewiring of cell membranes and organelles 130 , 134 , 155 , 184 – 187 . New analytical tools to visualize phosphoinositide lipids in vivo and the development of CRISPR technology to tag endogenous lipid-modifying enzymes and phosphoinositide-binding effector proteins paired with correlative live microscopy approaches will help to resolve these issues.…”

Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes

“…Significant associations were observed between morbid obese Han Chinese and CSMD3 (obesity related, IMPC) and ERBB4 (Chiang et al 2019 ). INPP4B protects against metabolic syndrome and associated disorders (Zhang et al 2021 ) and EXOC4 is involved in insulin-stimulated glucose transport and is associated with type II diabetes and fasting glucose (Laramie et al 2008 ). There is no scientific literature available for the mouse gene Galnt2l and no ortholog has been detected so far in human.…”