Abstract
Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish larvae treated with GABA at three days post fertilization (dpf) showed a significant increase in the total body length from 6 to 12 dpf through upregulation of growth-stimulating genes, including IGF-1, growth hormone-1 (GH-1), growth hormone receptor-1 (GHR-1), and cholecystokinin A (CCKA). In particular, at 9 dpf, GABA increased total body length from 3.60 ± 0.02 to 3.79 ± 0.03, 3.89 ± 0.02, and 3.92 ± 0.04 mm at concentrations of 6.25, 12.5, and 25 mM, and the effect of GABA at 25 mM was comparable to 4 mM β-glycerophosphate (GP)-treated larvae (3.98 ± 0.02 mm). Additionally, the highest concentration of GABA (50 mM) -induced death in 50% zebrafish larvae at 12 dpf. GABA also enhanced IGF-1 expression and secretion in preosteoblast MC3T3-E1 cells, concomitant with high levels of the IGF-1 receptor gene (IGF-1R). In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R. Furthermore, we investigated the effect of GABA receptors on growth performance along with IGF-1 activation. Inhibitors of GABAA and GABAB receptors, namely bicuculline and CGP 46381, respectively, considerably inhibited GABA-induced growth rate in zebrafish larvae accompanied by a marked decrease in the expression of growth-stimulating genes, including IGF-1, GH-1, GHR-1, and CCKA, but not with an inhibitor of GABAC receptor, TPMPA. Additionally, IGF-1 and IGF-1R expression was impaired in bicuculline and CGP 46381-treated MC3T3-E1 cells, but not in the cells treated with TPMPA. Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABAA and GABAB receptors and leads to growth promotion performance via IGF-1R.
Highlights
The growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis is primarily responsible for the promotion of longitudinal growth in children and adolescents [1]
3.86 ± 0.03 mm at 6.25, 12.5, 25, and 50 mM gamma-aminobutyric acid (GABA), respectively) compared to the untreated larvae (3.60 ± 0.02 mm); we noticed that the effect of GABA on growth rate was sustained during 9–12 dpf (3.89 ± 0.03, 3.96 ± 0.05, 4.01 ± 0.03, and 3.92 ± 0.04 mm at 6.25, 12.5, 25, and 50 mM GABA, respectively) compared to the untreated larvae (3.77 ± 0.03 mm)
GABA+TPMPA-treated cells, respectively; Figure 5F). These results indicate that GABAmediated IGF-1 and IGF-1 receptor gene (IGF-1R) expressions are regulated by GABAA and GABAB receptors
Summary
The growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis is primarily responsible for the promotion of longitudinal growth in children and adolescents [1]. GH deficiency is associated with visceral obesity [5], impaired quality of life [6], and increased mortality [7] among children and is mediated via inhibition of IGF-1 expression, while growth hormone replacement therapies have been shown to improve these disorders [8]. Most serum IGF-1 tend to interact with IGFBP-3 [9], which is transactivated by GH [10], indicating that crosstalk between GH and IGF-1 is interconnected and responsible for host growth, and regulation of metabolic disorders. GABA-mediated growth performance of zebrafish larvae was impaired in the presence of a GABAA receptor antagonist, bicuculline, and a GABAB receptor antagonist, CGP 46381, indicating that supplementation with GABA upregulates IGF-1 expression through GABAA and GABAB receptors, leading to stimulated growth performance via IGF-1R
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