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Background: The thyroid hormone (TH) metabolite 3,5-diiodothyronine (3,5-T2) is considered as a potential drug for treatment of nonalcoholic fatty liver disease (NAFLD) based on its prominent antisteatotic effects in murine models of obesity without the detrimental thyromimetic side effects known for classical TH. To expand our understanding of its mode of action, we comprehensively characterized the effects of 3,5-T2 on hepatic gene expression in a diet-induced murine model of obesity by a combined liver proteome and transcriptome analysis. Materials and Methods: Male C57BL/6 mice fed high-fat diet (HFD) to induce NAFLD or standard diet (SD) as control were treated with 2.5 μg/g body weight 3,5-T2 or saline for 4 weeks. We performed mass spectrometry analyses and integrated those proteome data with earlier published microarray-based transcriptome data from the same animals. In addition, concentrations of several sex steroids in serum and different tissues were determined by gas chromatography-tandem mass spectrometry. Results: We observed limited concordance between transcripts and proteins exhibiting differential abundance under 3,5-T2 treatment, which was only partially explainable by methodological reasons and might, therefore, reflect noncanonical post-transcriptional events. The treatment affected the levels of more and partially different proteins under HFD as compared with SD, demonstrating response modulation by the hepatic lipid load. The hepatic physiological signatures of 3,5-T2 treatment inferable from the omics data comprised the reduction of oxidative stress and alteration of apolipoprotein profiles, both due to decreased liver fat content. In addition, induction of several classical TH target genes and genes involved in the biosynthesis of cholesterol, bile acids (BAs), and male sex steroids was observed. The latter finding was supported by hepatic sex steroid measurements. Conclusion: While confirming the beneficial hepatic liver fat reduction by 3,5-T2 treatment, our data suggest that besides the well-known induction of fatty acid oxidation the stimulation of cholesterol- and BA synthesis with subsequent excretion of the latter through bile might represent a further important mechanism in this context. The obvious intensified male sex steroid exposition of the liver in 3,5-T2-treated HFD animals can be predicted to cause enhanced hepatic "masculinization," with not yet clear but potentially detrimental physiological consequences.

Pregnancy alters B cell development and function. B cell activation is initiated by antigens binding to the BCR leading to B cell survival, proliferation, antigen presentation and antibody production. We performed a genome-wide transcriptome profiling of splenic B cells from pregnant (P) and non-pregnant (NP) mice and identified 1136 genes exhibiting differential expression in B cells from P mice (625 up- and 511 down-regulated) compared to NP animals. In silico analysis showed that B cell activation through BCR seems to be lowered during pregnancy. RT-qPCR analysis confirmed these data. Additionally, B cells from pregnant women stimulated in vitro through BCR produced lower levels of inflammatory cytokines compared to non-pregnant women. Our results suggest that B cells acquire a state of hypo-responsiveness during gestation, probably as part of the maternal immune strategy for fetal tolerance but also open new avenues to understand why pregnant women are at highest risk for infections., (Copyright © 2021 Elsevier Inc. All rights reserved.)