Targeting the Inositol Pyrophosphate Biosynthetic Enzymes in Metabolic Diseases

Abstract

In mammals, a family of three inositol hexakisphosphate kinases (IP6Ks) synthesizes the inositol pyrophosphate 5-IP7 from IP6. Genetic deletion of Ip6k1 protects mice from high fat diet induced obesity, insulin resistance and fatty liver. IP6K1 generated 5-IP7 promotes insulin secretion from pancreatic β-cells, whereas it reduces insulin signaling in metabolic tissues by inhibiting the protein kinase Akt. Thus, IP6K1 promotes high fat diet induced hyperinsulinemia and insulin resistance in mice while its deletion has the opposite effects. IP6K1 also promotes fat accumulation in the adipose tissue by inhibiting the protein kinase AMPK mediated energy expenditure. Genetic deletion of Ip6k3 protects mice from age induced fat accumulation and insulin resistance. Accordingly, the pan IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates obesity, insulin resistance and fatty liver in diet induced obese mice by improving Akt and AMPK mediated insulin sensitivity and energy expenditure. TNP also protects mice from bone loss, myocardial infarction and ischemia reperfusion injury. Thus, the IP6K pathway is a potential target in obesity and other metabolic diseases. Here, we summarize the studies that established IP6Ks as a potential target in metabolic diseases. Further studies will reveal whether inhibition of this pathway has similar pleiotropic benefits on metabolic health of humans.

Inositol Pyrophosphates: Signaling Molecules with Pleiotropic Actions in Mammals

“…In addition, pharmacological inhibition of IP6K by the IP6K inhibitor TNP [N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine] increases AMPK phosphorylation and AMPK signaling events in the adipocytes of high-fat-diet-fed mice [59]. More detailed perspectives on the IP6K-mediated control of metabolic homeostasis by IP6Ks have been reviewed [64].…”

The Key Role of IP6K: A Novel Target for Anticancer Treatments?

“…These important features rely on the di(β)phosphate group to enable competition of these molecules with phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ) in order to bind to pleckestrin homology domains (PH) [ 27 ]. In mammals, generation of knockout mouse models has established the in vivo impacts and significance of IPs pathways [ 28 ], while pharmacological modulation of inositol and its pyrophosphate-related pathways have proved to be beneficial in several pathological settings [ 29 , 30 , 31 ].…”

Role of Inositols and Inositol Phosphates in Energy Metabolism

“…The four common forms of inositol pyrophosphates found in nature are 5-diphosphoinositol (1,3,4,6)-tetrakisphosphate(5PP-IP4), 1-diphosphoinositol (2,3,4,5,6) pentakisphosphate (1PP-IP5 or 1-IP7), 5-diphosphoinositol (1,2,3,4,6) pentakisphosphate (5PP-IP5 or 5-IP7) and 1,5-bisdiphosphoinositol (2,3,4,6) tetrakisphosphate (1,5PP2-IP4 or 1,5-IP8) [19]. The synthesis of 5PP-IP5 occurs by the conversion of IP6 by the enzyme inositol hexakisphosphate kinase 1 (IP6K1) [14,15].…”

“…The effects of inositol phosphates and IP6Ks have long been considered for a target of obesity and metabolic diseases [19]. Many experiments in mice revealed that IP6K knockout displayed reduced body weight, fat accumulation, and percentage of fat mass as well as increased percentage of lean body mass [21,81], suggesting the role of inositol pyrophosphates on obesity.…”