Effects of Free Fatty Acids on ACTH and CRH Release and Responsivenes, on Sympathetic Activity, and, Potentially, Cerebral Blood Flow

This article [Migrenne et al., 2006: (http://diabetes.diabetesjournals.org/cgi/content/full/55/Supplement_2/S139)(http://cat.inist.fr/?aModele=afficheN&cpsidt=18366946)] (why is the journal Diabetes not indexed in Pubmed?) is really interesting, and the authors discuss research showing that the infusion of oleate or other free fatty acids (FFAs) into the carotid artery can cause those FFAs to enter hypothalamic neurons and either augment or decrease insulin release, in either a plasma-glucose-dependent or a glucose-independent manner, by altering the sympathetic outflow from the brain to the pancreas and other sites. The beta-oxidation of FFAs, in the hypothalamus and other parts of the brain, is required for many of these effects to occur, as discussed by Migrenne et al. (2006). This is relevant to the possibility that elevations in some saturated FFAs may produce mood-elevating or mild anticonvulsant effects, even as they may contribute to insulin resistance and other undesirable conditions, etc. [(http://hardcorephysiologyfun.blogspot.com/2009/04/protection-against-ischemic-damage-by.html)(http://hardcorephysiologyfun.blogspot.com/2009/04/low-cholesterol-levels-and-risk-of.html)]. Kok et al. (2004) [Kok et al., 2004: (http://ajpendo.physiology.org/cgi/content/full/287/5/E848)(http://www.ncbi.nlm.nih.gov/pubmed/15280154?dopt=Abstract)] cite research (reference 63) showing that high-fat diets tend to increase FFA levels, and this is fairly well-known to be the case, in my opinion. Kok et al. (2004) found that the acipimox-induced decreases in FFA levels had reduced ACTH levels in obese people. Although the authors of many articles present research to show that FFAs produce sympathetic activation or increase ACTH release, Lanfranco et al. (2004) [Lanfranco et al., 2004: (http://jcem.endojournals.org/cgi/content/full/89/3/1385)(http://www.ncbi.nlm.nih.gov/pubmed/15001638?dopt=Abstract)] found that an acute increase in plasma FFA levels reduced both cortisol and ACTH, and the authors discussed evidence suggesting the FFAs had exerted their inhibitory influence on ACTH secretion by acting on the hypothalamus (i.e. acting on neurons or astrocytes). There's some evidence that FFAs can increase sympathetic activation by acting on plasma membrane ion channels, and unsaturated FFAs can inhibit or otherwise affect beta-adrenoreceptor activation. FFAs can modify ligand binding to a number of different G-protein coupled receptors. Many of the effects on the sympathetic outflow from the CNS appear to be the result of the beta-oxidation of FFAs in the hypothalamus, though, presumably in astrocytes. Tataranni et al. (1999) [Tataranni et al., 1999: (http://www.pnas.org/cgi/content/full/96/8/4569)(http://www.ncbi.nlm.nih.gov/pubmed/10200303)] found that the elevation in plasma FFA levels after a meal correlated positively with regional cerebral blood flow (rCBF) to the dorsolateral prefrontal cortex, in association with an increase in satiety after the meal. That's a significant finding, and it could partly be a result of the beta-oxidation of those FFAs in cerebral vascular endothelial cells. The dorsolateral prefrontal cortex is obviously a site whose neuronal activity is thought to be crucially important in cognitive functioning and mood regulation, etc. [(http://scholar.google.com/scholar?q=%22dorsolateral+prefrontal+cortex%22+%22cerebral+blood+flow%22+depression&hl=en&lr=); (http://scholar.google.com/scholar?hl=en&lr=&q=%22dorsolateral+prefrontal+cortex%22+%22cerebral+blood+flow%22+cognitive)]. The recovery from depression was associated with increases in rCBF to the dorsolateral prefrontal cortex, for example [Bench et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7675913)]. It should be noted that something like resistance exercise tends to elevate both FFAs and ACTH and cortisol levels. The elevations in cortisol levels following resistance exercise can be very significant, and they're not really "bad," in my opinion. One can view that type of elevation as being a "strong signal" to essentially override glucocorticoid resistance at the level of the CNS or even in cells outside the brain. In asthma, for example, responsiveness to beta-adrenoreceptor agonists, which can produce anti-inflammatory effects on many cell types, can be restored within 24 hours by glucocorticoid administration. In chronic stress and depression, the issue tends not to be elevations in cortisol per se but resistance to feedback inhibition of ACTH release, by the pituitary, and CRH release from the hypothalamus. CRH generally activates noradrenergic neurons in the locus ceruleus, and an acute increase in noradrenaline availability in the hypothalamus can decrease CRH release from hypothalamic neurons [Hillhouse et al., 1975: (http://www.ncbi.nlm.nih.gov/pubmed/1079076); Valentino et al., 1988: (http://www.jneurosci.org/cgi/reprint/8/3/1016.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/3258021)]. Those types of regulatory mechanisms don't work very effectively, even under the best of circumstances, and the regulation of CRH release is very complex.