While brown adipose tissue (BAT) is well‐recognized for its ability to dissipate energy in the form of heat, recent studies suggest multifaced roles of BAT in the regulation of glucose and lipid homeostasis beyond stimulating thermogenesis. One of the functions involves interorgan communication with metabolic organs, such as the liver, through BAT‐derived secretory factors, a.k.a., batokine. However, the identity and the roles of such mediators remain insufficiently understood. Here, we employed proteomics and transcriptomics in human thermogenic adipocytes and identified previously unappreciated batokines, including phospholipid transfer protein (PLTP). We found that increased circulating levels of PLTP, via systemic or BAT‐specific overexpression, significantly improve glucose tolerance and insulin sensitivity, increased energy expenditure, and decrease the circulating levels of cholesterol, phospholipids, and sphingolipids. Such changes were accompanied by increased bile acids in the circulation, which in turn enhances glucose uptake and thermogenesis in BAT. Our data suggest that PLTP is a batokine that contributes to the regulation of systemic glucose and lipid homeostasis as a mediator of BAT‐liver interorgan communication.

-The effects of endocrine disruptors on testicular steroidogenesis in fetal rats were investigated in a study involving in utero exposure. In the major part of this study, pregnant rats at gestational day (GD)15 were given a single oral administration of the test substance, and then the expression of the following mRNAs in GD20 fetuses was determined: testicular steroidogenic acute-regulatory protein (StAR), a cholesterol transporter mediating the rate-limiting step of steroidogenesis, a ß-subunit of pituitary luteinizing hormone (LH), and a regulator of gonadal steroidogenesis. Among the substances tested, only di(2-ethylhexyl)phthalate (DEHP) reduced the expression of fetal testicular StAR. The others listed below exhibited little effect on fetal StAR: 2,2',4,4'-tetrabromodiphenylether, tributyltin chloride, atrazine, permethrin, cadmium chloride (Cd), lead acetate (Pb) and methylmercury (CH 3 HgOH). None of them, including DEHP, lacked the ability to reduce the expression of pituitary LHß mRNA. The present study also examined the potential of metals as modifiers of fetal steroidogenesis by giving them to pregnant dams in drinking water during GD1 and GD20. Under these conditions, Cd and Pb at a low concentration (0.01 ppm) significantly attenuated the fetal testicular expression of StAR mRNA without a concomitant reduction in LHß. No such effect was detected with CH 3 HgOH even at 1 ppm. These results suggest that: 1) DEHP, Cd and Pb attenuate the fetal production of sex steroids by directly acting on the testis, and 2) chronic treatment during the entire gestational period is more useful than a single administration for determining the hazardous effect of a suspected endocrine disruptor on fetal steroidogenesis.

Exposure of pregnant rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at a low dose causes developmental disorders such as growth retardation and sexual immaturity in their pups. Our previous studies have demonstrated that TCDD attenuates the expression of pituitary luteinizing hormone in fetuses, resulting in the impairment of sexual behavior after they reach maturity. In this study, we focused on growth disturbance and investigated whether TCDD affects the expression of growth hormone (GH), another pituitary hormone which is essential for normal development in perinatal pups. The result showed that maternal exposure to TCDD (1 µg/kg) at gestational day (GD) 15 reduced the fetal expression of GH from the onset at GD18. In accordance with this, TCDD attenuated the pup weight during the perinatal period. We then examined the effect of TCDD on the serum concentration of corticosterone, which plays a key role in the proliferation of GH-producing cells, and found that TCDD reduces the circulating level of corticosterone in the mothers at GD18 and the male fetuses at GD19. The reduction in fetuses seems to be due to increased inactivation rather than reduced synthesis, because TCDD induces the fetal expression of hepatic enzymes participating in the metabolism of glucocorticoids without changing the expression of steroidogenic proteins in the pituitary-adrenal axis. Supplying corticosterone to TCDD-exposed mothers restored or tended to restore a TCDD-induced reduction in pup weight as well as the levels of pituitary GH mRNA and serum GH. These results suggest that TCDD lowers GH expression and growth retardation owing, at least partially, to a reduction in the circulating level of glucocorticoid in pregnant mothers and their fetuses.

No abstract

This randomized clinical trial investigates the effect of 15-mg edoxaban in patients aged 80 years and older who are not candidates for standard-dose oral anticoagulants owing to bleeding risk.

Background: Dioxin attenuates the fetal production of luteinizing hormone (LH) to imprint impaired sexual behavior. Results: Fetal exposure to dioxin induces histone deacetylases to attenuate the acetylation status of histones twisted around the LH␤ gene. Conclusion: Histone deacetylation in the pituitary contributes to the dioxin-induced damage to fetal/infant steroidogenesis. Significance: This study provides a new insight into the mechanism underlying sexual immaturity caused by dioxin.

No abstract

IMPORTANCEThe prevalence of atrial fibrillation (AF) increases with age and is more common in frail patients. However, data are lacking on outcomes of oral anticoagulants (OACs) in very elderly patients with AF with frailty, who are ineligible for standard anticoagulant treatment. OBJECTIVETo compare very-low-dose edoxaban (15 mg daily) vs placebo across frailty status, including each of 5 frailty assessment parameters, among patients with AF involved in the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial. DESIGN, SETTING, AND PARTICIPANTSThis is a cohort study using data from ELDERCARE-AF, a multicenter, randomized, double-blind, placebo-controlled phase 3 study of Japanese patients with AF aged 80 years or older who were ineligible for OACs at doses approved for stroke prevention because of their high bleeding risks. Eligible patients were randomly assigned (1:1) to receive edoxaban or placebo. The study duration was from August 5, 2016, to November 5, 2019, with the last patient followed up on December 27, 2019. Data analysis was performed from February 2021 to February 2022. EXPOSURE Edoxaban (15 mg) once daily or placebo. MAIN OUTCOMES AND MEASURESThe primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding.RESULTS A total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 nonfrail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. In the placebo group, the estimated event rates (SE) for stroke or systemic embolism were 7.1% (1.6%) per patient-year in the frail group and 6.1% (1.3%) per patient-year in the nonfrail group. Edoxaban was associated with lower event rates for stroke or systemic embolism with no interaction with frailty status or frailty assessment parameters. Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than in the placebo group, and no heterogeneity was observed with frailty status. Although both all-cause death and net clinical composite outcome occurred more frequently in the frail group than in the nonfrail group, there was no association with frailty status between the edoxaban and placebo groups.CONCLUSIONS AND RELEVANCE Regardless of frailty status, among Japanese patients with AF aged 80 years or older who were ineligible for standard OACs, once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.