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. 2023 May 29;13(1):8700.
doi: 10.1038/s41598-023-35222-4.

Kynurenine promotes Calcitonin secretion and reduces cortisol in the Japanese flounder Paralichthys olivaceus

Takahiro Ikari  1 , Yukihiro Furusawa  2 , Yoshiaki Tabuchi  3 , Yusuke Maruyama  4 , Atsuhiko Hattori  4 , Yoichiro Kitani  1 , Kenji Toyota  1 , Arata Nagami  5 , Jun Hirayama  6 , Kazuki Watanabe  4   6 , Atsushi Shigematsu  5 , Muhammad Ahya Rafiuddin  5 , Shouzo Ogiso  1 , Keisuke Fukushi  7 , Kohei Kuroda  1 , Kaito Hatano  1 , Toshio Sekiguchi  1 , Ryotaro Kawashima  6 , Ajai K Srivastav  8 , Takumi Nishiuchi  9 , Akihiro Sakatoku  10 , Masa-Aki Yoshida  11 , Hajime Matsubara  5 , Nobuo Suzuki  12
Affiliations

Kynurenine promotes Calcitonin secretion and reduces cortisol in the Japanese flounder Paralichthys olivaceus

Takahiro Ikari et al. Sci Rep. .

Abstract

Deep ocean water (DOW) exerts positive effects on the growth of marine organisms, suggesting the presence of unknown component(s) that facilitate their aquaculture. We observed that DOW suppressed plasma cortisol (i.e., a stress marker) concentration in Japanese flounder (Paralichthys olivaceus) reared under high-density condition. RNA-sequencing analysis of flounder brains showed that when compared to surface seawater (SSW)-reared fish, DOW-reared fish had lower expression of hypothalamic (i.e., corticotropin-releasing hormone) and pituitary (i.e., proopiomelanocortin, including adrenocorticotropic hormone) hormone-encoding genes. Moreover, DOW-mediated regulation of gene expression was linked to decreased blood cortisol concentration in DOW-reared fish. Our results indicate that DOW activated osteoblasts in fish scales and facilitated the production of Calcitonin, a hypocalcemic hormone that acts as an analgesic. We then provide evidence that the Calcitonin produced is involved in the regulatory network of genes controlling cortisol secretion. In addition, the indole component kynurenine was identified as the component responsible for osteoblast activation in DOW. Furthermore, kynurenine increased plasma Calcitonin concentrations in flounders reared under high-density condition, while it decreased plasma cortisol concentration. Taken together, we propose that kynurenine in DOW exerts a cortisol-reducing effect in flounders by facilitating Calcitonin production by osteoblasts in the scales.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Changes in the plasma cortisol concentrations in flounder at 5 and 10 days after rearing with surface seawater (SSW) or deep ocean water (DOW). (A) Schematic of experimental setup for Fig. 1B and C. Fish were kept under low density condition with SSW, then transferred to the high density condition with SSW (B) or DOW (C). Blood analytical samples were prepared from fish at the indicated points after the transfer to the high density condition. Black and white bars represent low density and high density conditions, respectively. Flounder in SSW and DOW, n = 7.
Figure 2
Figure 2
Changes in the plasma component (total protein: TP, albumin: ALB, and urea nitrogen: UN) and mineral (sodium ion: Na+, potassium ion: K+, chloride ion: Cl−) concentrations at 10 days after rearing flounder with SSW or DOW. SSW: n = 7; DOW: n = 7.
Figure 3
Figure 3
Changes in the plasma calcium ion (Ca2+) (mg/dl) (A) and Calcitonin (pg/ml) (B) concentrations at 10 days after rearing flounder with SSW or DOW. SSW: n = 7; DOW: n = 7, *P < 0.05.
Figure 4
Figure 4
Gene network analysis of flounder brain: Analysis of Calcitonin's analgesic action and stress response. Differentially expressed genes in the brain of flounder reared with DOW were compared to those in the brain of flounder reared with SSW using the Ingenuity Pathway Analysis tools. The network is represented graphically with nodes (genes) and edges (the biological associations between the nodes). bambi: bmp and activin membrane bound inhibitor, calcr: calcitonin receptor, cartpt: cart prepropeptide, chrm2: cholinergic receptor muscarinic 2, crh: corticotropin releasing hormone, Erk1/2: Extracellular signal-regulated kinase, ghr: growth hormone receptor, gper1: G protein-coupled estrogen receptor 1, grk3: G protein-coupled receptor kinase 3, grk5: G protein-coupled receptor kinase 5, grm1: glutamate metabotropic receptor 1, grm5: glutamate metabotropic receptor 5, nos1: nitric oxide synthase 1, oprd1: opioid receptor delta 1, pomc: proopiomelanocortin, trpv1: transient receptor potential cation channel subfamily V member 1.
Figure 5
Figure 5
Effects of SSW and DOW on osteoblastic activity (A), mRNA expression of osteoblastic markers (B, dlx5), (C, collagen type I alpha 1: col1a1), and (D, calcitonin) in fish scales. SSW: n = 8; DOW: n = 8, *P < 0.05; **P < 0.01.
Figure 6
Figure 6
Effects of kynurenine on the concentrations of plasma cortisol (A), Ca2+ (B), and Calcitonin (C) at 5 days after rearing founder with or without kynurenine (10−6 M). Each n = 10, *P < 0.05.
Figure 7
Figure 7
Effects of kynurenine on osteoblastic activity (A) and calcitonin mRNA expression (B) in goldfish scales. Osteoblastic activity and calcitonin mRNA expression were assessed using an independent sample t test or paired t test, respectively. Each n = 8, *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 8
Figure 8
A proposed model of the mechanism underlying kynurenine-mediated suppression of cortisol secretion. Ct: Calcitonin, Ctr: Calcitonin receptor, DOW: Deep ocean water, crh: corticotropin-releasing hormone, pomc: pro-opiomelanocortin.
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