Gamma-Aminobutyric Acid (GABA) Promotes Growth in Zebrafish Larvae by Inducing IGF-1 Expression via GABAA and GABAB Receptors

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.

Effect of Fermented Sarco Oyster (Crassostrea gigas) Extract on Muscle Strength Enhancement in Postmenopausal Females: A Randomized, Double-Blind, Placebo-Controlled Trial

“…They are rich in protein, minerals, and various essential amino acids [ 9 ]. GABA is a non-protein amino acid that functions as a primary inhibitory neurotransmitter for the central nervous system and contributes to motor control, GH secretion, and emotion regulation [ 7 , 20 ]. Oysters contain a small amount of GABA, but not enough to promote their use as a functional food.…”

“…IGF-1 plays a key role and has been shown to stimulate muscle cell proliferation and act as a regulator for both muscle protein synthesis and degradation [ 5 ]. Studies have proven that γ-aminobutyric acid (GABA) can directly or indirectly stimulate GH release and IGF-1 expression [ 6 , 7 ].…”

Fermented Oyster (Crassostrea gigas) Extract Cures and Prevents Prednisolone-Induced Bone Resorption by Activating Osteoblast Differentiation

“…The ultra-performance liquid chromatography (UPLC) for amino acids of FO revealed that FO contained approximately 24.5% GABA from the total amino acid content [ 21 ]. Furthermore, in our recent studies, we found that GABA directly regulated growth performances in zebrafish larvae through GABA A and GABA B receptors, indicating the potent influence of GABA in FO-mediated growth performances [ 27 ]. Nevertheless, the therapeutic and preventive effects of FO have not been elucidated in glucocorticoid-induced secondary bone resorption.…”

Identification of Potential miRNA–mRNA Regulatory Network Associated with Pig Growth Performance in the Pituitaries of Bama Minipigs and Landrace Pigs

“…Gamma-aminobutyric acid (GABA) is widely distributed in the peripheral endocrine organs, such as the pituitary [ 34 ]. A study conducted by Athapaththu, A. et al found that GABA induced IGF-1 expression through GABA(A) and GABA(B) receptors and promotes the growth rate of zebrafish larvae through the IGF-1-IGF-1R axis [ 35 ]. Moreover, the malfunction of signaling molecules in the CCK/SRC/PI3K cascade reaction with leptin/JAK2/PI3K/STAT3 signaling pathway may lead to eating disorders [ 36 ].…”