IGF-Binding Protein-2 Protects Against the Development of Obesity and Insulin Resistance

Wheatcroft, Stephen; Kearney, Mark T.; Shah, Ajay M.; Ezzat, Vivienne; Miell, John; Modo, Michel; Williams, Steven; Cawthorn, William P.; Medina-Gómez, Gema; Vidal-Puig, António; Sethi, J.; Crossey, Paul A.

doi:10.2337/db06-0436

Cited by 242 publications

(237 citation statements)

References 44 publications

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“…We now extend these observations and show that IGFBP1 predicts incident HF, all‐cause mortality, and CVD mortality in our cohort, along with 3 other regulators of metabolic disease and adipocyte function: IGFBP2, adipsin, and leptin. IGFBP2 is the predominant insulin‐like growth factor binding protein (IGFBP) produced by white adipose tissue and is thought to protect against obesity and insulin resistance in mice 8, 22. Previous studies, however, did not demonstrate any relation to CVD outcomes 10, 21.…”

Section: Discussionmentioning

confidence: 99%

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Lyass

Courchesne

et al. 2018

JAHA

210

228

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BackgroundThe discovery of novel and highly predictive biomarkers of cardiovascular disease (CVD) has the potential to improve risk‐stratification methods and may be informative regarding biological pathways contributing to disease.Methods and ResultsWe used a discovery proteomic platform that targeted high‐value proteins for CVD to ascertain 85 circulating protein biomarkers in 3523 Framingham Heart Study participants (mean age, 62 years; 53% women). Using multivariable‐adjusted Cox models to account for clinical variables, we found 8 biomarkers associated with incident atherosclerotic CVD, 18 with incident heart failure, 38 with all‐cause mortality, and 35 with CVD death (false discovery rate, q<0.05 for all; P‐value ranges, 9.8×10−34 to 3.6×10−2). Notably, a number of regulators of metabolic and adipocyte homeostasis were associated with cardiovascular events, including insulin‐like growth factor 1 (IGF1), insulin‐like growth factor binding protein 1 (IGFBP1), insulin‐like growth factor binding protein 2 (IGFBP2), leptin, and adipsin. In a multimarker approach that accounted for clinical factors, growth differentiation factor 15 (GDF15) was associated with all outcomes. In addition, N‐terminal pro‐b‐type natriuretic peptide, C‐reactive protein, and leptin were associated with incident heart failure, and C‐type lectin domain family 3 member B (CLEC3B; tetranectin), N‐terminal pro‐b‐type natriuretic peptide, arabinogalactan protein 1 (AGP1), soluble receptor for advanced glycation end products (sRAGE), peripheral myelin protein 2 (PMP2), uncarboxylated matrix Gla protein (UCMGP), kallikrein B1 (KLKB1), IGFBP2, IGF1, leptin receptor, and cystatin‐C were associated with all‐cause mortality in a multimarker model.ConclusionsWe identified numerous protein biomarkers that predicted cardiovascular outcomes and all‐cause mortality, including biomarkers representing regulators of metabolic homeostasis and inflammatory pathways. Further studies are needed to validate our findings and define clinical utility, with the ultimate goal of improving strategies for CVD prevention.

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Section: Discussionmentioning

confidence: 99%

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Lyass

Courchesne

et al. 2018

JAHA

210

228

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“…Conversely, high IGFBP-2 levels as seen by overexpression of IGFBP-2 in mice appears to prevent diet induced obesity and insulin resistance, with IGFBP-2 also preventing murine adipocytes differentiation in vitro (Wheatcroft et al 2007b). Interestingly, recent studies by Xi et al (2013) have shown that IGFBP-2-based peptides containing the HBD motifs, efficiently inhibited preadipocyte differentiation in male mice, suggesting that IGFBP-2 cell surface interactions via these motifs might be implicated in the modulation of adipogenesis.…”

Section: Igfbp-2 and Metabolismmentioning

confidence: 99%

IGFBP-2 - taking the lead in growth, metabolism and cancer

Yau

Azar

Sabin

et al. 2015

J. Cell Commun. Signal.

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The activity of the Insulin-like Growth Factors (IGFs) ligands elicited via their receptors and transduced by various intracellular signal pathways is modulated by the IGF Binding Proteins (IGFBPs). Among all the IGFBPs, IGFBP-2 has been implicated in the regulation of IGF activity in most tissue and organs. Besides binding to IGFs in the circulation these IGF-regulatory activities of IGFBP-2 involve interactions with components of the extracellular matrix, cell surface proteoglycans and integrin receptors. In addition to these local peri-cellular activities, IGFBP-2 exerts other key functions within the nucleus, where IGFBP-2 directly or indirectly promotes transcriptional activation of specific genes. All of these IGFBP-2 activities, intrinsic or dependent on IGFs, contribute to its functional roles in growth/development, metabolism and malignancy as evidenced by studies in IGFBP-2 animal models and also by many in vitro studies. Finally, preclinical studies have demonstrated that IGFBP-2 administration can be beneficial in improving metabolic responses (inhibition of adipogenesis and enhanced insulin sensitivity), while blockade of IGFBP-2 appears to be an effective approach to inhibiting tumour growth and metastasis.

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“…Consequently, it is necessary to assume that there are age‐ and tissue‐dependent effects of the RGD‐domain present in IGFBP‐2 for the control of fat accretion. At younger ages, overexpression of mouse IGFBP‐2 increased gonadal fat mass (Rehfeldt et al ., 2010), whereas overexpression of human IGFBP‐2 in mice blocked the development of age‐related obesity later in life (Wheatcroft et al ., 2007). The latter cannot be observed in the model included in this study; instead, these results indicate differential effects of mouse IGFBP‐2 in perinephric and other fat tissues.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

et al. 2015

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SummaryImpaired growth is often associated with an extension of lifespan. However, the negative correlation between somatic growth and life expectancy is only true within, but not between, species. This can be observed because smaller species have, as a rule, a shorter lifespan than larger species. In insects and worms, reduced reproductive development and increased fat storage are associated with prolonged lifespan. However, in mammals the relationship between the dynamics of reproductive development, fat metabolism, growth rate, and lifespan are less clear. To address this point, female transgenic mice that were overexpressing similar levels of either intact (D‐mice) or mutant insulin‐like growth factor‐binding protein‐2 (IGFBP‐2) lacking the Arg‐Gly‐Asp (RGD) motif (E‐ mice) were investigated. Both lines of transgenic mice exhibited a similar degree of growth impairment (−9% and −10%) in comparison with wild‐type controls (C‐mice). While in D‐mice, sexual maturation was found to be delayed and life expectancy was significantly increased in comparison with C‐mice, these parameters were unaltered in E‐mice in spite of their reduced growth rate. These observations indicate that the RGD‐domain has a major influence on the pleiotropic effects of IGFBP‐2 and suggest that somatic growth and time of sexual maturity or somatic growth and life expectancy are less closely related than thought previously.

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IGF-Binding Protein-2 Protects Against the Development of Obesity and Insulin Resistance

Cited by 242 publications

References 44 publications

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

Protein Biomarkers of Cardiovascular Disease and Mortality in the Community

IGFBP-2 - taking the lead in growth, metabolism and cancer

Dissociation of somatic growth, time of sexual maturity, and life expectancy by overexpression of an RGD ‐deficient IGFBP ‐2 variant in female transgenic mice

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