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

journal contribution
posted on 2009-08-21, 00:00 authored by H Su, J Gunter, Melissa de Vries, Timothy ConnorTimothy Connor, Stephen Wanyonyi, F Newell, D Segal, Juan Molero Navajas, O Reizes, J Prins, L Hutley, Ken WalderKen Walder, J Whitehead
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.

History

Journal

Biochemical and biophysical research communications

Volume

386

Issue

2

Pagination

351 - 355

Publisher

Academic Press

Location

San Diego, Calif.

ISSN

0006-291X

eISSN

1090-2104

Language

eng

Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2009, Elsevier