ABSTRACT

Dietary protein restriction in young rats decreases serum insulin-like growth factor-I (IGF-I) concentrations and the amount of liver IGF-I mRNA, suggesting that regulation for the liver IGF-I gene expression in this model occurs at a pretranslational level. To determine whether there is also translational control, we assessed the association of the liver IGF-I mRNA transcripts with polysomes in livers of normally fed (15% dietary protein) versus protein-restricted (5% dietary protein) rats. One week of dietary protein restriction reduces serum IGF-I concentrations by 54% and the amount of liver IGF-I mRNA by 35%, with the 7·5 kb size-class of IGF-I mRNA being the most affected (−48%). Protein restriction reduces the amount of the polysomal IGF-I mRNAs by 30%, a value in close agreement with the changes in total IGF-I mRNAs. Protein restriction is not associated with changes in the distribution of IGF-I mRNAs between the polysomal and non-polysomal fractions. All major size-classes of IGF-I mRNA transcripts (7·5, 4·7, 1·7, 0·9–1·2 kb) are associated with the polysomes in both dietary groups, suggesting involvement in the initiation phase of the IGF-I translation. We conclude that no untranslatable pool of IGF-I mRNAs is present in the liver of protein-restricted animals. Protein restriction, however, decreases slightly the mean size of polysomes. This decrease in ribosomal number associated with the IGF-I mRNA could decrease translational efficiency. Our data suggest that dietary protein restriction does not impair the initiation of IGF-I mRNA translation.

Journal of Endocrinology (1992) 132, 141–147

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.

Abstract

Zinc depletion attenuates growth and decreases circulating IGF-I. To investigate the mechanisms responsible for the IGF-I decline, we determined the effects of dietary zinc (Zn) deficiency on body and organ growth, serum IGF-I, serum GH-binding protein (GHBP), liver GH receptors and liver expression of their corresponding gene. After 1 week of adaptation to a normal zinc diet, a zinc-deficient diet (ZD; Zn, 0 p.p.m.) or a zinc-normal diet (CTR; Zn, 75 p.p.m.) was available ad libitum to 4-week-old Wistar rats for 4 weeks. Pair-fed animals (PF) received the zinc-normal diet in the same absolute amount as that consumed the day before by the ZD group. The food intake of ZD and PF rats was reduced by 32% (P<0·001) compared with the CTR group. Zinc depletion specifically reduced body weight gain (−22%, P<0·05), serum IGF-I concentrations (−52%, P<0·001), hepatic GH receptors (−28%; P<0·05) and serum GHBP levels (−51%; P<0·05), compared with the PF group. GH concentrations were reduced in ZD animals compared with CTR rats (P<0·01). The caloric restriction of PF animals also decreased body weight gain (−50%, P<0·001), serum IGF-I concentrations (−21%, P<0·05), liver GH receptors (−38%, P<0·001) and serum GHBP levels (−38%, P<0·01), when compared with the CTR group. Both ZD and PF groups had reduced liver IGF-I and GH receptor/GHBP mRNA levels in comparison with the CTR group (P<0·01). However, only liver IGF-I mRNA levels were specifically reduced by zinc deficiency (ZD vs PF rats; P<0·05). Our observations suggest that beside the decline of GH secretion, decreased hepatic GH receptors and/or GHBP concentrations might be responsible for the decline of circulating IGF-I in ZD animals.

Journal of Endocrinology (1995) 144, 449–456

Dietary zinc deficiency in rats causes growth retardation associated with decreased circulating IGF-I concentrations. To investigate the potential role of low IGF-I in this condition, we attempted to reverse the growth failure by administration of exogenous IGF-I. Rats were fed for 4 weeks a zinc-deficient diet (ZD, Zn 0 ppm) or were pair-fed a zinc-normal diet (PF, Zn 75 ppm). We compared the anabolic action of recombinant human (rh) IGF-I infused at the dose of 120 microg/day for the last experimental week in ZD, PF and freely fed control (CTRL) rats. Zinc deficiency caused growth stunting (weight gain 47% of PF; P<0.001), decreased circulating IGF-I (52% of PF; P<0.01) and liver IGF-I mRNA (67% of PF; P<0.01). Serum insulin-like growth factor-binding protein-3 (IGFBP-3) assessed by ligand blot was also reduced in ZD rats (65% of PF; P<0. 01). While exogenous IGF-I increased body weight in CTRL (+12 g; P<0. 01) and PF (+7 g; not significant) animals, growth was not stimulated in ZD rats (-1.5 g) in comparison with the corresponding untreated groups. However, circulating IGF-I and IGFBP-3 levels were restored by IGF-I infusion to levels similar to those in untreated CTRL rats. In conclusion, restoration of normal circulating levels of IGF-I and IGFBP-3 by rhIGF-I infusion fails to reverse the growth retardation induced by zinc deficiency. These results suggest that growth retardation related to zinc deficiency is not only caused by low serum IGF-I concentrations, but also by inhibition of the anabolic actions of IGF-I.