Loss of adipose TET proteins enhances ß-adrenergic responses and protects against obesity by epigenetic regulation of ß3-AR expression.

ß-adrenergic receptor (ß-AR) signaling plays predominant roles in modulating energy expenditure by triggering lipolysis and thermogenesis in adipose tissue, thereby conferring obesity resistance. Obesity is associated with diminished ß3-adrenergic receptor (ß3-AR) expression and decreased ß-adrenergic responses, but the molecular mechanism coupling nutrient overload to catecholamine resistance remains poorly defined. Ten-eleven translocation (TET) proteins are dioxygenases that alter the methylation status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine and further oxidized derivatives. Here, we show that TET proteins are pivotal epigenetic suppressors of ß3-AR expression in adipocytes, thereby attenuating the responsiveness to ß-adrenergic stimulation. Deletion of all three Tet genes in adipocytes led to increased ß3-AR expression and thereby enhanced the downstream ß-adrenergic responses, including lipolysis, thermogenic gene induction, oxidative metabolism, and fat browning in vitro and in vivo. In mouse adipose tissues, Tet expression was elevated after mice ate a high-fat diet. Mice with adipose-specific ablation of all TET proteins maintained higher levels of ß3-AR in both white and brown adipose tissues and remained sensitive to ß-AR stimuli under high-fat diet challenge, leading to augmented energy expenditure and decreased fat accumulation. Consequently, they exhibited improved cold tolerance and were substantially protected from diet-induced obesity, inflammation, and metabolic complications, including insulin resistance and hyperlipidemia. Mechanistically, TET proteins directly repressed ß3-AR transcription, mainly in an enzymatic activity-independent manner, and involved the recruitment of histone deacetylases to increase deacetylation of its promoter. Thus, the TET-histone deacetylase-ß3-AR axis could be targeted to treat obesity and related metabolic diseases.

A fast and label-free detection of hydroxymethylated DNA using a nozzle-jet printed AuNPs@Ti3C2 MXene-based electrochemical sensor.

5-hydroxymethylcytosine (5hmC) is a key epigenetic mark in the mammalian genome that has been proposed as a promising cancer biomarker with diagnostic and prognostic potentials. A new type of two-dimensional (2D) material called MXene includes transition metal carbides and nitrides and possesses unique physico-chemical properties suitable for diverse applications, including electrochemical sensors. Here, we report a new nozzle-jet printed electrochemical sensor using gold nanoparticles (AuNPs)@Ti3C2 MXene nanocomposite for the real-time and label-free detection of 5hmC in the genome. We utilized Ti3C2 MXene as a platform to immobilize AuNPs, which have been shown to exhibit different affinity interactions toward 5-methylcytosine (5 mC) and 5hmC, and thus produce distinct electrochemical responses. To fabricate the electrode, a highly conductive and adhesive silver ink was prepared to generate a silver line onto polyethylene terephthalate (PET) substrate using nozzle-jet printing, followed by deposition of AuNPs@Ti3C2 MXene ink at one end via dropcasting. Analyses of morphology and chemical composition showed that all steps of the sensor fabrication were successful. The fabricated sensor coupled with cyclic voltammetry showed excellent performance in distinguishing 5 mC- or 5hmC-enriched cellular genomic DNAs. As a proof-of-concept investigation, we confirmed that our sensor readily and consistently detected 5hmC diminution in multiple tumors, compared to the paired normal tissues. Thus, our simple and cost-effective sensing strategy using printable AuNPs@Ti3C2 MXene ink holds promise for a wide range of practical applications in epigenetic studies as well as clinical settings.

The risk profile of rhegmatogenous retinal detachment before and after using a fluoroquinolone: a 12 year nationwide self-controlled case series study.

Objectives: To determine whether or not fluoroquinolone use increases the incidence of retinal detachment. Design: Self-controlled case series analysis. Participants: Participants were identified using the South Korean National Health Insurance Database between 1 January 2004 and 31 December 2015. A total of 15 134 patients who experienced rhegmatogenous retinal detachment (RRD) with at least one prescription of a fluoroquinolone were included. Methods: Incidence rate ratios (IRRs) and their 95% CIs were calculated using conditional Poisson regression. The main outcome measure was a recorded diagnosis of RRD (ICD-10: H33.0) with a claim for the surgical code for RRD. Results: We found an increased risk of retinal detachment in the first 1-30 days following the initiation of fluoroquinolone therapy (IRR 1.85; 95% CI 1.71-1.95), which rose for the 31-60 days period (IRR 2.05; 95% CI 1.43-2.95) but remained constant after more than 60 days (IRR 1.25; 95% CI 0.75-2.10). However, the elevated risk was also found in the 1-30 day period prior to the initiation of fluoroquinolone therapy (IRR 1.58; 95% CI 1.49-1.68) and also 31-60 days before medication use (IRR 1.11; 95% CI 1.03-1.19). Conclusions: Our case-based study indicated that the risk after fluoroquinolone exposure doubled; however, the risk profile before and after fluoroquinolone use means that the association between fluoroquinolone use and retinal detachment might not be a causal relationship.