Protective Effects of Transient Glucose Exposure in Adult C. elegans

C. elegans are used to study molecular pathways, linking high glucose levels (HG) to diabetic complications. Persistent exposure of C. elegans to a HG environment induces the mitochondrial formation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), leading to neuronal damage and decreased lifespan. Studies suggest that transient high glucose exposure (TGE) exerts different effects than persistent exposure. Thus, the effects of TGE on ROS, AGE-formation and life span were studied in C. elegans. Four-day TGE (400 mM) as compared to controls (0mM) showed a persistent increase of ROS (4-days 286 ± 40 RLUs vs. control 187 ± 23 RLUs) without increased formation of AGEs. TGE increased body motility (1-day 0.14 ± 0.02; 4-days 0.15 ± 0.01; 6-days 0.16 ± 0.02 vs. control 0.10 ± 0.02 in mm/s), and bending angle (1-day 17.7 ± 1.55; 3-days 18.7 ± 1.39; 6-days 20.3 ± 0.61 vs. control 15.3 ± 1.63 in degree/s) as signs of neuronal damage. Lifespan was increased by 27% (21 ± 2.4 days) after one-day TGE, 34% (22 ± 1.2 days) after four-days TGE, and 26% (21 ± 1.4 days) after six-days TGE vs. control (16 ± 1.3 days). These experiments suggest that TGE in C. elegans has positive effects on life span and neuronal function, associated with mildly increased ROS-formation. From the perspective of metabolic memory, hormetic effects outweighed the detrimental effects of a HG environment.

Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?

In medicine, a legacy effect is defined as the sustained beneficial effect of a given treatment on disease outcomes, even after cessation of the intervention. Initially described in optimized control of diabetes, it was also observed in clinical trials exploring intensification strategies for other cardiovascular risk factors, such as hypertension or hypercholesterolemia. Mechanisms of legacy were particularly deciphered in diabetes, leading to the concept of metabolic memory. In a more discreet manner, other memory phenomena were also described in preclinical studies that demonstrated long-lasting deleterious effects of lipids or angiotensin II on vascular wall components. Interestingly, epigenetic changes and reactive oxygen species (ROS) appear to be common features of “memory” of the vascular wall.

Diet composition influences the metabolic benefits of short cycles of very low caloric intake

Diet composition, calories, and fasting times contribute to the maintenance of health. However, the impact of very low-calorie intake (VLCI) achieved with either standard laboratory chow (SD) or a plant-based fasting mimicking diet (FMD) is not fully understood. Here, using middle-aged male mice we show that 5 months of short 4:10 VLCI cycles lead to decreases in both fat and lean mass, accompanied by improved physical performance and glucoregulation, and greater metabolic flexibility independent of diet composition. A long-lasting metabolomic reprograming in serum and liver is observed in mice on VLCI cycles with SD, but not FMD. Further, when challenged with an obesogenic diet, cycles of VLCI do not prevent diet-induced obesity nor do they elicit a long-lasting metabolic memory, despite achieving modest metabolic flexibility. Our results highlight the importance of diet composition in mediating the metabolic benefits of short cycles of VLCI.

Intermittent Leucine Deprivation Produces Long-Lasting Improvement in Insulin Sensitivity by Increasing Hepatic Gcn2 Expression

<a>Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended is unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after resuming a control diet for 49 days) effect on improved whole-body and hepatic insulin sensitivity in mice, indicating the potential formation of metabolic memory. Furthermore, the effects of ILD depended on hepatic general control nondepressible 2 (GCN2) expression as verified by gain-and loss-of-function experiments. Moreover, ILD increased <i>Gcn2 </i>expression by reducing its DNA methylation at two CpG promoter sites controlled by </a><a>demethylase</a> growth arrest and DNA damage inducible b. Finally, ILD also improved insulin sensitivity in insulin-resistant mice. Thus, ILD induces long-lasting improvements in insulin sensitivity by increasing hepatic <i>Gcn2</i> expression via a reduction in its DNA methylation. These results provide novel insights into understanding the link between leucine deprivation and insulin sensitivity, as well as potential nutritional intervention strategies for treating insulin resistance and related diseases. We also provide evidence for liver-specific metabolic memory after ILD and novel epigenetic mechanisms for <i>Gcn2</i> regulation.

Intermittent Leucine Deprivation Produces Long-Lasting Improvement in Insulin Sensitivity by Increasing Hepatic Gcn2 Expression

<a>Leucine deprivation improves insulin sensitivity; however, whether and how this effect can be extended is unknown. We hypothesized that intermittent leucine deprivation (ILD) might produce a long-term effect on improved insulin sensitivity via the formation of metabolic memory. Consistently, seven ILD cycles treatment (1-day leucine-deficient diet, 3-day control diet) in mice produced a long-lasting (after resuming a control diet for 49 days) effect on improved whole-body and hepatic insulin sensitivity in mice, indicating the potential formation of metabolic memory. Furthermore, the effects of ILD depended on hepatic general control nondepressible 2 (GCN2) expression as verified by gain-and loss-of-function experiments. Moreover, ILD increased <i>Gcn2 </i>expression by reducing its DNA methylation at two CpG promoter sites controlled by </a><a>demethylase</a> growth arrest and DNA damage inducible b. Finally, ILD also improved insulin sensitivity in insulin-resistant mice. Thus, ILD induces long-lasting improvements in insulin sensitivity by increasing hepatic <i>Gcn2</i> expression via a reduction in its DNA methylation. These results provide novel insights into understanding the link between leucine deprivation and insulin sensitivity, as well as potential nutritional intervention strategies for treating insulin resistance and related diseases. We also provide evidence for liver-specific metabolic memory after ILD and novel epigenetic mechanisms for <i>Gcn2</i> regulation.

Fibroblast Memory in Development, Homeostasis and Disease

Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease.

Advanced glycation end products and oxidative stress as a basis for metabolic abnormalities in patients with type 1 diabetes after successful simultaneous pancreas-kidney transplantation

Aim. To compare advanced glycation end-products (AGE, RAGE) and 3-nitrotyrosine (3-HT) in patients with DM 1 after successful simultaneous pancreas-kidney transplantation (SPK) and kidney transplantation alone (KTA). To assess relationship between levels of AGE, RAGE, 3-HT and renal transplant (RT) function, carbohydrate and mineral metabolism. Materials and methods. The study included 58 patients who received kidney transplantation in end-stage renal disease (ESRD). 36 patients received SPK. There were performed routine laboratory, examination of AGE, RAGE, 3-NT, parathyroid hormone (PTH), 25(OH)vitamin D, calcium, phosphorus, FGF23, osteoprotegerin (OPG), and fetuin-A levels. Results. All patients after SPK reached normoglycemia (HbA1c 5.7 [5.3; 6.1] %; C-peptide 3.24 [2.29; 4.40] ng/ml) with the achievement of significant difference vs patients after KTA. Arterial hypertension (AH) was more frequent in recipients of SPK before transplantation than after (p=0.008). AH also persisted in greater number of cases in patients after KTA than after SPK. Patients after SPK had higher AGE (р=0.0003) and lower RAGE (р=0.000003) levels. OPG in patients after SPK was significantly higher (р=0.04). The correlation analysis revealed significant positive correlation between 3-HT and OPG (p0.05; r=0.30), RAGE and eGFR (r=-0.52), HbA1c (r=0.48), duration of AH (r=0.34), AGE with HbA1c (r=0.51). Conclusion. The results of the "metabolic memory" markers analysis may indicate their contribution to the persistence of the metabolic consequences of CKD and DM 1 after achievement of normoglycemia and renal function restoration and their possible participation in development of recurrent nephropathy, vascular calcification, and bone disorders.