Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LDand the impact of leptin treatment have not been investigated so far.Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controlsmatched for age, gender, and bodymass index. The impact ofmetreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated withmarkers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment

Development of a Thioredoxin-Based Cofactor Regeneration System for NADPH-Dependent Oxidoreductases

Nicotinamide cofactor-dependent oxidoreductases have become a valuable tool for the synthesis of high value chiral compounds. The feasibility of biocatalytic processes involving these enzymes stands and falls with the efficiency of the regeneration of cofactors. In this study, we describe a novel NADPH regeneration method based on the natural thioredoxin electron delivery system. Thioredoxin 1 (Trx1) and thioredoxin reductase (TR) from Thermus thermophilus were characterized for the dithiol-dependent reduction of NADP+, revealing good catalytic activities and a particularly remarkable thermostability. The TR/Trx1 system was then coupled with two representative NADPH-dependent oxidoreductases, alcohol dehydrogenase and cyclohexanone monooxygenase. Reaction conditions for both systems were optimized for reaction yield and selectivity. The results demonstrate the feasibility of the TR/Trx1-system for its application as NADPH regeneration system