In obesity, fat accumulation exceeds storage-capacity of adipose tissue depots. Liver primarily stores excess fat, which eventually leads to obesity induced nonalcoholic fatty liver disease (NAFLD). Our laboratory originally showed that insulin stimulates the inositol phosphate kinase IP6K1 to produce IP7 (5-diphosphoinositolpentakisphosphate), which in turn inhibits insulin sensitizing enzyme Akt. Genetic deletion and pharmacological inhibition of IP6K1 protect mice from high fat diet (HFD)-induced obesity, insulin resistance (IR) and NAFLD. Aging is one of the most common causes of metabolic diseases. The present study was undertaken to investigate whether IP6K1 deletion protects mice from age induced metabolic aberrations.
Body composition and liver fat were analyzed in 18-months old chow-fed WT and global IP6K1-KO (KO) mice by NMR, histology and lipidomic analysis. Real-time PCR and Western blot were done to delineate the signaling pathway leading to improved insulin sensitivity and less body fat in aged KO mice.
Aged KO mice gain less body weight and body/liver-fat. Lipidomic analyses indicate that the 18:1 cholesteryl ester and multiple triglyceride molecular species are decreased in KO liver. Aged KO mice also display improved insulin sensitivity as evident from enhanced AKT phosphorylation. Moreover, aged IP6K1-KOs display augmented level of the thermogenic uncoupling protein-1 (UCP1) in the inguinal (IWAT), but not in classic brown (BAT) adipose-depot. The aged knockouts also display a slight (not significant) increase in energy expenditure.
Targeting IP6K1 is expected to ameliorate obesity, diabetes, NAFLD. Human studies may determine whether these findings translate to improved life and health span.