Control of adipose tissue expandability in response to high fat diet by the insulin-like growth factor-binding protein-4.
Adipose tissue expansion requires growth and proliferation of adipocytes and the concomitant expansion of their stromovascular network. We have used an ex vivo angiogenesis assay to study the mechanisms involved in adipose tissue expansion. In this assay, adipose tissue fragments placed under pro-angiogenic conditions form sprouts composed of endothelial, perivascular, and other proliferative cells. We find that sprouting was directly stimulated by insulin and was enhanced by prior treatment of mice with the insulin sensitizer rosiglitazone. Moreover, basal and insulin-stimulated sprouting increased progressively over 30 weeks of high fat diet feeding, correlating with tissue expansion during this period. cDNA microarrays analyzed to identify genes correlating with insulin-stimulated sprouting surprisingly revealed only four positively correlating (Fads3, Tmsb10, Depdc6, and Rasl12) and four negatively correlating (Asph, IGFbp4, Ppm1b, and Adcyap1r1) genes. Among the proteins encoded by these genes, IGFbp4, which suppresses IGF-1 signaling, has been previously implicated in angiogenesis, suggesting a role for IGF-1 in adipose tissue expandability. Indeed, IGF-1 potently stimulated sprouting, and the presence of activated IGF-1 receptors in the vasculature was revealed by immunostaining. Recombinant IGFbp4 blocked the effects of insulin and IGF-1 on mouse adipose tissue sprouting and also suppressed sprouting from human subcutaneous adipose tissue. These results reveal an important role of IGF-1/IGFbp4 signaling in post-developmental adipose tissue expansion.
From the Program in Molecular Medicine.
Olga
O
Gealekman
From the Program in Molecular Medicine.
Kunal
K
Gurav
From the Program in Molecular Medicine.
My
M
Chouinard
From the Program in Molecular Medicine.
Juerg
J
Straubhaar
Department of Medicine, and Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Michael
M
Thompson
Department of Medicine, and.
Samir
S
Malkani
Department of Medicine, and.
Celia
C
Hartigan
From the Program in Molecular Medicine, silvia.corvera@umassmed.edu.
Silvia
S
Corvera
D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction
D004041:Dietary Fats; D018974:Insulin-Like Growth Factor Binding Protein 4; D007334:Insulin-Like Growth Factor I
Adipocyte; Angiogenesis; Endothelial Cell; Insulin; Insulin-like Growth Factor (IGF); Obesity; Vascular Biology