Neudesin in obesity and type 2 diabetes mellitus: the effect of acute fasting and weight reducing interventions

Helena Kratochvilova,1–3 Zdenka Lacinova,1–3 Jana Klouckova,1–3 Petra Kavalkova,2,3 Anna Cinkajzlova,1–3 Pavel Trachta,4 Jarmila Krizova,4 Marek Benes,5 Karin Dolezalova,6 Martin Fried,6 Zuzana Vlasakova,7 Terezie Pelikanova,7 Julius Spicak,5 Milos Mraz,2,3,7 Martin Haluzik1–3,7 1Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2Department of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic; 3Department of Medical Biochemistry and Laboratory Diagnostics, General University Hospital, Prague, Czech Republic; 4Third Department of Medicine, Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 5Hepatogastroenterology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 6Department of Surgery, OB Clinic, Prague, Czech Republic; 7Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Context: Neudesin has recently been identified as a novel regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored.Objective: The aim of this study was to assess the effects of obesity and type 2 diabetes mellitus (T2DM) along with selected weight reducing interventions on serum neudesin levels and adipose tissue mRNA expression.Patients and methods: Fifteen obese subjects with T2DM undergoing endoscopic duodenal-jejunal bypass liner (DJBL) implantation, 17 obese subjects (11 with T2DM, 6 without T2DM) scheduled for gastric plication (GP), 15 subjects with functional hypoglycemia subjected to 72-hour acute fasting (AF), and 12 healthy controls were included in the study.Results: Baseline neudesin levels were comparable between all groups. DJBL increased neudesin at 6 and 10 months after the procedure (1.77±0.86 vs 2.28±1.27 vs 2.13±1.02 ng/mL, P=0.001 for baseline vs 6 vs 10 months) along with reduction in body weight and improvement of HbA1c without any effect on neudesin mRNA expression in subcutaneous adipose tissue. Conversely, GP did not affect neudesin levels despite marked reduction in body weight and improvement of HbA1c. In contrast, AF decreased neudesin levels during the entire period (1.74±0.54 vs 1.46±0.48 ng/mL, P=0.001 for baseline vs 72 hours) with no impact of subsequent re-alimentation on neudesin concentrations.Conclusion: Neudesin levels are differentially regulated during AF and chronic weight reduction induced by DJBL or GP. Further studies are needed to assess its possible significance in energy homeostasis regulation in humans. Keywords: neudesin, obesity, type 2 diabetes mellitus, bariatric surgery, acute fasting, weight reduction, energy homeostasi

Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX

In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form γ-H2AX) in megabase chromatin domains flanking sites of DNA damage. To investigate the role of H2AX in mammalian cells, we generated H2AX-deficient (H2AX(Δ)(/)(Δ)) mouse embryonic stem (ES) cells. H2AX(Δ)(/)(Δ) ES cells are viable. However, they are highly sensitive to ionizing radiation (IR) and exhibit elevated levels of spontaneous and IR-induced genomic instability. Notably, H2AX is not required for NHEJ per se because H2AX(Δ)(/)(Δ) ES cells support normal levels and fidelity of V(D)J recombination in transient assays and also support lymphocyte development in vivo. However, H2AX(Δ)(/)(Δ) ES cells exhibit altered IR-induced BRCA1 focus formation. Our findings indicate that H2AX function is essential for mammalian DNA repair and genomic stability