Development of vasculature and mRNA expression of 17 pro- or antiangiogenic factors were studied during adipose tissue development in nutritionally induced or genetically determined murine obesity models. Subcutaneous (SC) and gonadal (GON) fat pads were harvested from male C57Bl/6 mice kept on standard chow [standard fat diet (SFD)] or on high-fat diet for 0-15 wk and from male ob/ob mice kept on SFD. Ob/ob mice and C57Bl/6 mice on high-fat diet had significantly larger SC and GON fat pads, accompanied by significantly higher blood content, increased total blood vessel volume, and higher number of proliferating cells. mRNA and protein levels of angiopoietin (Ang)-1 were down-regulated, whereas those of thrombospondin-1 were up-regulated in developing adipose tissue in both obesity models. Ang-1 mRNA levels correlated negatively with adipose tissue weight in the early phase of nutritionally induced obesity as well as in genetically determined obesity. Placental growth factor and Ang-2 expression were increased in SC adipose tissue of ob/ob mice, and thrombospondin-2 was increased in both their SC and GON fat pads. mRNA levels of vascular endothelial growth factor (VEGF)-A isoforms VEGF-B, VEGF-C, VEGF receptor-1, -2, and -3, and neuropilin-1 were not markedly modulated by obesity. This modulation of angiogenic factors during development of adipose tissue supports their important functional role in obesity.

SummaryTo investigate a potential role of stromelysin-1 (MMP-3) in development of adipose tissue, 5 week old male MMP-3 deficient mice (MMP-3-/-) and wild-type (MMP-3+/+) controls were kept on a high fat diet (HFD) for 15 weeks. MMP-3-/- mice were hyperphagic and gained more weight than the MMP-3+/+ mice. At the time of sacrifice, the body weight of the MMP-3-/- mice was significantly higher than that of the MMP-3+/+ mice, as was the weight of the isolated subcutaneous (SC) and gonadal (GON) fat deposits. Significant adipocyte hypertrophy was observed in the GON but not in the SC adipose tissue of MMP-3-/- mice. Fasting plasma glucose and cholesterol levels were comparable in both genotypes, whereas triglyceride levels were significantly lower in MMP-3-/- mice. Staining with an endothelial cell specific lectin revealed a significantly higher blood vessel density and larger total stained area in the GON adipose tissues of MMP-3-/- mice. Thus, in a murine model of nutritionally induced obesity, MMP-3 impairs adipose tissue development, possibly by affecting food intake and/or adipose tissue-related angiogenesis.Theme paper: Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

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In order to evaluate a potential functional role of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in development of obesity, we studied the effect of overexpression of human TIMP-1 (hTIMP-1) in C57Bl/6J mice in vivo and in 3T3-F442A preadipocytes in vitro. Stable long-term overexpression of hTIMP-1 in mice was achieved by adenoviral gene transfer, yielding plasma levels exceeding 250 ng/ml at eight weeks after injection. Mice overexpressing hTIMP-1 and kept on a high fat diet for 14 weeks had body weights, adipose tissue weights, and adipocyte diameters that were somewhat, but not significantly, lower than those of control mice. Similar observations were made after overexpression of hTIMP-1 in mice with lipectomy of the subcutaneous adipose tissue, kept on a high fat diet for 20 weeks. In both in vivo models, blood vessels in the adipose tissues were significantly smaller after hTIMP-1 gene transfer than in control mice. Overexpression of hTIMP-1 in 3T3-F442A preadipocytes had no effect on their subsequent differentiation into mature adipocytes. Thus, overexpression of hTIMP-1 in mice had no significant effect on ongoing adipogenesis or adipose tissue development, although the blood vessel size in adipose tissues was reduced.