title: Macrophage elastase suppresses white adipose tissue expansion with cigarette smoking.
abstract: Macrophage elastase (MMP12) is a key mediator of cigarette smoke (CS)-induced emphysema, yet its role in other smoking related pathologies remains unclear. The weight suppressing effects of smoking are a major hindrance to cessation efforts, and MMP12 is known to suppress the vascularization on which adipose tissue growth depends by catalyzing the formation of antiangiogenic peptides endostatin and angiostatin. The goal of this study was to determine the role of MMP12 in adipose tissue growth and smoking-related suppression of weight gain. Whole body weights and white adipose depots from wild-type and Mmp12-deficient mice were collected during early postnatal development and after chronic CS exposure. Adipose tissue specimens were analyzed for angiogenic and adipocytic markers and for content of the antiangiogenic peptides endostatin and angiostatin. Cultured 3T3-L1 adipocytes were treated with adipose tissue homogenate to examine its effects on vascular endothelial growth factor (VEGF) expression and secretion. MMP12 content and activity were increased in the adipose tissue of wild-type mice at 2 weeks of age, leading to elevated endostatin production, inhibition of VEGF secretion, and decreased adipose tissue vascularity. By 8 weeks of age, adipose MMP12 levels subsided, and the protein was no longer detectable. However, chronic CS exposure led to macrophage accumulation and restored adipose MMP12 activity, thereby suppressing adipose tissue mass and vascularity. Our results reveal a novel systemic role for MMP12 in postnatal adipose tissue expansion and smoking-associated weight loss by suppressing vascularity within the white adipose tissue depots.
authors.affiliation: 1 Department of Medicine, UPMC and University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Takao
authors.initials: T
authors.lastname: Tsuji
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Kelly
authors.forename: Saeko
authors.initials: S
authors.lastname: Takahashi
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Leme
authors.forename: A McGarry
authors.initials: AM
authors.lastname: Houghton
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D041721:3T3-L1 Cells; D052436:Adipose Tissue, White / Q000098:blood supply / Q000201:enzymology* / Q000276:immunology; D050154:Adiposity; D000818:Animals; D001835:Body Weight; D043169:Endostatins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D053508:Matrix Metalloproteinase 12 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012907:Smoking / Q000276:immunology / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043169:Endostatins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D053508:Matrix Metalloproteinase 12
keywords: angiogenesis; obesity; proteases