In spite of these interesting observations some additional q

In spite of these interesting observations, some additional questions arise from the study. For example, consistent with previous reports, circadian phase and period length are influenced by diet (). However, here the HFD has the general effect in WT mice of shortening period length rather than lengthening it. Some differences between this study and others include the time of HFD feeding onset and the percent of kilocalories from fat, which could plausibly influence the effects of the severe hypercholesterolemia alone on period length. But perhaps additional factors such as micronutrient contribution could also contribute to this change in free-running period. Furthermore, additional studies using littermate controls for the −/− m/m model could be used to validate changes in HFD-induced aortic plaque size in single vs. double knockout models under entrained LD vs. free-running DD conditions, as well as the circadian behavior phenotype in entrained conditions. While the expected genetic variance between the WT and double knockout strain used in the study lies somewhere between 0.01 and 2%, this still corresponds to between 0.27 and 5.4 million base pairs of the mouse genome. As a growing number of intracellular factors with zeitgeber properties are identified, it is not impossible that even subtle effects of genetic background could contribute to the observed phenotypes. In summary, the authors reveal a novel and interesting contribution of the LDLR to circadian behavior. Provocatively, these results suggest that the recently recognized contributions of the LDLR in the brain should be studied more directly at the level of signaling within the central pacemaker. Furthermore, −/− mice have recently been reported to also have altered circadian behavior () and LDLR is the primary receptor for ApoE in the brain, where it plays a particularly important role in amyloid-beta clearance (). It is interesting to speculate the extent to which the observed phenotype depends on LDLR interaction with ApoE vs. other functions of the LDLR. Interestingly, a HFD induces de novo oscillation of expression in the liver, mostly likely a necessary Oxamflatin to such nutrient insult (). With new studies revealing the importance of peripheral signals in regulating circadian behavior and clock function in the CNS (), the authors may have discovered a unique role for cholesterol in maintaining this important circadian crosstalk between tissues and thereby implicating LDLR as a protective mechanism for the clock under nutrient challenge conditions. Disclosures
The importance of trained immunity for vertebrate host defense is evidenced by broad non-specific protection conferred by certain vaccines (), while it may play a maladaptive role in chronic inflammatory diseases such as atherosclerosis (). The training effect manifests as a significantly heightened sensitivity to a secondary encounter with a pathogen or microbial product, characterized by enhanced secretion of pro-inflammatory mediators specifically by cells of the innate immune system. Most studies in the field of trained immunity have accordingly focused on differentiated innate immune cells such as monocytes, macrophages or natural killer cells. Importantly, these studies have revealed extensive reprogramming of the epigenome as the basis for innate immune memory (). Epigenetic changes act at the level of chromatin: the dynamic complex of DNA and histone proteins that spatially determines the transcriptional competency of a gene by regulating its accessibility to the transcriptional machinery of the cell. Posttranslational chemical modification of chromatin components such as histone N-terminal tails distinguishes and instructs the assembly of open and closed chromatin structures, thereby influencing gene expression. The transfer of methyl groups (methylation) to lysine residues of specific histones by the SET domain of methyltransferase enzymes has emerged as an important factor enhancing the expression of antimicrobial genes by innate immune cells (). Recent studies linking metabolic changes in trained cells with epigenetic reprogramming implicate particular classes of histone modifying enzymes as proponents of innate immune memory (). However, the identities of the specific enzymes responsible for the myriad epigenetic changes remain elusive.