A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels. (Endocrinology 153: 3587-3592, 2012)