Elsevier

Molecular Metabolism

Volume 5, Issue 10, October 2016, Pages 903-917
Molecular Metabolism

Original article
TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] ameliorates diet induced obesity and insulin resistance via inhibition of the IP6K1 pathway

https://doi.org/10.1016/j.molmet.2016.08.008Get rights and content
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Highlights

  • Pharmacologic inhibition of IP6K by TNP, at the onset of high fat feeding, decelerates initiation of DIO and insulin resistance in mice.

  • TNP, when treated to DIO mice, promotes weight loss and restores metabolic homeostasis.

  • TNP does not reduce high fat diet induced weight gain in IP6K1-KO mice.

  • TNP promotes insulin sensitivity by stimulating Akt activity, whereas it reduces body weight primarily by enhancing thermogenic energy expenditure.

  • Long-term TNP treatment does not display deleterious side effects.

Abstract

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.

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Keywords

IP6K
Inositol pyrophosphate
Obesity
Energy expenditure
Diabetes
Akt

Abbreviations

IP6K
Inositol hexakisphosphate kinase
5-IP7
diphosphoinositol pentakisphosphate
TNP
[N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine]
CD
chow-diet
HFD
high-fat diet
DIO
diet-induced obesity
T2D
type-2 diabetes
EE
energy expenditure
H&E
hematoxylin and eosin
AUC
area under curve
WAT
white adipose tissue
EWAT
epididymal adipose tissue
IWAT
inguinal adipose tissue
RWAT
retroperitoneal adipose tissue
BAT
brown adipose tissue
Q-NMR
quantitative nuclear magnetic resonance
HPLC
high performance liquid chromatography
PCR
polymerase chain reaction
QRT-PCR
quantitative reverse transcription polymerase chain reaction
GTT
glucose tolerance test
ITT
insulin tolerance test
T308
threonine 308
S473
serine 473
S9
serine 9
VO2
volume of oxygen consumption
RER
Respiratory exchange ratio
ALT
alanine aminotransferase
AST
aspartate transaminase
IP6K1-KO
IP6K1 knockout
GSK3
glycogen synthase kinase
PKA
protein kinase A
UCP-1/3
uncoupling protein 1/3
Cidea
cell death activator-A
PPARγ
peroxisome proliferator-activated receptor gamma
PGC1α
PPAR coactivator 1 alpha
PRDM16
PR domain containing 16
CPT1a
carnitine palmitoyltransferase I
SREV-TNP
short-term TNP treatment for reversal of DIO
Pro-TNP
TNP treatment for protection against DIO
Rev-TNP
long-term TNP treatment for reversal of DIO
RevT-TNP
Long-term TNP treatment for reversal of DIO at thermoneutral temperature

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Current address: Department of Chemistry, University of Cambridge, UK.