IMPAIRED GROWTH-HORMONE SECRETION IN OBESE SUBJECTS IS PARTIALLY REVERSED BY ACIPIMOX-MEDIATED PLASMA-FREE FATTY-ACID DEPRESSION

GH secretion in response to provocative stimuli is blunted in obese pa tients. On the other hand, increases in plasma free fatty acids (FFA) inhibit the GH response to a variety of stimuli, and FFA levels in pla sma are increased with obesity. To ascertain whether FFA might be resp onsible for the GH secretory alterations of obesity, we studied sponta neous and stimulated GH secretion in 31 obese patients after FFA reduc tion by acipimox, a lipid-lowering drug devoid of serious side-effects . Each subject underwent two paired tests. In one, acipimox was admini stered orally at a dose of 250 mg at -270 min and at a dose of 250 mg at -60 min; in the matched test, placebo was given at similar interval s. To induce GH release, three stimuli acting through different mechan isms were used: pyridostigmine (60 mg, orally, at -60 min), GHRH (100 mu g, iv, at 0 min), and GHRH plus OH-releasing peptide (GHRP-6; His-D -Trp-Ala-Trp-D-Phe-Lys-NH2; both at a dose of 100 mu g, iv, at 0 min). GH secretion was analyzed as the area under the secretory curve (AUG; mean +/- SE; micrograms per L/60 min). Acipimox pretreatment alone (n = 13) induced a large reduction in FFA levels compared with placebo t reatment. The FFA reduction led to a slight GH rise (AUG, 123 +/- 47), not different from that in the placebo group (61 +/- 15). In the pyri dostigmine-treated group (n = 6), the acipimox-pyridostigmine AUC (408 +/- 107) was significantly higher (P < 0.05) than that in the placebo -pyridostigmine group (191 +/- 25). Furthermore, the GHRH-mediated (n = 6) AUC of GH secretion in the placebo test (221 +/- 55) was tripled by FFA reduction due to acipimox, with an AUC of (691 +/- 134;P < 0.05 ). Even the most potent GH stimulus known to date, i.e. GHRH plus GHRP -6, was enhanced by FFA suppression. In fact, the placebo-GHRH-GHRP-6 AUC was 1591 +/- 349, lower (P < 0.05) than that in the acipimox-GHRH- GHRP-6 test (2373 +/- 242). The enhancing effects of FFA lowering on G HRH-mediated and GHRH- plus GHRP-6-mediated GK release were synergisti c. These results indicate that in obese subjects, unlike normal weight subjects, FFA reduction per se does not stimulate GH secretion. A red uction in FFA with acipimox, however, increased pyridostigmine-, GHRH- , and even GHRH- plus GHRP-6-mediated GH release, suggesting that FFA reduction operates through a different mechanism from that of these th ree stimuli. The abnormally high FFA levels may be a contributing fact or for the disrupted GH secretory mechanisms in obesity.