Free Fatty Acids Activate the Adrenocortical Axis in Rats* Hypothalamic-Pituitary-

Intravenous administration of Intralipid 10% increases blood levels of essential free fatty acids. In rats and man, this is associated with an inhibition of GH secretion from the anterior pituitary. Because GH is lipolytic, the inhibition of its secretion may represent a negative feedback action of the fats on pituitary sensitivity to GH-releasing hormone. Since corticosterone, the final secretory product of the rat hypothalamic-pituitary-adrenocortical (HPA) axis, is also lipolytic, we tested the hypothesis that FFA would inhibit the HPA axis. Rats were cannulated via the jugular vein and infused with different doses of heparin-Intralipid 10% or heparin-saline; sequential blood samples were obtained and analyzed for ACTH, corticosterone, FFA, and glucose. Intralipid at 2.85 ml/kg increased plasma FFA to over 3 meq/liter by 15 min, with a return to baseline by 60-90 min. There was no effect of the infusion on plasma osmolarity or pH. At 60 min, plasma ACTH levels were significantly elevated to over 1500 pg/ml in Intralipidinfused rats, but were unchanged in saline controls. This dose of Intralipid increased corticosterone levels by nearly 20.fold at 120 min. At 180 min, corticosterone levels were still significantly greater than those in saline controls. Lower doses of Intralipid also significantly elevated both FFA and corticosterone levels, but by 180 min, levels of both were similar to those in controls. The effects of Intralipid on corticosterone secretion could not be attributed to the presence of glycerol in the suspension, since glycerol infusions had no significant effect on steroid levels compared to those in saline controls. In dexamethasone-pretreated rats, there was no significant rise in plasma corticosterone after either of two Intralipid doses, suggesting that the action of Intralipid was at a site within the HPA axis above the adrenal gland. This finding also suggested that the high steroid levels after Intralipid treatment were not due to interference with the corticosterone RIA. This was verified by the finding that there was no increase in plasma immunoreactive corticosterone after Intralipid infusion into adrenalectomized rats. Intralipid also caused an increase in plasma glucose levels that was first significant at 60 min and declined to baseline by 180 min, possibly reflecting increased autonomic activity or peripheral insensitivity to insulin. The results suggest that high circulating FFA levels activate, rather than inhibit, the HPA axis in rats. Since stress activates glucocorticoid production and increases FFA levels due to lipolysis, it is possible that FFA and the HPA axis constitute a previously unrecognized positive feedback loop. Finally, the widespread use of Intralipid to ameliorate clinical disorders of metabolism should be considered in light of its potential effects on adrenal steroid secretion.