Objective: Obesity and type 2 diabetes (T2D) lead to various life-threatening diseases such as coronary heart disease, stroke, osteoarthritis, asthma, and neurodegeneration. Therefore, extensive research is ongoing to identify novel pathways that can be targeted in obesity/T2D. Deletion of the inositol pyrophosphate (5-IP7) biosynthetic enzyme, inositol hexakisphosphate kinase-1 (IP6K1), protects mice from high fat diet (HFD) induced obesity (DIO) and insulin resistance. Yet, whether this pathway is a valid pharmacologic target in obesity/T2D is not known. Here, we demonstrate that TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine], a pan-IP6K inhibitor, has strong anti-obesity and anti-diabetic effects in DIO mice.
Methods: Q-NMR, GTT, ITT, food intake, energy expenditure, QRT-PCR, ELISA, histology, and immunoblot studies were conducted in short (2.5-week)- and long (10-week)-term TNP treated DIO C57/BL6 WT and IP6K1-KO mice, under various diet and temperature conditions.
Results: TNP, when injected at the onset of HFD-feeding, decelerates initiation of DIO and insulin resistance. Moreover, TNP facilitates weight loss and restores metabolic parameters, when given to DIO mice. However, TNP does not reduce weight gain in HFD-fed IP6K1-KO mice. TNP specifically enhances insulin sensitivity in DIO mice via Akt activation. TNP decelerates weight gain primarily by enhancing thermogenic energy expenditure in the adipose tissue. Accordingly, TNP's effect on body weight is partly abolished whereas its impact on glucose homeostasis is preserved at thermoneutral temperature.
Conclusion: Pharmacologic inhibition of the inositol pyrophosphate pathway has strong therapeutic potential in obesity, T2D, and other metabolic diseases.
Keywords: 5-IP7, diphosphoinositol pentakisphosphate; ALT, alanine aminotransferase; AST, aspartate transaminase; AUC, area under curve; Akt; BAT, brown adipose tissue; CD, chow-diet; CPT1a, carnitine palmitoyltransferase I; Cidea, cell death activator-A; DIO, diet-induced obesity; Diabetes; EE, energy expenditure; EWAT, epididymal adipose tissue; Energy expenditure; GSK3, glycogen synthase kinase; GTT, glucose tolerance test; H&E, hematoxylin and eosin; HFD, high-fat diet; HPLC, high performance liquid chromatography; IP6K; IP6K, Inositol hexakisphosphate kinase; IP6K1-KO, IP6K1 knockout; ITT, insulin tolerance test; IWAT, inguinal adipose tissue; Inositol pyrophosphate; Obesity; PCR, polymerase chain reaction; PGC1α, PPAR coactivator 1 alpha; PKA, protein kinase A; PPARγ, peroxisome proliferator-activated receptor gamma; PRDM16, PR domain containing 16; Pro-TNP, TNP treatment for protection against DIO; Q-NMR, quantitative nuclear magnetic resonance; QRT-PCR, quantitative reverse transcription polymerase chain reaction; RER, Respiratory exchange ratio; RWAT, retroperitoneal adipose tissue; Rev-TNP, long-term TNP treatment for reversal of DIO; RevT-TNP, Long-term TNP treatment for reversal of DIO at thermoneutral temperature; S473, serine 473; S9, serine 9; SREV-TNP, short-term TNP treatment for reversal of DIO; T2D, type-2 diabetes; T308, threonine 308; TNP, [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine]; UCP-1/3, uncoupling protein 1/3; VO2, volume of oxygen consumption; WAT, white adipose tissue.