Inositol Hexakisphosphate Kinase 3 Regulates Metabolism and Lifespan in Mice

Abstract

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.

Global IP6K1 deletion enhances temperature modulated energy expenditure which reduces carbohydrate and fat induced weight gain

“…We used the IP6K inhibitor TNP for the following reasons; i) IP6K1 is the major isoform in the adipose tissue [39], [41], ii) TNP significantly reduces 5-IP7 levels in 3T3L1 adipocytes [40], iii) TNP ameliorates DIO in mice by augmenting EE [43], and iv) TNP enhances AMPK signaling in the adipose tissue and adipocytes [41]. TNP protected glucose induction mediated inhibition of AMPK in 3T3L1 preadipocytes (Figure 6I).…”

“…Moreover, deletion of IP6K3, which is the predominant isoform in murine and human skeletal muscle protects mice from age induced fat accumulation and insulin resistance. Moreover, IP6K3-KO mice live longer [39]. However, IP6K3-KO mice are not protected from DIO [39], which further suggests that IP6K1 regulates body weight primarily via its effects on the adipose tissue.…”

“…Moreover, IP6K3-KO mice live longer [39]. However, IP6K3-KO mice are not protected from DIO [39], which further suggests that IP6K1 regulates body weight primarily via its effects on the adipose tissue. Nevertheless, pan inhibition of the inositol pyrophosphate pathway is expected to have beneficial effects in obesity, diabetes, and aging.…”

“…IP6Ks also regulate certain functions such as lipolysis, via protein-interaction [36], [37], [38]. In rodents, IP6K1 is the major isoform in adipose and other tissues, whereas IP6K3 expression is higher in the skeletal muscle [39]. Mice with IP6K1 deletion (IP6K1-KO) are protected from HFD-induced weight gain and insulin resistance [40].…”

IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution

“…Recent studies indicate that mice with a germline deletion of inositol hexakisphosphate kinase 1 ( Ip6k1 ), the major isoform of three known inositol hexakisphosphate kinases , are protected against HFD‐induced weight gain and insulin resistance . A family of three mammalian IP6 kinases (IP6Ks) primarily generates the inositol pyrophosphate 5‐IP7 from IP6 .…”