Jan 6, 2015
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

Endocrinology. 2012 Aug; 153(8): 3587–3592.
Published online 2012 Jun 1. doi: 10.1210/en.2012-1330
PMCID: PMC3404348
PMID: 22669895
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.

Chronic elevations of circulating FFA levels cause metabolic derangements, such as insulin resistance, and contribute to the metabolic syndrome (20). Our findings have an important implication for the regulation of circulating FFA levels. Although elevated FFA levels can be attributed to a primary change in adipocytes (20), our data suggest another potential site of regulation: the brain. It may be possible that any impairment in brain sensing of circulating FFA (21) unnecessarily increases HPA-axis activity and thus lipolysis to elevate circulating FFA levels. Our findings also have an important implication for NA or other lipid drugs acting by lowering plasma FFA levels (7, 13). Our data suggest that significant HPA-axis activation can occur during treatments with these drugs (when plasma FFA levels fall too low), causing FFA rebound and/or compromising beneficial effects of lowering plasma FFA.

....The activation of the HPA axis was independent of plasma glucose, because plasma glucose was clamped at basal levels by exogenous glucose infusion, if necessary, in all experiments........

The Intralipid dose employed in the present study was larger than that required to maintain basal FFA levels during NA or insulin infusion, resulting in plasma FFA significantly higher than basal levels (Figs. 3and and4).4). When Intralipid was infused at a lower rate to maintain plasma FFA at basal levels during NA infusion, the ACTH and corticosterone responses were not fully abolished (data not shown). To understand these data, it should be noted that Intralipid is mainly composed of plant-derived essential FFA (C18:2 and C18:3) (27), whereas rat plasma contains mainly nonessential FFA, such as palmitate (C16:0) and oleate (C18:1) (28). Therefore, when total FFA levels were maintained at basal, plasma levels of nonessential FFA might be still significantly below their basal levels (whereas those of essential FFA might be above their basal levels), as demonstrated by a previous study in rats (28). This may explain why ACTH and corticosterone responses were not abolished at basal FFA levels. In contrast, when total plasma FFA levels were elevated substantially above basal (Fig. 3), plasma levels of nonessential FFA might be maintained at or above basal, abolishing ACTH and corticosterone responses. Thus, our data are consistent with the notion that the activation of the HPA axis might be due to reduced plasma levels of nonessential (e.g. oleate) but not total FFA. Regarding this, Obici et al. (17) showed that central administration of oleate, but not octanoate (C8:0), decreased food intake and hepatic glucose production, suggesting that oleate, but not octanoate, was sensed by the brain. A subsequent study by Ross et al. (18) showed that similar responses occurred with palmitate (although it was substantially less potent) but not with linoleate (C18:2). Therefore, there is the intriguing possibility that specific (e.g. oleate and/or palmitate), but not all, circulating FFA are involved in the regulation of HPA-axis activity. Further study is warranted to test this important issue.


Another study by same researchers,here they compared different fatty acids in combination with FFA suppression and compared them , on coconot oil stress hormones are lower , followed by olive oil which is still better than safflower oil. In other studies also it shown that non essential fats are better at suppressing stress respond.

Also note that 35% suppression of FFAs didnt make stress respond in this study ,but a 90% suppression did.
Regulation of Hypothalamic-Pituitary-Adrenal Axis by Circulating Free Fatty Acids in Male Wistar Rats: Role of Individual Free Fatty Acids


And another study that shows excess FFA also causes an stress respond(rats)
Free fatty acids activate the hypothalamic-pituitary-adrenocortical axis in rats. - PubMed - NCBI

But here a human study shows no stress respond to FFA infusion

It even decreased their acth and cortisol , but saline infusion did the same!

Free fatty acids exert an inhibitory effect on adrenocorticotropin and cortisol secretion in humans. - PubMed - NCBI


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