Nutrient-hormone interaction in the ovine liver: methionine supply selectively modulates growth hormone-induced IGF-I gene expression

Abstract

This study tested the hypothesis that specific amino acids are responsible for modulating the insulin-like growth factor-I (IGF-I) response to growth hormone (GH) in ovine hepatocytes. Cells were grown in media of defined amino acid composition, based on physiological concentrations (P.C.) of amino acids in sheep plasma. Relative to culture in 5 P.C., amino acid limitation to 0·2 P.C. had inhibitory effects on IGF-I RNA expression, peptide release and p70 S6 kinase phosphorylation (P<0·01 in each case). Limitation of methionine levels to 0·2 P.C. against a background of 5 P.C. for the other amino acids blocked GH-stimulated IGF-I peptide release and RNA expression, although basal expression was unaffected. In contrast, limitation of the other amino acids present in the culture medium had no effect on basal or GH-stimulated IGF-I expression. Selective methionine limitation to 0·2 P.C. levels had no effect on cellular or secretory protein synthesis rates relative to cells grown in complete 5 P.C. medium but did cause a partial reduction in p70 S6 kinase phosphorylation, which was also observed when medium was selectively limited for other essential amino acids. The addition of rapamycin (5 ng/ml) to cells grown in 5 P.C. media completely abolished p70 S6 kinase phosphorylation (P<0·001), implicating mTOR in the response of S6 kinase phosphorylation to changing amino acid supply. By contrast, inclusion of rapamycin (100 ng/ ml) had no effect on levels of IGF-I gene expression. These results indicate that methionine is the key limiting amino acid involved in the modulation of IGF-I expression in the ovine liver. This nutrient-hormone interaction is a highly selective phenomenon, occurring against a background of modest effects on general protein synthetic control. The partial inhibitory effects of methionine on mTOR activity are not sufficient to account for this selectivity of action.

Lifespan modification by glucose and methionine in Drosophila melanogaster fed a chemically defined diet

“…Methionine metabolism is abnormal in long-lived mutant mice that are deficient in growth hormone, prolactin and thyroid stimulating hormone (Uthus and Brown-Borg 2003;Brown-Borg et al 2005;Uthus and Brown-Borg 2006). Furthermore, methionine restriction specifically inhibits the induction of IGF-I expression by growth hormone in pig hepatocytes (Stubbs et al 2002), indicating a potential regulatory interaction of methionine metabolism on the growth hormone-IGF-I signaling pathway. It is also conceivable that methionine restriction could impact on the amino acid (leucinesensitive) TOR pathway, if only through indirect effects on branched chain amino acid metabolism Kimball and Jefferson 2006).…”

Dietary methionine effects on IGF-I and GHR mRNA expression in broilers

“…IGF-I release mechanism is induced by GH and it is interfered by methionine concentrations. Animals fed low-content total amino acid diet showed no reduction on IGF-I release, suggesting a selective methionine-inhibitory response to GH transcription factor interference in liver IGF-I gene expression (Stubbs et al, 2002).…”

“…Methionine supplementation interferes in growth factor regulation such as, GHR and IGF-I, and this action of methionine may be related to the activity of mTOR (mammalian target of rapamycin). mTOR is an enzyme involved in protein synthesis regulation by mechanisms dependent or not on insulin (Stubbs et al, 2002). Amino acids act not only in translation initiation and on elongation factors, but amino acids also act on signaling pathways for the synthesis of proteins that were previously thought to be influenced only by hormones (Kimball and Jefferson, 2006).…”

Acute heat stress and dietary methionine effects on IGF-I, GHR, and UCP mRNA expression in liver and muscle of quails

“…Although how changes in amino acid supplementation can initiate changes in expression of genes such as GH and IGF-I is not yet fully clarified, it is suggested that the mammalian target of rapamycin (mTOR) activity, an enzyme involved in regulating protein synthesis, may mediate this effect (Stubbs et al 2002).…”