1. Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity.
- Author
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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, and Whitehead JP
- Subjects
- 3T3-L1 Cells, Animals, Diet, Enzyme Inhibitors pharmacology, Guanosine pharmacology, Male, Mice, Mice, Inbred C57BL, Mycophenolic Acid pharmacology, Mycophenolic Acid therapeutic use, Obesity enzymology, Adipogenesis drug effects, Enzyme Inhibitors therapeutic use, IMP Dehydrogenase antagonists & inhibitors, Mycophenolic Acid analogs & derivatives, Obesity drug therapy, Weight Loss
- 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.
- Published
- 2009
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