Effect of gelatinase inhibition on adipogenesis and adipose tissue development.
1. The potential of the matrix metalloproteinase (MMP) inhibitor ABT-518 to affect pre-adipocyte differentiation in vitro and adipose tissue development in vivo was investigated using mouse models of adipogenesis and obesity. 2. Differentiation of 3T3-F442A pre-adipocytes into mature adipocytes was enhanced in a dose-dependent manner by the addition of ABT-518 (0-100 μmol/L). This was associated with increased expression of the adipogenic markers adipocyte fatty acid-binding protein 2 (AP2), peroxisome proliferator-activated receptor γ and adiponectin. 3. Feeding 5-week-old male wild-type mice with a high-fat diet, with or without ABT-518 (to achieve a dose of 100 mg/kg per day), for 16 weeks resulted in a significant reduction in bodyweight throughout the experimental period. Magnetic resonance spectroscopy revealed that the lipid : water ratio was significantly lower in ABT-518-treated mice. The total weight of isolated subcutaneous or gonadal fat depots did not differ significantly following ABT-518 treatment, but adipocyte and blood vessel size were significantly reduced in the gonadal fat. 4. Administration of ABT-518-2 (100 mg/kg per day for 10 weeks) to 5-week-old male wild-type mice with established obesity maintained on a high-fat diet had no effect on total bodyweight at the end of the experiment, but was associated with reduced blood vessel size in the fat depots. 5. Thus, the MMP inhibitor ABT-518 stimulates differentiation of 3T3-F442A pre-adipocytes in vitro. It mildly reduces bodyweight gain in a murine model of diet-induced obesity, but does not affect established obesity.
Center for Molecular and Vascular Biology Biomedical NMR Unit/MoSAIC, Katholieke Universiteit Leuven, Leuven, Belgium.
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M
Van Hul
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Bauters
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Himmelreich
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N
Kindt
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B
Noppen
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M
Vanhove
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Lijnen
D016475:3T3 Cells; D052438:Adipocytes, White / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D048429:Cell Size / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005559:Formamides / Q000494:pharmacology / Q000627:therapeutic use*; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
D052242:Adiponectin; C499919:Adipoq protein, mouse; C493405:Fabp2 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005559:Formamides; C443806:N-(1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-((4,4-(trifluoromethoxyphenoxy)phenyl)sulfonyl)ethyl)-N-hydroxyformamide; D047495:PPAR gamma; D011480:Protease Inhibitors; D012333:RNA, Messenger; D018093:Gelatinases