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

Abstract

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) T he brain plays a crucial role in energy homeostasis. When the blood glucose level falls, the brain senses it and activates various neuroendocrine mechanisms to restore blood glucose levels (1). These responses, known as glucose counterregulatory responses, are critical for the survival of the brain and have been extensively studied. According to the "selfish brain" theory (2), the brain places the highest priority on covering its own energy requirements when regulating energy homeostasis, activating stress responses upon a fall in cerebral energy (i.e. ATP) levels and suppressing insulin secretion to allocate glucose to the brain rather than the periphery. Free fatty acids (FFA) are another major fuel in mammals. It is established that FFA, like glucose, are sensed by the brain, and excess supply of FFA to the brain can suppress food intake and reduce hepatic glucose output (3). However, it is unclear whether the brain responds to a fall in plasma FFA, as it does with glucose, to activate mechanisms for its restoration. There is ample evidence that acute depression (or elevation) of plasma FFA stimulates (or inhibits) growth hormone secretion (4, 5). Because growth hormone is known to increase lipolysis in adipocytes, these effects of FFA on growth hormone secretion provide a negative feedback mechanism in the regulation of plasma FFA. The underlying mechanisms appear to be complex (4), but the brain (i.e. hypothalamus) may be responsible for at least some FFA effects (6). In addition, there are scattered data showing that nicotinic acid (NA) administration, which...

Ontogeny of the corticotrophin-releasing hormone system in slow- and fast-growing chicks (Gallus gallus)

“…Additionally, higher plasma CORT levels and/or increased sensitivity to glucocorticoid actions have a significant impact on glucose and fatty acid homeostasis [43,44]. Results in mammals indicated that stress-induced circulating free fatty acid levels were altered by activation of the HPA axis [45,46]. In the present study, we found that isolation stress increased plasma NEFA levels significantly in layers but not broiler chicks, while plasma glucose levels were unchanged in both (Fig.…”

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

“…Indeed, plasma epinephrine levels significantly increase (about 2.5-fold) after oral ingestion of NiAc in fasting humans (31). In a rat study, FFA was acutely lowered in the fasting state either by NiAc, an A 1 adenosine receptor agonist, or by insulin in combination with glucose infusion to maintain euglycemia (32). In support of the above idea, increases in plasma adrenocorticotropic hormone and the lipolytic hormone corticosterone were attenuated with insulin/glucose (a situation somewhat akin to the fed state) compared with the other interventions.…”

Metabolic response in liver and Brockmann bodies of rainbow trout to inhibition of lipolysis; possible involvement of the hypothalamus–pituitary–interrenal (HPI) axis

“…Blood, liver, and BB samples were taken 6 h after treatment, which was chosen since in previous studies in the same species that was the time period necessary to achieve changes in the FA-sensing mechanisms when levels of FA were increased (Librán-Pérez et al 2012, 2013b, 2014a. Initial concentrations of SDZ were selected based on the studies carried out previously in mammals (Cox et al 1997;Oh et al 2012), and then in preliminary studies (data not shown) we evaluated different SDZ doses. Since SDZ is known to reduce mean arterial pressure and heart rate at high doses (Cox et al 1997) we selected a dose (60 µg kg −1 ) that is able to lower levels of circulating FA without inducing any other alteration.…”

“…The treatment with SDZ WAG 994 (SDZ), a selective A1 adenosine receptor agonist that inhibits lipolysis (Jacobson and Gao 2006), has been used in mammals to experimentally induce decreased levels of FA, which are sensed in central areas through FA-sensing mechanisms (Le Foll et al 2009;Blouet and Schwartz 2010). The detection elicits counter-regulatory responses to restore FA levels, which have been associated with the activation of the hypothalamus-pituitary-adrenal (HPA) axis (Oh et al 2012(Oh et al , 2014. Thus, the enhanced lypolysis (especially in liver) induced by raised levels of circulating glucocorticoids would restore plasma FA levels (Oh et al 2012(Oh et al , 2014.…”

“…The detection elicits counter-regulatory responses to restore FA levels, which have been associated with the activation of the hypothalamus-pituitary-adrenal (HPA) axis (Oh et al 2012(Oh et al , 2014. Thus, the enhanced lypolysis (especially in liver) induced by raised levels of circulating glucocorticoids would restore plasma FA levels (Oh et al 2012(Oh et al , 2014.…”