Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose ...tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m², relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m²/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (ΔRd:13.2 ± 1.8 vs. 9.6 ± 1.8 µmol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D.
Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a ...comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.
Multidimensional trait frameworks are increasingly used to understand plant strategies for growth and survival. However, it is unclear if frameworks developed at a global level can be applied in ...local communities and how well these frameworks—based largely on plant morphological traits—align with plant physiology and response to stress.
We tested the ability of an integrated framework of plant form and function to characterise seedling trait variation and drought response among 22 grasses and forbs common in a semi‐arid grassland. We measured above‐ground and below‐ground traits, and survival to explore how drought response is linked to three trait dimensions (resource conservation, microbial collaboration, and plant size) associated with the framework as well as non‐morphological dimensions (e.g. physiological traits) that are under‐represented in global trait frameworks.
We found support for three globally‐recognised axes representing trade‐offs in strategies associated with tissue investment (leaf nitrogen, leaf mass per area, root tissue density), below‐ground resource uptake (root diameter, specific root length), and size (shoot mass). However, in contrast to global patterns, above‐ground and below‐ground resource conservation gradients were oppositely aligned: root tissue density was positively correlated with leaf N rather than leaf mass per area. This likely reflects different investment strategies of annual and perennial herbaceous species, as fast‐growing annual species invested in lower density roots and less nitrogen‐rich leaves to maximise plant‐level carbon assimilation. Species with longer drought survival minimised water loss through small above‐ground size and low leaf‐level transpiration rates, and drought survival was best predicted by a principal component axis representing plant size.
Contrary to our expectations, drought survival in seedlings did not align with the conservation or collaboration axes suggesting that seedlings with different functional strategies can achieve similar drought survival, as long as they minimise water loss. Our results also show that within local communities, expected trait relationships could be decoupled as some plant groups achieve similar performance through different trait combinations. The effectiveness of species mean trait values in predicting drought response highlights the value of trait‐based methods as a versatile tool for understanding ecological processes locally across various ecosystems.
Read the free Plain Language Summary for this article on the Journal blog.
Read the free Plain Language Summary for this article on the Journal blog.
The consequences of exposure to prenatal maternal anxiety for the development of child temperament were examined in a sample of 120 healthy, 2-year-old children. Prenatal maternal state and ...pregnancy-specific anxiety (PSA) were measured five times during pregnancy, and maternal state anxiety was measured again at 2 years post partum. Child temperament was measured at 2 years using the Early Childhood Behavior Questionnaire. The relationship between the trajectory of maternal anxiety across gestation and negative affectivity was evaluated using hierarchical linear growth curve modeling. Higher maternal PSA between 13 and 17 weeks of gestation was associated with increased negative temperament in the children. This association could not be explained by postnatal maternal anxiety, demographic, or obstetric factors. Prenatal maternal state anxiety was not associated with child temperament. These findings demonstrate that PSA early in gestation has a distinctive influence on the developing fetus.
Diamond-Blackfan anemia (DBA) is a rare hematopoietic disease characterized by a block in red cell differentiation. Most DBA cases are caused by mutations in ribosomal proteins and characterized by ...higher than normal activity of the tumor suppressor p53. Higher p53 activity is thought to contribute to DBA phenotypes by inducing apoptosis during red blood cell differentiation. Currently, there are few therapies available for patients with DBA. We performed a chemical screen using zebrafish ribosomal small subunit protein 29 (
) mutant embryos that have a p53-dependent anemia and identified calmodulin inhibitors that rescued the phenotype. Our studies demonstrated that calmodulin inhibitors attenuated p53 protein amount and activity. Treatment with calmodulin inhibitors led to decreased p53 translation and accumulation but does not affect p53 stability. A U.S. Food and Drug Administration-approved calmodulin inhibitor, trifluoperazine, rescued hematopoietic phenotypes of DBA models in vivo in zebrafish and mouse models. In addition, trifluoperazine rescued these phenotypes in human CD34
hematopoietic stem and progenitor cells. Erythroid differentiation was also improved in CD34
cells isolated from a patient with DBA. This work uncovers a potential avenue of therapeutic development for patients with DBA.
Epoxyeicosatrienoic acids (EETs) are lipid-derived signaling molecules with cardioprotective and vasodilatory actions. We recently showed that 11,12-EET enhances hematopoietic induction and ...engraftment in mice and zebrafish. EETs are known to signal via G protein-coupled receptors, with evidence supporting the existence of a specific high-affinity receptor. Identification of a hematopoietic-specific EET receptor would enable genetic interrogation of EET signaling pathways, and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify an EET receptor based on the expression of G protein-coupled receptors in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are expressed in three EET-responsive cell lines, but not expressed in an EET-unresponsive line. Of these, only recombinant GPR132 showed EET-responsiveness in vitro, using a luminescence-based β-arrestin recruitment assay. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. In contrast to high-affinity EET receptors, GPR132 is reported to respond to additional hydroxy-fatty acids in vitro, and we found that these same hydroxy-fatty acids enhance hematopoiesis in the zebrafish. We conducted structure–activity relationship analyses using both cell culture and zebrafish assays on diverse medium-chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, whereas unoxygenated or saturated fatty acids had lower activity. Absence of the carbon-1 position carboxylic acid prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of oxygenated polyunsaturated fatty acids to enhance both embryonic and adult hematopoiesis.
Abstract
In 1970, a male student at the University of Waterloo in Waterloo, Ontario deemed the campus women's liberation group to be a ‘fraternity for frustrated females’. This perspective was ...commonplace at the supposedly liberal school, as male dissent against autonomous women's organising continued throughout the early 1970s. While women organised protests against sexist campus events, held consciousness‐raising groups and encouraged discussion about gender roles in society, many male students turned away from women's pleas for change and were not receptive to encouraging equality on campus. This research examines the attempted involvement of male students in the women's liberation movement at the University of Waterloo and the anti‐feminist rhetoric that percolated on campus. By using a micro‐history of the University of Waterloo and analysing the student newspaper,
The Chevron
, it illustrates the ways in which women students organised despite backlash from male students and the daily sexism women faced on campus. It reveals the challenges women faced in gaining equality and the climate of youth masculinity in a period of tumultuous social change.
Elevated levels of plasma branched-chain amino acids (BCAAs) have been associated with insulin resistance and type 2 diabetes since the 1960s. Pharmacological activation of branched-chain α-ketoacid ...dehydrogenase (BCKDH), the rate-limiting enzyme of BCAA oxidation, lowers plasma BCAAs and improves insulin sensitivity. Here we show that modulation of BCKDH in skeletal muscle, but not liver, affects fasting plasma BCAAs in male mice. However, despite lowering BCAAs, increased BCAA oxidation in skeletal muscle does not improve insulin sensitivity. Our data indicate that skeletal muscle controls plasma BCAAs, that lowering fasting plasma BCAAs is insufficient to improve insulin sensitivity and that neither skeletal muscle nor liver account for the improved insulin sensitivity seen with pharmacological activation of BCKDH. These findings suggest potential concerted contributions of multiple tissues in the modulation of BCAA metabolism to alter insulin sensitivity.
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