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β‐Hydroxybutyric Acid Inhibits Growth Hormone‐Releasing Hormone Synthesis and Secretion Through the GPR 109A/Extracellular Signal‐Regulated 1/2 Signalling Pathway in the Hypothalamus
Author(s) -
Fu S.P.,
Liu B.R.,
Wang J.F.,
Xue W.J.,
Liu H.M.,
Zeng Y.L.,
Huang B.X.,
Li S.N.,
Lv Q.K.,
Wang W.,
Liu J.X.
Publication year - 2015
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12256
Subject(s) - endocrinology , medicine , hypothalamus , mapk/erk pathway , receptor , kinase , signal transduction , biology , chemistry , microbiology and biotechnology
β‐hydroxybutyric acid ( BHBA ) has recently been shown to regulate hormone synthesis and secretion in the hypothalamus. However, little is known about the effects of BHBA ‐mediated hormone regulation or the detailed mechanisms by which BHBA regulates growth hormone‐releasing hormone ( GHRH ) synthesis and secretion. In the present study, we examined the expression of the BHBA receptor GPR 109A in primary hypothalamic cell cultures. We hypothesised that BHBA regulates GHRH via GPR 109A and its downstream signals. Initial in vivo studies conducted in rats demonstrated that GHRH m RNA expression in the hypothalamus was strongly inversely correlated with BHBA levels in the cerebrospinal fluid during postnatal development (r = −0.89, P < 0.01). Furthermore, i.c.v. administration of BHBA acutely decreased GHRH m RNA expression in rats. Further in vitro studies revealed a decrease in GHRH synthesis and secretion in primary hypothalamic cells after treatment with BHBA ; this effect was inhibited when hypothalamic cells were pretreated with pertussis toxin ( PTX ). BHBA had no effect on GHRH synthesis and secretion in GT 1‐7 cells, which do not exhibit cell surface expression of GPR 109A. Furthermore, BHBA acutely decreased the transcription of the homeobox gene for Gsh‐1 in the hypothalamus in both in vivo and in vitro , and this effect was also inhibited by PTX in vitro . In primary hypothalamic cells, BHBA activated the extracellular signal‐regulated kinase ( ERK) 1/2, p38 and c‐Jun N‐terminal kinase mitogen‐activated protein kinase ( MAPK) kinases, as shown by western blot analysis. Moreover, inhibition of ERK 1/2 with U0126 attenuated the BHBA ‐mediated reduction in Gsh‐1 expression and GHRH synthesis and secretion. These results strongly suggest that BHBA directly regulates GHRH synthesis and secretion via the GPR 109A/ ERK 1/2 MAPK pathway, and also that Gsh‐1 is essential for this function.