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

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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 .mu.g/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 < 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.