Inositol Hexakisphosphate Kinase 3 Regulates Metabolism and Lifespan in Mice

Sci Rep. 2016 Aug 31:6:32072. doi: 10.1038/srep32072.


Inositol hexakisphosphate kinase 3 (IP6K3) generates inositol pyrophosphates, which regulate diverse cellular functions. However, little is known about its own physiological role. Here, we show the roles of IP6K3 in metabolic regulation. We detected high levels of both mouse and human IP6K3 mRNA in myotubes and muscle tissues. In human myotubes, IP6K3 was upregulated by dexamethasone treatment, which is known to inhibit glucose metabolism. Furthermore, Ip6k3 expression was elevated under diabetic, fasting, and disuse conditions in mouse skeletal muscles. Ip6k3(-/-) mice demonstrated lower blood glucose, reduced circulating insulin, deceased fat mass, lower body weight, increased plasma lactate, enhanced glucose tolerance, lower glucose during an insulin tolerance test, and reduced muscle Pdk4 expression under normal diet conditions. Notably, Ip6k3 deletion extended animal lifespan with concomitant reduced phosphorylation of S6 ribosomal protein in the heart. In contrast, Ip6k3(-/-) mice showed unchanged skeletal muscle mass and no resistance to the effects of high fat diet. The current observations suggest novel roles of IP6K3 in cellular regulation, which impact metabolic control and lifespan.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Composition
  • Body Weight
  • Cell Line
  • Dexamethasone / pharmacology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diet, High-Fat / adverse effects
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology*
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Islets of Langerhans / enzymology
  • Longevity / genetics
  • Longevity / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Muscle Fibers, Skeletal / enzymology
  • Muscle, Skeletal / enzymology
  • Myocardium / metabolism
  • Organ Specificity
  • Phosphorylation
  • Phosphotransferases (Phosphate Group Acceptor) / deficiency
  • Phosphotransferases (Phosphate Group Acceptor) / genetics
  • Phosphotransferases (Phosphate Group Acceptor) / physiology*
  • Protein Processing, Post-Translational
  • Rats
  • Ribosomal Protein S6 / metabolism


  • Insulin
  • Ribosomal Protein S6
  • Dexamethasone
  • Phosphotransferases (Phosphate Group Acceptor)
  • inositol hexakisphosphate kinase
  • Glucose