Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss

SIMPLE SUMMARY: Obesity and diabetes have detrimental impacts on skeletal health that result in an increased fracture risk and impaired fracture healing, conditions associated with significant morbidity and mortality and that are costly to treat. Managing obesity-induced bone loss is complicated by the fact that anti-diabetic drugs have negative or unknown impacts on bone health, which limits their effectiveness. Inositol hexakisphosphate kinase 1 (IP6K1) functions as a prominent regulator of energy expenditure based on data showing its inhibition protects mice from diet-induced obesity. In this paper, we show that the pharmacological inhibition of IP6K1 after the onset of a high-fat diet feeding protects mice against weight gain and its associated metabolic derangements even under thermo-neutral conditions, and that kinase inhibition also preserves bone mass, bone micro-architecture, and the pool of skeletal stem/progenitors in bone marrow. Obesity also has negative impacts on male fertility, but prolonged IP6K1 inhibition had no adverse impacts on male reproductive parameters. These findings identify IP6K1 as a preferred target for glycemic control due to the bone sparing effects of IP6K1 inhibition. ABSTRACT: Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown. To determine if IP6K1 inhibition in obese mice affords protection against obesity-induced metabolic derangements and bone loss, we maintained 2-month-old mice on a normal chow control diet or HFD under thermal neutral conditions for 100 d. Beginning on day 40, HFD-fed mice were divided into two groups and administered daily injections of vehicle or the pan-IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine]. HFD-fed mice developed obesity, hyperglycemia, hyperlipidemia, and secondary osteoporosis, while TNP administration protected mice against HFD-induced metabolic and lipid derangements and preserved bone mass, mineral density, and trabecular microarchitecture, which correlated with reduced serum leptin levels, reduced marrow adiposity, and preservation of marrow resident skeletal stem/progenitor cells (SSPCs). TNP also exhibited hypotensive activity, an unrealized benefit of the drug, and its prolonged administration had no adverse impacts on spermatogenesis. Together, these data indicate that the inhibition of IP6K1 using selective inhibitors, such as TNP, may provide an effective strategy to manage obesity and T2DM due to its bone sparing effects.