As vascular function represents a critical link between diab

As vascular function represents a critical link between diabetes and cognition, it is plausible that circulating factors could affect n-phenylacetyl-l-prolylglycine ethyl ester function. Experiments involving shared circulatory systems have played a crucial role in the study of obesity and T2D (Coleman, 2010), and a series of studies have shown that young blood has numerous rejuvenative properties in aging mice (Villeda et al., 2014; Ruckh et al., 2012; Salpeter et al., 2013; Loffredo et al., 2013; Katsimpardi et al., 2014). However, these recent experiments all highlight a dichotomy between the young and old. To the best of our knowledge, our study represents the first evidence that plasma infusion also holds promise in the age-independent context of MetS. Here, infusion of plasma collected from lean, non-diabetic LFD donors was sufficient to improve cognitive function in HFD mice, and this improvement occurred in the face of concurrent obesity and continued consumption of a high fat diet. These data suggest that administration of plasma, or of specific factors found within, may represent a potential strategy for the treatment of the cognitive complications of diabetes. It is unlikely that the cognitive gains observed following plasma infusion are solely due to one factor, as recent contradictory findings in aging studies indicate (Loffredo et al., 2013; Egerman et al., 2015). Additionally, dilution and temporal factors likely reduce the impact of any one individual factor; for example, HFD mice received 100μl infusions but have >2.5ml total blood volume and the analysis occurred 24h after the final infusion. In this regard, while our untargeted metabolomics analysis revealed 45 significantly altered metabolites, the effect size of each individual factor was small (fold change for 99% of metabolites was <2.0). Still, two main patterns of note were revealed in HFD mice infused with ‘healthy’ LFD plasma: lower concentrations of multiple AAs and their byproducts, and higher concentrations of numerous GPLs. Elevated levels of branched chain (bc) AAs are associated with obesity and IR, and are predictive of future development of T2D (Newgard et al., 2009; Wang et al., 2011). However, we did not observe significant changes in bc AAs, likely because both plasma recipient groups still had MetS. Instead, our analysis revealed alterations in several AAs that more closely resemble the metabolic changes that accompany aging (Houtkooper et al., 2011). The analysis also highlighted alterations in various classes of GPLs, particularly PEs and PCs. While it is unclear how elevated plasma concentrations of PEs and PCs affect cognitive function, they are present in relatively high amounts in neural membranes where they play metabolic, structural and functional roles (Farooqui et al., 2000). Moreover, lower levels of brain GPLs have been associated with neurodegenerative disease (Wood et al., 2015). Additionally, a common second messenger produced from PEs and PCs is arachidonic acid, which was also significantly elevated in HFD mice receiving infusions of LFD plasma. Arachidonic acid is a common precursor to several vasoactive eicosanoids which represent an intriguing biological link between IR, microvascular function and cognition (Iliff et al., 2009; Shim et al., 2014). Also of interest is asymmetric dimethylarginine (ADMA), a methylated form of l-arginine, which was present in significantly lower concentrations in HFD mice receiving infusions of LFD plasma. ADMA has been proposed as a potential link between vascular disease and dementia, as it is found in higher concentrations in T2D individuals (Abbasi et al., 2001) and inhibits nitric oxide synthesis and vasodilation (Asif et al., 2013). The following are the supplementary data related to this article.
Funding L.A.J. was supported by NIEHS grant T32-ES07060, NIH grant T32-HL094294, NSF grant SMA-1408653, the Collins Medical Trust, an OHSU Tartar Award, the Oregon Tax Check-off Program for Alzheimer\'s Research administered by the Layton Aging & Alzheimer\'s Disease Center at OHSU, and the OHSU development account of J.R. K.L.Z. was supported by NIHF32NS082017. N.J.A. was supported by NIHR21AG043857. D.G.Z. was supported by NIDAT32DA007262. J.F.S. was supported by NIH grant S10RR027878 and the OSU Mass Spectrometry Core Facility of the Environmental Health Sciences Center grant P30ES000210. The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies.