FP08-4 Specific Heparin Binding Domains Within IGFBP2 Mediate Its Ability to Inhibit Preadipocyte Differentiation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP08-Obesity: Novel Mechanisms of Body Weight Regulation
Basic/Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:15 AM
Room 301 (Moscone Center)

Poster Board SAT-650
Gang Xi*1, Melissa Solum1, Christine Wai1, Clifford J Rosen2 and David R Clemmons1
1University of North Carolina at Chapel Hill, Chapel Hill, NC, 2Maine Medical Cntr Research Inst, Scarborough, ME
IGFBP2 contains two heparin binding domains (HBD), localized in the linker (HBD1) and C-terminal regions (HBD2). HBD2 shares sequence similarity with HBDs in other IGFBPs. We reported that an HBD1 peptide stimulated osteoblast growth but HBD2 had no effect. IGFBP2 prevents the development of obesity but the roles of the HBD domains have not been determined. Therefore we investigated if peptides containing the HBD1 or 2 sequences could replicate the effect of the whole molecule on fat development. The results showed that addition of wild type IGFBP-2 markedly inhibited the differentiation of primary preadipocytes isolated from IGFBP-2 -/- mice. Both HBD1 and HBD2 inhibited fat cell differentiation but HBD2 was more effective. Substitution of key charged residues in the HBD1 or HBD2 regions resulted in attenuation of their ability to inhibit differentiation. The HBD2 mutant form of IGFBP2 which contained an intact HBD1 sequence was less effective, suggesting that the HBD2 domain might play more important role in inhibiting adipogenesis. To determine the effect of the HBD1 and HBD2 peptides on fat development in vivo, these two peptides were pegylated and administered to IGFBP-2-/- mice (50ug S.C., 3 times/week) for 12 weeks. Interestingly, both peptides significantly suppressed body weight gain after 12 weeks, compared to a control peptide. MRI scanning showed that both peptides reduced the gain of fat mass. However, HBD2 was more effective than HBD1 (e.g. 65 ± 15% reduction vs. 30 ± 3% reduction). In addition, although administration of both peptides significantly reduced the accumulation of both inguinal and visceral fat mass, HBD2 was to be more effective. For example, inguinal fat mass and visceral fat mass were reduced 35 ± 8% (p<0.05) of 28 ± 3% (p<0.05), respectively, in HBD2 treated mice, compared to control peptide treated mice. In contrast, they were reduced 21± 4% (p<0.05) and 6 ± 3% (p, NS) in HBD-1 treated mice, respectively. In addition, administration of both peptides reduced the triglyceride content in the inguinal fat pad and plasma adiponectin but only HBD2 significantly increased the plasma leptin levels compared to control peptide.This study clearly demonstrates that the HBD2 domain of IGFBP2 is the primary region that accounts for its ability to inhibit adipogenesis in vitro and fat development in vivo. Since the the HBD1 domain is more effective in osteoblasts, this suggests that the roles of the HBD domains may be cell type specific.

Nothing to Disclose: GX, MS, CW, CJR, DRC

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