ABSTRACT
OBJECTIVE: Obesity is a major health problem associated with high morbidity and mortality. NSAID-activated gene (NAG-1) is a TGF-ß superfamily member reported to alter adipose tissue levels in mice. We investigated whether hNAG-1 acts as a regulator of adiposity and energy metabolism. DESIGN/SUBJECTS: hNAG-1 mice, ubiquitously expressing hNAG-1, were placed on a control or high-fat diet for 12 weeks. hNAG-1-expressing B16/F10 melanoma cells were used in a xenograft model to deliver hNAG-1 to obese C57BL/6 mice. RESULTS: As compared with wild-type littermates, transgenic hNAG-1 mice have less white fat and brown fat despite equivalent food intake, improved glucose tolerance, lower insulin levels and are resistant to dietary- and genetic-induced obesity. hNAG-1 mice are more metabolically active with higher energy expenditure. Obese C57BL/6 mice treated with hNAG-1-expressing xenografts show decreases in adipose tissue and serum insulin levels. hNAG-1 mice and obese mice treated with hNAG-1-expressing xenografts show increased thermogenic gene expression (UCP1, PGC1α, ECH1, Cox8b, Dio2, Cyc1, PGC1ß, PPARα, Elvol3) in brown adipose tissue (BAT) and increased expression of lipolytic genes (Adrb3, ATGL, HSL) in both white adipose tissue (WAT) and BAT, consistent with higher energy metabolism. CONCLUSION: hNAG-1 modulates metabolic activity by increasing the expression of key thermogenic and lipolytic genes in BAT and WAT. hNAG-1 appears to be a novel therapeutic target in preventing and treating obesity and insulin resistance.
Subject(s)
Adipose Tissue/metabolism , Growth Differentiation Factor 15/metabolism , Lipolysis , Obesity/prevention & control , Thermogenesis , Adipose Tissue/pathology , Animals , Blotting, Western , Diet, High-Fat , Eating , Energy Metabolism , Enzyme-Linked Immunosorbent Assay , Humans , Insulin Resistance , Mice , Mice, Inbred C57BL , Mice, Obese , Oxidative Stress/drug effects , Real-Time Polymerase Chain ReactionABSTRACT
Membrane-type I matrix metalloproteinase (MT1-MMP) is associated with multiple forms of cancer including mammary cancer. To directly evaluate the significance of MT1-MMP expression in tumor progression and metastasis using a genetically induced cancer model, we crossed MT1-MMP-deficient mice to MMTV-polyoma virus middle T-antigen (PyMT) mice. Expression of PyMT in the MT1-MMP-deficient background consistently resulted in hyperplasia of the mammary gland as seen in wild-type PyMT littermates. Following orthotopic transplantation of PyMT+ glands into the cleared mammary fat pad of syngeneic recipient mice, MT1-MMP-deficient tumors were palpable earlier than wild-type tumors. Moreover, MT1-MMP-deficient tumors grew to the experimental end point size quicker than control tumors, but demonstrated markedly reduced ability to metastasize to the lungs of recipient mice. Accordingly, MT1-MMP-deficient mice displayed an overall reduction in metastasis count of 50%. MT1-MMP was expressed solely in the stroma of PyMT-induced tumors and those metastatic nodules that formed in the lungs were devoid of MT1-MMP expression. Stromal fibroblasts isolated from MT1-MMP-deficient tumors did not degrade type I collagen suggesting that efficient dissemination of tumor cells is dependent on stromal cell remodeling of the tumor environment. The data demonstrate directly that MT1-MMP-mediated proteolysis by stromal cells is important in the metastatic process.
Subject(s)
Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Mammary Neoplasms, Experimental/genetics , Mammary Neoplasms, Experimental/pathology , Matrix Metalloproteinase 14/physiology , Neoplasm Metastasis , Animals , Cell Proliferation , Collagen/metabolism , Disease Progression , Female , Gene Expression Regulation, Neoplastic , Matrix Metalloproteinase 14/genetics , Matrix Metalloproteinase 14/metabolism , Mice , Models, Biological , Neoplasm Invasiveness , Protein Processing, Post-Translational , Stromal Cells/metabolism , Tumor Cells, Cultured , Up-RegulationABSTRACT
To study whether eruption of teeth and root growth require remodeling of collagen in the peridental tissues, we studied molar development in mice deficient in MT1-MMP, an enzyme essential for remodeling of soft tissue-hard tissue interfaces. The lower jaws of deficient mice and their wildtype littermates were subjected to stereologic analysis. It was shown that in deficient animals, eruption and root elongation were severely inhibited, signifying a role of the enzyme in these developmental processes.
