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Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity
Authors:Hua Su  Melissa de Vries  Stephen Wanyonyi  David Segal  Ofer Reizes  Louise J Hutley  Jonathan P Whitehead
Institution:a Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia
b Metabolic Research Unit, School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Vic., Australia
c Cleveland Clinic Foundation, Lerner Research Institute, Cleveland, OH, USA
d Verva Pharmaceuticals Ltd., Geelong, Vic., Australia
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.
Keywords:IMPDH  Adipocyte  Guanine nucleotides  Obesity
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