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  • The endoplasmic reticulum ER stress pathway may also

    2018-11-14

    The endoplasmic reticulum (ER) stress pathway may also be involved in the palmitate-mediated regulation of circadian clock properties. Recent evidence supports a link between the circadian clock and ER homeostasis involving mutual regulation of each other (Pluquet et al., 2014). Moreover, SFAs such as palmitate induce ER stress via multiple mechanisms (Milanski et al., 2009; Baldwin et al., 2012; Ariyama et al., 2010) whereas the omega-3 fatty isradipine manufacturer DHA attenuates ER stress (Kolar et al., 2011). Because ER stress has been linked to inflammation in metabolic disorders (Cao et al., 2016), further studies are needed to determine whether ER stress plays a role in palmitate-mediated modulation of circadian timekeeping in parallel to, or perhaps in concert with, the inductive effects of this SFA on inflammatory signaling. The association between circadian clock dysfunction and metabolic disorders is largely based on studies that involve the complete disruption of rhythmicity using genetic or environmental approaches. However, the present data have novel implications for how differential and cell-specific modulation, rather than complete malfunction, of peripheral circadian clocks may be germane factors in the amplification of proinflammatory responses to HFD and SFA excess that are closely linked to systemic metabolic dysregulation. In both fibroblasts and differentiated adipocytes, palmitate-mediated inflammatory signaling is gated rhythmically and at times of peak induction, provides feedback that modulates the phase of the core clock mechanism. Because the phase-shifting responses to palmitate appear to differ among peripheral cell types, this feedback modulation is likely to disrupt the local coordination of circadian timekeeping among cell-autonomous clocks within a given tissue, thus further potentiating SFA-induced inflammation that contributes to systemic insulin resistance. The palmitate-induced inflammatory signals directly responsible for the feedback modulation of circadian phase remain to be determined, but future studies are warranted to examine the role of proinflammatory cytokines such as IL-6 in mediating the phase-shifting effects of this SFA. Finally, these interactions between peripheral circadian clocks and pathways linking fatty acid metabolism to tissue inflammation suggest that chronotherapeutic strategies using DHA and/or metformin, an AMPK agonist exploited in the treatment of hyperglycemia in type II diabetes (Akbar, 2003), may be critical in the management of metabolic diseases associated with fatty acid overload. The following are the supplementary data related to this article.
    Disclosure Statement
    Author Contributions
    Acknowledgments This study was supported by the Center for Translational Environmental Health ResearchP30ES023512 (R.S.C.) and NIH grant R35CA197707 (R.S.C.).
    Introduction Investigation of low-abundance peptides (peptides circulating at the low picomolar range) has provided insights into human physiology and pathophysiology. For example, the identification of the incretin hormone, glucagon-like peptide-1 (GLP-1), paved the way to strategies for the treatment of diabetes and obesity (Holst, 2013b; Sadry and Drucker, 2013; Wewer Albrechtsen et al., 2014). Furthermore, low-abundance peptides derived from the gastrointestinal tract, including GLP-1 (Supplementary Fig. 1), are crucial mediators of the weight-reducing and antidiabetic actions of bariatric surgery (Madsbad et al., 2014; Madsbad and Holst, 2014). Detection and characterization of low-abundance peptides are, therefore, of major clinical interest (Bouillon et al., 2015; Gillette and Carr, 2013a; Keshishian et al., 2007a; Lin et al., 2009; Meng et al., 2011; isradipine manufacturer Sadry and Drucker, 2013). Therefore, we developed a streamlined, unbiased mass spectrometry-based platform for the characterization of low-abundance peptides (Fig. 1.). Importantly, and in contrast to current targeted mass spectrometry-based detection methods (Fonslow et al., 2011; Gillette and Carr, 2013b; Keshishian et al., 2007b; Parker and Borchers, 2014; Surinova et al., 2011) (e.g., the SISCAPA technology), this method functions without prior immune-based fractionation/precipitation, which makes this method unbiased and suitable for biomarker discovery. The clinical applicability of the platform was validated by detecting and characterizing physiological aspects of a hitherto neglected gut hormone, oxyntomodulin.