Manipulation of the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) Axis: A Treatment Strategy to Reverse the Effects of Early Life Developmental Programming

Abstract

Evidence from human clinical, epidemiological, and experimental animal models has clearly highlighted a link between the early life environment and an increased risk for a range of cardiometabolic disorders in later life. In particular, altered maternal nutrition, including both undernutrition and overnutrition, spanning exposure windows that cover the period from preconception through to early infancy, clearly highlight an increased risk for a range of disorders in offspring in later life. This process, preferentially termed "developmental programming" as part of the developmental origins of health and disease (DOHaD) framework, leads to phenotypic outcomes in offspring that closely resemble those of individuals with untreated growth hormone (GH) deficiency, including increased adiposity and cardiovascular disorders. As such, the use of GH as a potential intervention strategy to mitigate the effects of developmental malprogramming has received some attention in the DOHaD field. In particular, experimental animal models have shown that early GH treatment in the setting of poor maternal nutrition can partially rescue the programmed phenotype, albeit in a sex-specific manner. Although the mechanisms remain poorly defined, they include changes to endothelial function, an altered inflammasome, changes in adipogenesis and cardiovascular function, neuroendocrine effects, and changes in the epigenetic regulation of gene expression. Similarly, GH treatment to adult offspring, where an adverse metabolic phenotype is already manifest, has shown efficacy in reversing some of the metabolic disorders arising from a poor early life environment. Components of the GH-insulin-like growth factor (IGF)-IGF binding protein (GH-IGF-IGFBP) system, including insulin-like growth factor 1 (IGF-1), have also shown promise in ameliorating programmed metabolic disorders, potentially acting via epigenetic processes including changes in miRNA profiles and altered DNA methylation. However, as with the use of GH in the clinical setting of short stature and GH-deficiency, the benefits of treatment are also, in some cases, associated with potential unwanted side effects that need to be taken into account before effective translation as an intervention modality in the DOHaD context can be undertaken.

Keywords: developmental programming; early life nutrition; epigenetics; growth hormone; insulin-like growth factor.

Figure 1

Hepatic insulin-like growth factor binding protein 2 (IGFBP-2) expression in (a) adult male offspring from mothers either undernourished (UN) or fed high fat (HF) diets during pregnancy as compared to offspring from normally nourished mothers; (b) hepatic IGFBP-2 expression in adult male offspring of UN mothers treated with growth hormone (GH) during the pre-weaning period. * p < 0.05 versus Control. Data are mean ± standard error of the mean (SEM), n = 10 per group. Note that the UN groups shown for (a,b) are derived from independent animal cohorts. Figure 1a reimaged from [63].