Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity.
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.
Su
Hua
H
Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia.
Gunter
Jennifer H
JH
de Vries
Melissa
M
Connor
Tim
T
Wanyonyi
Stephen
S
Newell
Felicity S
FS
Segal
David
D
Molero
Juan Carlos
JC
Reizes
Ofer
O
Prins
Johannes B
JB
Hutley
Louise J
LJ
Walder
Ken
K
Whitehead
Jonathan P
JP
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006151:Guanosine / Q000494:pharmacology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology; D015431:Weight Loss
D004791:Enzyme Inhibitors; D006151:Guanosine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid