Differential effects of a gelatinase inhibitor on adipocyte differentiation and adipose tissue development

Summary A potential role for the gelatinases in adipocyte differentiation in vitro and adipose tissue development in vivo was investigated using the gelatinase inhibitor tolylsam (( R )‐3‐methyl‐2‐[4‐(3‐ p ‐tolyl‐[1,2,4]oxadiazol‐5‐yl)‐benzenesulphonylamino]‐butyric acid). Differentiation of murine 3T3‐F442A preadipocytes (12 days after reaching confluence) into mature adipocytes in vitro was promoted in the presence of tolylsam (10–100 μmol/ L ). De novo development of fat tissue in nude mice injected with preadipocytes and kept on a high‐fat diet was significantly impaired following treatment with tolylsam (100 mg/kg per day for 4 weeks). Adipose tissue development in matrix metalloproteinase ( MMP )‐2 deficient mice, kept on a high‐fat diet, was significantly impaired following administration of tolylsam (100 mg/kg per day for 15 weeks). This was associated with markedly enhanced metabolic rate. Treatment of MMP ‐2‐deficient mice with tolylsam (100 mg/kg per day, 15 weeks) was associated with the preservation of collagen and a reduction in blood vessel size in adipose tissues in vivo . Furthermore, plasma levels of triglycerides and free fatty acids were reduced by tolylsam treatment of MMP ‐2‐deficient mice (100 mg/kg per day, 15 weeks), whereas nutrient adsorption in the intestine was not affected. The results of the present study indicate that tolylsam promotes preadipocyte differentiation in vitro , but impairs adipose tissue development in vivo .