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. 2022 Aug 24;11(9):1257.
doi: 10.3390/biology11091257.

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

Siddaraju V Boregowda  1 , Manjunatha K Nanjappa  2 , Cori N Booker  1 , Jacqueline Strivelli  1 , Valentina M Supper  3 , Paul S Cooke  2 , Donald G Phinney  1
Affiliations

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

Siddaraju V Boregowda et al. Biology (Basel). .

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.

Keywords: anti-obesity drugs; diet; high fat; inositol hexakisphosphate kinase 1; mesenchymal stem cells; obesity; osteoporosis; skeletal; stem cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TNP protects mice from HFD-induced weight gain, hyperglycemia, and hyperlipidemia. (a) Schematic of the feeding regimen and timing of daily TNP administration (10 mg/kg BW, IP). NC, normal chow; HFD, high-fat diet. (b) Mouse body weights measured at weekly intervals over the feeding time course and estimation plot of vehicle and TNP-treated HFD mice showing raw data (left) and the group means difference with 95% confidence interval (right). (c) Baseline and endpoint measures of body fat, lean mass, and fluid mass in mice from (a). (d,e) Endpoint measure of blood glucose levels (d) and serum cholesterol, LDL, HDL, and TAG levels (e) in mice from (a). (f) Endpoint measures of systolic, diastolic, and mean arterial pressure and pulse rate of mice in (a). Data are mean ± SD (n = 8–14 mice/group). In Prism 9, p-values are by one-way ANOVA and Tukey’s post hoc test for (b–f).
Figure 2
Figure 2
TNP prevents obesity-induced bone loss. (a,g) Representative micro-CT images of the proximal (a) and midshaft (g) tibiae of mice maintained on NC or HFD with or without TNP administration. (b–f) Quantification of BV/TV (b), Tb.N (c), Conn. D (d) and Tb.Sp (e), and SMI (f) by micro-CT. (h–k) Quantification of B.Ar/T.Ar (h), M.Ar (i), BMD (j), and Ct. Th (k) by micro-CT. (l) Quantification of plasma leptin levels by ELISA. (m) Representative micro-CT images of marrow adiposity in tibiae stained with osmium tetroxide. (n) Quantitation of MAT volume by micro-CT in bones from (m). (o) Scatter plot of Tb. N vs. MAT volume for all mice. Data are mean ± SD (n = 8–10 mice/group). In Prism 9, p-values are one-way ANOVA and Tukey’s post hoc test for (b–f,h–l,n,) and Pearson’s correlation coefficient and corresponding p-value for (o).
Figure 3
Figure 3
TNP administration prevents the HFD-induced contraction of the SSPC pool in the bone marrow. (a) Representative dot plots from flow cytometric analysis of whole bone marrow cells stained with antibodies against lineage-specific markers (CD31, CD45, and Ter119) and LEPR. (b) Percentage of Lin−LEPR+ SSPCs recovered from the bone marrow of mice fed NC or HFD and treated with vehicle or TNP. Data are mean ± SD (n = 6–9 mice/group). (c,d) Extent of osteo-induction (c) and adipo-induction (d) of human MSCs from the indicated donors when cultured in vehicle vs. TNP (10 mg/L) over a 3-week time course of cellular differentiation. Data are mean ± SD from biological replicates performed in quadruplicate. In Prism 9, p-values are by one-way ANOVA and Tukey’s post hoc test for (b) and Student’s t-test (vehicle vs. TNP) for c and d with * p < 0.05, *** p < 0.005, ns = not significant.
Figure 4
Figure 4
Prolonged TNP administration does not impair spermatogenesis in male mice. (a) Weight of testes and epididymis from vehicle- or TNP-treated HFD mice. (b) Average spermatid counts and spermatid concentrations per testes. (c) Daily sperm production and sperm production efficiency. (d) Percentages of sperm with normal morphology or abnormalities, including angulated midpieces and headless tails. Data are mean ± SD (n = 6–7 mice/group). In Prism 9, p-values are by Student’s t-test.
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