We note that zinc speciation at and

We note that zinc speciation at and 2 mol. equiv. of myristate is already markedly different; this means that FFAZn2+ crosstalk is in operation under normal physiological conditions. At present, there are few data to allow tracking of the effects of such physiological crosstalk, although there are some indications that physiological states that are associated with elevated plasma FFA, such as moderate exercise, are also associated with decreased plasma levels of zinc [76]. More data are available to find correlations under extreme conditions, for instance disease states such as metabolic syndrome [77], diabetes [78,79], and cardiovascular disease [33,80] – all of which are characterised by elevated plasma FFA levels and depressed plasma zinc concentrations [81]. We suggest that albumin is at the centre of a causal relationship that links these independent observations, and that the FFA-modulated zinc speciation leads to increased zinc export from plasma into cells. In the following sections, we will consider both changes in zinc speciation in plasma, as well as potential effects of shifting zinc from plasma to kinase inhibitor in relation to metabolic, cardiovascular and neurodegenerative diseases, respectively. An overview of these potential effects and how they may contribute to particular disease states is outlined in Table 1.
Energy metabolism and metabolic diseases Numerous associations between Zn2+ and endocrine signalling in relation to energy metabolism have previously been established [96]. Notably, Zn2+ affects either production, secretion, or activity of glucagon [97], insulin [98], adiponectin [99], and leptin [22]. Particularly intriguing interactions in the context of FFA-Zn crosstalk have been identified for insulin and leptin. Insulin is critical for glycemic control and stimulates glucose uptake from plasma into cells, and leptin regulates organismal energy uptake and expenditure [100].
Cardiovascular disease and haemostasis Increased plasma FFA are not only a hallmark of metabolic syndrome, dyslipidaemia and type 2 diabetes, but are also implicated in several ways in cardiomyopathy [128] and other diseases of the circulatory system. Several observations indicate their possible impact on plasma zinc speciation and export from plasma in the context of cardiovascular disease (or its diagnosis) and are described in the following sub-sections.
Zinc, albumin and FFAs in the brain: Implications for neurological disorders Zinc is by far the most abundant d-block metal ion in the brain, is involved in learning and memory and affects mood [[149], [150], [151], [152]]. In turn, both dietary zinc deficiency and alterations in plasma/serum zinc levels are associated with neuropsychiatric disorders [153] including major depressive disorders [151,154] and neurodegenerative diseases including Alzheimer's disease (AD) [20,155,156]. Due to the complexity of the homeostatic and signalling networks involved, it is not straightforward to dissect causes and consequences in such correlations [157,158], but it is possible that low plasma zinc is a sign of systemic zinc dyshomeostasis. We are not aware of a direct correlation with plasma FFA levels in the case of neurological disorders, but it seems worthwhile to consider whether crosstalk between zinc and FFAs may also operate in other extracellular media such as cerebrospinal and interstitial fluid (CSF and ISF). Although measurements of brain zinc compartmentalisation and speciation are challenging for a range of reasons [149,159], there are now clear indications for localised zinc dyshomeostasis in brains affected by neurological conditions [160,161]. However, the lack of sufficiently powered clinical studies precludes concluding whether or not targeting metal homeostasis in the brain is a viable therapeutic approach for neurological disorders [162]. Our incomplete understanding of molecular mechanisms means that it is not even clear in what way the respective metal ions should be manipulated, with supplementation [158,163,164], chelation and modulation [162] all being discussed. Nonetheless, the following discussion will show that extracellular zinc concentrations and speciation play a critical role in physiological and pathophysiological processes in the brain.