Associations of GHR, IGF-1 and IGFBP-3 expression in adipose tissue cells with obesity-related alterations in corresponding circulating levels and adipose tissue function in children

Abstract

Components of the growth hormone (GH) axis, such as insulin-like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP-3), GH receptor (GHR) and GH-binding protein (GHBP), regulate growth and metabolic pathways. Here, we asked if serum levels of these factors are altered with overweight/obesity and if this is related to adipose tissue (AT) expression and/or increased fat mass. Furthermore, we hypothesized that expression of GHR, IGF-1 and IGFBP-3 is associated with AT function. Serum GHBP levels were increased in children with overweight/obesity throughout childhood, while for IGF-1 levels and the IGF-1/IGFBP-3 molar ratio obesity-related elevations were detectable until early puberty. Circulating levels did not correlate with AT expression of these factors, which was decreased with overweight/obesity. Independent from obesity, expression of GHR, IGF-1 and IGFBP-3 was related to AT dysfunction,and increased insulin levels. Serum GHBP was associated with liver fat percentage and transaminase levels. We conclude that obesity-related elevations in serum GHBP and IGF-1 are unlikely to be caused by increased AT mass and elevations in GHBP are more closely related to liver status in children. The diminished AT expression of these factors with childhood obesity may contribute to early AT dysfunction and a deterioration of the metabolic state.

Growth Hormone Mediators and Glycemic Control in Youths With Type 2 Diabetes

“…Plasma GHR levels were recently reported to be associated with incident T2D in a large cohort study, and reductions in GHR levels were identified as a causal mediator of improvements in glycemia after bariatric surgery in adults with T2D . Prior studies showed that circulating GHR positively correlates with hepatosteatosis and adiposity in children with obesity, and we did find in our exploratory analyses that GHR level is positively associated with both BMI z score and fat mass in both sexes. Therefore, it is possible that an increase in GHR level due to increased BMI and insulin resistance in individuals with T2D may attenuate GH activity in the liver to stimulate IGF-1 synthesis.…”

IGF-1 and IGF-2 as Molecules Linked to Causes and Consequences of Obesity from Fetal Life to Adulthood: A Systematic Review

“…Data on the relationship between IGF-1 levels and weight in children are inconsistent. There are studies describing comparable [2], lower [29][30][31][32][33], or higher [3,20,[34][35][36][37][38][39][40][41] IGF-1 levels and higher IGF-2 levels [4] in obese children compared to their normal-weight peers. However, IGF-1 shows a tendency to drop in children with extremely high BMI values [39].…”

“…Children with obesity are usually taller than their normal-weight peers, which may be caused by increased circulating levels of IGF-1 [3,20,52,53], as GH release is suppressed, which implies that their height is rather GF-independent [20] or might be caused by increased adrenal androgens [54]. One study [30] reports the higher stature of obese children but also lower IGF-1 compared to a normal-weight control group.…”

“…One study [30] reports the higher stature of obese children but also lower IGF-1 compared to a normal-weight control group. Furthermore, a higher BMI in childhood is positively correlated with a higher IGF-1 level due to associated hormones, such as insulin, that are well known as being influential on human growth [20,50] rather than being caused by excessive fat tissue [3].…”

“…The protein group of insulin-like growth factors plays a key role in metabolic processes [2]. Children experiencing overweight or obesity tend to have higher serum levels of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2), specifically during the phase before or at the onset of puberty [3,4]. In adulthood, IGF-1 can potentially work as a mitogen factor, and IGF-2 may contribute to greater tumor aggression [5,6].…”