Whole Body Ip6k1 Deletion Protects Mice from Age-Induced Weight Gain, Insulin Resistance and Metabolic Dysfunction

Abstract

(1) Background: We previously demonstrated that disruption of IP6K1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis. Age-induced metabolic dysfunction is a major risk factor for metabolic diseases. The involvement of IP6K1 in this process is unknown. (2) Methods: Here, we compared body and fat mass, insulin sensitivity, energy expenditure and serum-, adipose tissue- and liver-metabolic parameters of chow-fed, aged, wild type (aWT) and whole body Ip6k1 knockout (aKO) mice. (3) Results: IP6K1 was upregulated in the adipose tissue and liver of aWT mice compared to young WT mice. Moreover, Ip6k1 deletion blocked age-induced increase in body- and fat-weight and insulin resistance in mice. aKO mice oxidized carbohydrates more efficiently. The knockouts displayed reduced levels of serum insulin, triglycerides, and non-esterified fatty acids. Ip6k1 deletion partly protected age-induced decline of the thermogenic uncoupling protein UCP1 in inguinal white adipose tissue. Targets inhibited by IP6K1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK), were activated in the adipose tissue and liver of aKO mice. (4) Conclusions: Ip6k1 deletion maintains healthy metabolism in aging and thus, targeting this kinase may delay the development of age-induced metabolic dysfunction.

The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling

“…IP6Ks are recently becoming appreciated as a target for diseases [14,15]. Ip6k1 deletion has been shown to have beneficial effects on diet-and age-induced obesity, insulin resistance, NAFLD/NASH, osteoporosis, pneumonia, and thromboembolism [16,17,[19][20][21][22]50,51]. The deletion of the skeletal-muscle-enriched isoform Ip6k3 reduces blood glucose, insulin levels, and fat mass and extends the lifespan [46].…”

“…The average amount of food consumed per mouse per day was calculated. The mice had full access to drinking water throughout the study [22].…”

“…Inositol hexakisphosphate kinase-1 (IP6K1), an inositol pyrophosphate biosynthetic enzyme, is a target in diet-induced obesity (DIO) and obesity-related metabolic diseases [14,15]. The whole-body and adipocyte-specific deletion of Ip6k1 ameliorates DIO, insulin resistance, and hepatic steatosis [16][17][18][19][20][21][22]. Moreover, the pan-IP6K inhibitor TNP [N2-(m-trifluoro benzyl), N6-(p-nitrobenzyl)purine] [23,24] ameliorates these diseases [25].…”