This influence of maternal undernutrition on rat pups is in line with previous works on mice reporting that SIRT1 expression was reduced and many insulin-related signaling molecules were PD 0332991 citations altered explaining a reduction in longevity. Tryptophan supplementation has clearly the potential to alter clock-related dysregulation but it is not sufficient to revert the reduction in longevity related to perinatal undernutrition. A daily bolus of L-tryptophan had a profound effect on the profiles of PERIOD1 protein expression for both diets. Our microscopic approach is taking advantage of confocal imaging to trace the distribution of PERIOD1 in the different cellular compartments. The re-induction of PERIOD1 protein expression in our primary cells observed between 6 and 18 h was similar to the PERIOD1 reactivity described in rat brain region between 6 and 13 h. By focusing on the perinuclear and nuclear localization of PERIOD1, we have been able to appreciate the level of synchronization of our cells as well as the total nuclear intensity of expression according to previously described methods. A daily bolus of L-tryptophan had a profound effect on the profiles of PERIOD1 protein expression for both diets. These results are in line with our previous work indicating that perinatal undernutrition alters the circadian expression of period1 mRNA of hypothalamus of young rats. The environmental synchronizers are integrated by response elements located in the promoter region of 
period genes that drive the central oscillator complex. The period genes are also members of the immediate early gene family because cells like human normal fibroblasts exposed to cycloheximide, an inhibitor of transcription, retain a response toward stressful conditions characterized by a dramatic increase in PERIOD proteins. As shown on Figure S4, the expression profiles of period1 and bmal1 mRNA by cells collected from control-fed rats were not different from the ones obtained with control-fed rats supplemented with L-tryptophan suggesting that these alterations may be at the protein level, further works with cycloheximide are needed to clarify this point. The promoters of period1 and 2 genes contain a cAMP-responsive element that binds to CREB proteins. These CRE sites are integrating the cAMP response to a wide category of synchronizers as well as the response to a second wide category of synchronizers acting through the extracellular signal regulated kinase leading to the mitogen-activated kinase pathways, independently of the CLOCK: BMAL1 activity. We have used a serum shock to re-induce clock machinery; experiments are scheduled to explore which specific pathways are dysregulated by using molecular compounds like dexamethasone, Forskolin, dibutyryryl cAMP, phorbol-12-myristate, calcimycin, epidermal growth factor, insulin, or fibroblast growth factor. The expression of autophagic Sorafenib biomarkers over 30 hours of starvation were suggesting that a daily bolus of L-tryptophan did not alter the autophagic machinery of primary cells but that the phenotypes derived during the hyperphagic phase from rats enduring a perinatal malnutrition had deeply altered autophagic machinery. Similar cellular phenotypes obtained during the prediabetic phase did not show similar deregulation indicating that the alteration of autophagic machinery was only transient.