IGFBP-2 inhibits adipogenesis and lipogenesis in human visceral, but not subcutaneous, adipocytes.

Abstract

BACKGROUND/OBJECTIVE:

IGF-binding protein (IGFBP)-2 is the principal IGFBP produced by white adipocytes during adipogenesis, and circulating levels are reduced in obesity. Overexpression of IGFBP-2 in transgenic mice prevents obesity, but depot-specific effects of IGFBP-2 on adipo/lipogenesis are unknown. The present study aimed to investigate whether IGFBP-2 affects adipo/lipogenesis in a depot-specific manner and explore potential mechanisms.

METHODS:

Following adipocyte characterisation, IGFBP-2 levels were measured from human subcutaneous and visceral preadipocytes, and IGFBP-2 dose-responses were then undertaken with exogenous IGFBP-2 in an in vitro IGF-I-free system to examine adipo/lipogenesis. Following this, both types of adipocytes were transfected with human siRNA IGFBP-2 to assess auto-/para-/intra-crine effects, with and without additional add-back IGFBP-2. To elucidate the potential mechanisms, visceral preadipocytes were treated with either wild-type or Heparin Binding Domain (HBD)-mutant IGFBP-2 (which is unable to bind to cell-surface components), and experiments were also undertaken using Echistatin (an integrin receptor blocker). Outcomes included gene expression profiles, protein levels and phosphorylation and lipid staining.

RESULTS:

Human visceral adipocytes produced significantly more IGFBP-2 than subcutaneous adipocytes. Subsequent dose-responses to IGFBP-2 demonstrated significant reductions in adipo/lipogenesis in visceral, but not subcutaneous, adipocytes in response to increasing IGFBP-2. Silencing IGFBP-2 resulted in exaggerated adipo/lipogenesis in visceral, but not subcutaneous, adipocytes, an effect completely inhibited by add-back IGFBP-2. These effects occurred in the absence of changes in IGF-I levels. HBD-mutant IGFBP-2 had reduced effects compared with wild-type IGFBP-2. Wild-type IGFBP-2 increased phosphorylation of focal adhesion kinase (FAK) and decreased phosphatase and tensin homolog (PTEN) levels, suggestive of integrin-mediated signalling. Blockade of this signalling, using Echistatin, completely negated the effects of IGFBP-2 on visceral adipo/lipogenesis.

CONCLUSION:

IGFBP-2 inhibits both adipogenesis and lipogenesis in visceral, but not subcutaneous, adipocytes. This depot-specific impairment appears to be independent of IGF-I and involves cell-surface association of IGFBP-2 and activation of integrin signalling pathways.

• Authors: S W Yau, V C Russo, I J Clarke, F R Dunshea, G A Werther, M A Sabin
• Journal: International journal of obesity (2005) (Int J Obes (Lond)) Vol. 39 Issue 5 Pg. 770-81 (May 2015) ISSN: 1476-5497 [Electronic] England
• PMID: 25370576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin-Like Growth Factor Binding Protein 2
• Intercellular Signaling Peptides and Proteins
• Peptides
• Platelet Aggregation Inhibitors
• echistatin
• Insulin-Like Growth Factor I

Topics

• Adipocytes (metabolism)
• Adipogenesis (drug effects)
• Animals
• Cell Differentiation (drug effects)
• Cells, Cultured
• Gene Expression Regulation
• Humans
• Insulin-Like Growth Factor Binding Protein 2 (pharmacology)
• Insulin-Like Growth Factor I (metabolism)
• Intercellular Signaling Peptides and Proteins
• Intra-Abdominal Fat (drug effects, metabolism, physiopathology)
• Lipogenesis (drug effects)
• Mice
• Mice, Transgenic
• Peptides (pharmacology)
• Phosphorylation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)