Free Fatty Acids Block Growth Hormone (GH) Releasing Hormone-Stimulated GH Secretion in Man Directly at the Pituitary*

Abstract

Increases in plasma FFA levels inhibit GH responses to a variety of pharmacological and physiological stimuli. To gain further insight into the mechanism by which FFA exert their effect, we studied the plasma GH responses to GHRH-(1-44) (1 microgram/kg, iv) in normal subjects in whom plasma FFA levels were raised by a lipid-heparin infusion (250 mL 10% Intralipid plus 2500 U heparin). Paired tests were performed in 10 normal subjects, with and without lipid-heparin pretreatment. Lipid-heparin infusion from -30 to 120 min increased mean FFA levels from 0.41 +/- 0.03 (+/- SEM) to 3.12 +/- 0.40 mmol/L at 120 min. The mean plasma GH levels after GHRH administration were lower at all times; however, the values were significantly different (P less than 0.05) only at the later times (45, 60, and 90 min). When considered individually, an all or none pattern was observed; 5 subjects had no plasma GH response to GHRH, and 5 had no reduction. To investigate the time relationships between the FFA peak and subsequent GH blockade, a different protocol of paired tests was performed with GHRH with or without a different lipid-heparin infusion protocol. Lipid-heparin was infused from -90 to 0 min, with an additional heparin pulse at -15 min, to obtain a higher and earlier (0 min) FFA increase. FFA increased from 1.06 +/- 0.19 to 11.61 +/- 0.83 mmol/L at zero time. The GHRH-induced GH secretory peak (15.8 +/- 3.5 ng/ml) at 15 min was completely blocked (0.9 +/- 0.2 ng/ml), and the mean plasma GH levels were also lower at 30, 45, and 60 min. To determine whether the FFA-induced blockade of GH secretion was exerted in the pituitary, a series of in vitro studies was conducted using monolayer cultures of rat anterior pituitary glands, with GHRH concentrations of both 10(-10) and 10(-8) M and 10(-5) M forskolin to stimulate GH release. Both caprylic and oleic acid inhibited basal GH release and GHRH- or forskolin-induced GH release. PRL release was not altered, nor were toxic actions noted on the cells. In conclusion, FFA are able to block GH secretion directly at the pituitary level.

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.…”

Growth hormone in obesity

“…Its administration to both animals and humans induces an increase in serum concentrations of glycerol and NEFA. These latter, in turn, exert a negative feedback control on GH secretion acting at the pituitary 101 and the hypothalamus, probably by enhancing SRIH release. 102 In fact, in normal subjects, the increase in NEFA serum concentrations blunts the somatotropin responses to both GHRH and suprapituitary stimuli.…”

Regulation of somatotroph cell function by the adipose tissue

“…FFA elevations reduce or block GH secretion stimulated by a variety of stimuli or conditions, such as FFA depression, hypoglycemia, physical exercise or administration of GH releasing hormone (GHRH) or GHRP-6. 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.…”

“…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.…”