Reduced intestinal lipid absorption improves glucose metabolism in aged G2-Terc knockout mice.

BACKGROUND: Biological aging is an important factor leading to the development of pathologies associated with metabolic dysregulation, including type 2 diabetes, cancer, cardiovascular and neurodegenerative diseases. Telomere length, a central feature of aging, has additionally been identified as inversely associated with glucose tolerance and the development of type 2 diabetes. However, the effects of shortened telomeres on body weight and metabolism remain incompletely understood. Here, we studied the metabolic consequences of moderate telomere shortening using second generation loss of telomerase activity in mice. RESULTS: Aged male and female G2 Terc-/- mice and controls were characterized with respect to body weight and composition, glucose homeostasis, insulin sensitivity and metabolic activity. This was complemented with molecular and histological analysis of adipose tissue, liver and the intestine as well as microbiota analysis. We show that moderate telomere shortening leads to improved insulin sensitivity and glucose tolerance in aged male and female G2 Terc-/- mice. This is accompanied by reduced fat and lean mass in both sexes. Mechanistically, the metabolic improvement results from reduced dietary lipid uptake in the intestine, characterized by reduced gene expression of fatty acid transporters in enterocytes of the small intestine. Furthermore, G2-Terc-/- mice showed significant alterations in the composition of gut microbiota, potentially contributing to the improved glucose metabolism. CONCLUSIONS: Our study shows that moderate telomere shortening reduces intestinal lipid absorption, resulting in reduced adiposity and improved glucose metabolism in aged mice. These findings will guide future murine and human aging studies and provide important insights into the age associated development of type 2 diabetes and metabolic syndrome.

L-Serine Supplementation Blunts Fasting-Induced Weight Regain by Increasing Brown Fat Thermogenesis.

Weight regain after fasting, often exceeding the pre-fasting weight, is a common phenomenon and big problem for the treatment of obesity. Thus, novel interventions maintaining reduced body weight are critically important to prevent metabolic disease. Here we investigate the metabolic effects of dietary L-serine supplementation, known to modulate various organ functions. C57BL/6N-Rj male mice were supplemented with or without 1% L-serine in their drinking water and fed with a chow or high-fat diet. Mice were fed either ad libitum or subjected to repeated overnight fasting. Body weight, body composition, glucose tolerance and energy metabolism were assessed. This was combined with a detailed analysis of the liver and adipose tissues, including the use of primary brown adipocytes to study mitochondrial respiration and protein expression. We find that L-serine supplementation has little impact on systemic metabolism in ad libitum-fed mice. Conversely, L-serine supplementation blunted fasting-induced body weight regain, especially in diet-induced obese mice. This reduction in body weight regain is likely due to the increased energy expenditure, based on elevated brown adipose tissue activity. Thus, L-serine supplementation during and after weight-loss could reduce weight regain and thereby help tackle one of the major problems of current obesity therapies.

Ex vivo toxicological evaluation of experimental anticancer gold(i) complexes with lansoprazole-type ligands.

Gold-based compounds are of great interest in the field of medicinal chemistry as novel therapeutic (anticancer) agents due to their peculiar reactivity and mechanisms of action with respect to organic drugs. Despite their promising pharmacological properties, the possible toxic effects of gold compounds need to be carefully evaluated in order to optimize their design and applicability. This study reports on the potential toxicity of three experimental gold-based anticancer compounds featuring lansoprazole ligands (1-3) studied in an ex vivo model, using rat precision cut kidney and liver slices (PCKS and PCLS, respectively). The results showed a different toxicity profile for the tested compounds, with the neutral complex 2 being the least toxic, even less toxic than cisplatin, followed by the cationic complex 1. The dinuclear cationic gold complex 3 was the most toxic in both liver and kidney slices. This result correlated with the metal uptake of the different compounds assessed by ICP-MS, where complex 3 showed the highest accumulation of gold in liver and kidney slices. Interestingly compound 1 showed the highest selectivity towards cancer cells compared to the healthy tissues. Histomorphology evaluation showed a similar pattern for all three Au(i) complexes, where the distal tubular cells suffered the most extensive damage, in contrast to the damage in the proximal tubules induced by cisplatin. The binding of representative gold compounds with the model ubiquitin was also studied by ESI-MS, showing that after 24 h incubation only 'naked' Au ions were bound to the protein following ligands' loss. The mRNA expression of stress response genes appeared to be similar for both evaluated organs, suggesting oxidative stress as the possible mechanism of toxicity. The obtained results open new perspectives towards the design and testing of bifunctional gold complexes with chemotherapeutic applications.