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Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity.

Authors :
Su H
Gunter JH
de Vries M
Connor T
Wanyonyi S
Newell FS
Segal D
Molero JC
Reizes O
Prins JB
Hutley LJ
Walder K
Whitehead JP
Source :
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2009 Aug 21; Vol. 386 (2), pp. 351-5. Date of Electronic Publication: 2009 Jun 11.
Publication Year :
2009

Abstract

We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.

Details

Language :
English
ISSN :
1090-2104
Volume :
386
Issue :
2
Database :
MEDLINE
Journal :
Biochemical and biophysical research communications
Publication Type :
Academic Journal
Accession number :
19523919
Full Text :
https://doi.org/10.1016/j.bbrc.2009.06.040