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,...

Full description

Saved in:
Bibliographic Details
Published in:Biochemical and biophysical research communications 2009-08, Vol.386 (2), p.351-355
Main Authors: Su, Hua, Gunter, Jennifer H., de Vries, Melissa, Connor, Tim, Wanyonyi, Stephen, Newell, Felicity S., Segal, David, Molero, Juan Carlos, Reizes, Ofer, Prins, Johannes B., Hutley, Louise J., Walder, Ken, Whitehead, Jonathan P.
Format: Article
Language:English
Subjects:
3T3-L1 Cells
Adipocyte
Adipogenesis - drug effects
Animals
Diet
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Guanine nucleotides
Guanosine - pharmacology
IMP Dehydrogenase - antagonists & inhibitors
IMPDH
Male
Mice
Mice, Inbred C57BL
Mycophenolic Acid - analogs & derivatives
Mycophenolic Acid - pharmacology
Mycophenolic Acid - therapeutic use
Obesity
Obesity - drug therapy
Obesity - enzymology
Weight Loss
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2009.06.040