Effect of rhGH treatment on lipidome and brown fat activity in prepuberal small for gestational age children: a pilot study

Abstract

Recombinant human growth hormone (rhGH) therapy is the primary treatment for children born small for gestational age (SGA) who fail to show spontaneous catch-up growth by two or four years. While its effects on white adipose tissue are well-documented, this pilot study aimed to investigate its impact on the lipidome and the thermogenic and endocrine activities of brown adipose tissue (BAT) in SGA children following rhGH treatment. The study involved 11 SGA children divided into two groups: (a) SGA children who were not treated with rhGH (n = 4) and (b) SGA children who received rhGH treatment with Saizen^® (n = 7). This second group of seven SGA children was followed for 12 months after initiating rhGH treatment. Interventions included 12-hour fasting blood extraction and infrared thermography at baseline and 3 and 12 months post-treatment. Five appropriate-for-gestational-age (AGA) children served as controls. Exclusion criteria included endocrinological, genetic, or chronic diseases. Untargeted lipidomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS), and serum biomarker levels were measured using ELISA assays. Serum lipidomic analysis revealed that free fatty acids (FFAs) increased to levels close to those of the AGA group after three months of rhGH administration, including polyunsaturated fatty acids, correlating with reduced leptin levels. Elevated levels of 1a,1b-dihomo-PGJ2 and adrenic acid suggested potential aging markers. rhGH treatment also significantly reduced meteorin-like (METRNL) and monocyte chemoattractant protein-1 (MCP1) serum levels to control levels. rhGH influences the serum lipidome, promoting changes in maturation and metabolism. Further research is required to clarify the direct effects of rhGH on specific lipid species and batokines, potentially addressing metabolic disturbances linked to obesity and aging.

Keywords: Brown adipose tissue; Lipidome; Recombinant human growth hormone; Small for gestational age.

Fig. 1

Study design. Schematic overview of the participant groups compared and the various approaches of this project, including analytical techniques such as untargeted lipidomics and serum biomarker analysis performed.

Fig. 2A

B. The bar plots illustrate the changes in lipid levels between the different groups. Each bar represents the mean lipid level for (A) L-carnitine and acylcarnitines, and (B) free fatty acids (FFAs) within a specific group, with error bars indicating the Standard Error of the Mean (SEM) (AGA, n = 5; SGA n = 4, SGA-GH 0 m, n = 7; SGA-GH 3 m, n = 7). Statistical significance was determined using the Mann-Whitney U test, p < 0.05. *p ≤ 0.05; **p ≤ 0.01.

Fig. 3A-B

The bar plots depict the changes in (A) 1a,1b-dihomo-PGJ2 / 1a,1b-dihomo-15-deoxy-delta-12,14-PGD2 and (B) odd-chain fatty acid levels at different growth stages and rhGH treatment. Each bar represents the mean lipid level for a specific group, and error bars denote the standard error of the mean (SEM). Statistical significance was determined using the Mann-Whitney U test, p < 0.05. *p ≤ 0.05; **p ≤ 0.01.

Fig. 4

Heatmaps of Lipid Changes by Lipid Category. Heatmaps illustrating the differential expression of lipid species across study groups and time points. Lipid species detected in the study were categorized into distinct categories: (A) glycerophospholipids, (B) fatty acyls, (C) sphingolipids, and (D) glycerolipids. Each heatmap represents the relative abundance of lipid species, with color gradients indicating the degree of change. Red and blue colors represent increased and decreased lipid levels, respectively. Compared with AGA controls, the heatmaps display lipid changes for SGA children before and after three months of rhGH treatment. These visualizations highlight significant lipid alterations associated with rhGH treatment and provide insights into the lipidomic profile changes influenced by the therapy.

Fig. 5A-C

Serum level profiles at baseline and after 3 and 12 months of rhGH treatment. Circulating (A) Leptin, (B) Monocyte chemoattractant protein-1 (MCP1), and (C) meteorin-like (METRNL) levels in AGA and SGA children untreated with rhGH and rhGH-treated SGA children at baseline, 3 and 12 months after rhGH administration. Data shown are means +/- SD. A two-tailed unpaired Student’s t-test was used to compare circulating protein levels in AGA, untreated SGA, and rhGH-treated SGA groups at baseline. One-way paired ANOVA was used to compare circulating protein levels in the SGA group at baseline, 3 and 12 months after rhGH treatment. *p ≤ 0.05; **p ≤ 0.01.

Fig. 6

Potential mechanisms underlying the metabolic shifts detected before and after rhGH administration compared with AGA children. The figure highlights key alterations, including increased free fatty acid (FFA) levels approaching those seen in AGA children, suggesting enhanced lipolysis and metabolic activity. Elevated levels of 1a,1b-dihomo-PGJ2 are indicative of potential aging markers and accelerated maturation processes. Increased carnitine levels facilitate fatty acid transport into mitochondria for β-oxidation, enhancing energy production. Conversely, decreased acylcarnitines reflect improved fatty acid utilization and mitochondrial function. Additionally, lower triacylglyceride (TG) levels post-treatment indicate altered lipid storage and metabolism. Arrows indicate the direction of change (↑ increase, ↓ decrease) in these metabolic markers, underscoring the dynamic metabolic adaptations in response to rhGH therapy and providing insights into its impact on lipid homeostasis and endocrine function in SGA children.