Evidence for a Direct Pituitary Inhibition by Free Fatty Acids of in vivo Growth Hormone Responses to Growth Hormone-Releasing Hormone in the Rat

Abstract

The aim of this study was to determinate whether elevations in circulating free fatty acids (FFA) inhibit in vivo growth hormone (GH) responses to GH-releasing hormone (GHRH) by increasing hypothalamic somatostatin release or by acting directly on the pituitary. Thus, we have studied the effect of an Intralipid-heparin infusion on in vivo GH responses to GHRH in normal rats, normal rats passively immunized with antisomatostatin antiserum, rats with medial hypothalamic ablation, and hypophysectomized rats bearing two hypophyses under the renal capsule. Administration of 1 ml of Intralipid (500 µl at -30 min and 500 µl at -25 min) plus heparin (50 IU at-15 min) induced a marked decrease in GH responses to both 1 and 5 µg/kg of GHRH (p < O.Ol at 5, 10 and 15 min for GHRH alone vs. GHRH plus Intralipid). A similar degree of inhibition was obtained after the administration of antisomatostatin antiserum (750 µl i.v. at-60 min) previous to a challenge with 5 µg/kg of GHRH plus 1 ml of Intralipid (p < 0.05 at 5 and 15 min, and p < 0.01 at 10 min for GHRH plus normal rabbit serum vs. GHRH plus Intralipid plus antisomatostatin antiserum). Furthermore, administration of 1 ml of Intralipid also markedly reduced GH responses to GHRH in rats with medial hypothalamic ablation (p < 0.01 at 5, 10, 15 and 30 min for GHRH alone vs. GHRH plus Intralipid) as well as in hypophysectomized rats bearing two hypophyses under the renal capsule (p < 0.01 at 5, 10 and 15 min for GHRH alone vs. GHRH plus Intralipid). In brief, our data show that elevations in circulating FFA levels inhibit in vivo GH responses to GHRH by acting directly at the pituitary level.

Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency

“…The chronic elevation of circulating FFA levels, which were further enhanced by fasting, could also have a key role in counteracting the GH response to starvation in obesity. 10,11,29 FFA has a strong inhibitory action on somatotroph secretion acting at either the pituitary or the hypothalamic level; 31,32,36 in fact, lipolysis inhibitors restore GH secretion in obesity. 10,11,29,37 In the absence of any significant increase in GH secretion obese patients in our study showed normal activation of lipolysis; this probably reflects the fasting-induced response of other contraregulatory hormones.…”

Maximal secretory capacity of somatotrope cells in obesity: comparison with GH deficiency

“…12,13,17,18,21,23,40 Con®rm-ing the metabolic pathogenesis of GH de®ciency in obesity there is the well known evidence that spontaneous and stimulated GH secretion are restored by weight loss 2,6 and that a clear inverse relationship exists between GH secretion and body mass. 2 From a diagnostic point of view, it has to be considered that the diagnosis of GH de®ciency in adulthood is still a matter of debate though there is clear evidence for usefulness of rhGH replacement.…”

Regulation of somatotroph cell function by the adipose tissue

“…3,4 There is now compelling evidence indicating that the FFA blockade of GH secretion is exerted at the pituitary level, probably by direct inhibition of somatotroph function. 4,5 The effect of FFA on GH secretion is exerted at physiological levels, since reduction in circulating FFA levels following administration of acipimox, per se stimulates basal GH secretion as well as increasing GH responses to different GH secretagogues in normal subjects. 6,7 Since obesity is associated with abnormal elevations in both fasting and postprandial FFA concentrations, it has been suggested that elevated FFA could be one of the mechanisms responsible for impaired GH secretion in obese subjects.…”