The relation between gut microbiota and the host has been suggested to benefit metabolic homeostasis. Brown adipose tissue (BAT) and beige adipocytes facilitate thermogenesis to maintain host core ...body temperature during cold exposure. However, the potential impact of gut microbiota on the thermogenic process is confused. Here, we evaluated how BAT and white adipose tissue (WAT) responded to temperature challenges in mice lacking gut microbiota. We found that microbiota depletion via treatment with different cocktails of antibiotics (ABX) or in germ-free (GF) mice impaired the thermogenic capacity of BAT by blunting the increase in the expression of uncoupling protein 1 (UCP1) and reducing the browning process of WAT. Gavage of the bacterial metabolite butyrate increased the thermogenic capacity of ABX-treated mice, reversing the deficit. Our results indicate that gut microbiota contributes to upregulated thermogenesis in the cold environment and that this may be partially mediated via butyrate.
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•Mice lacking gut microbiota have impaired UCP1-dependent thermogenesis in cold•These effects are replicated in germ-free mice treated with CL-316243•IL-4 has no differential effect on energy metabolism in either control or ABX mice•Gavage of ABX mice with butyrate partially rescues the effects on BAT recruitment
Li et al. use different antibiotic recipes and germ-free mice to demonstrate the dependence of UCP1-dependent thermogenesis in the cold on the presence of a healthy gut microbiome. Gavage with butyrate partly rescues the effect, indicating a role for this molecule in normal thermogenic responses to low temperature.
Marine heatwaves (MHWs) are prolonged discrete events of anomalously warm seawater observed around the world. The occurrence of MHWs in the Japan/East Sea (JES), a middle latitude marginal sea with ...abundant aquatic resources, has severe impacts on marine ecosystems and human society. We used satellite remote sensing products spanning 1982–2020 to investigate the mean states and variations of JES MHWs. The results show that the JES MHWs occurred twice per year. More than 40% of the MHWs were shorter than the mean duration of 12.6 days and weaker than the mean intensity of 2.4 °C. Frequent MHWs were observed in August, while high mean intensities were observed in winter and spring in the western JES. In recent years, the area’s averaged yearly sum of MHW intensity in the JES has increased dramatically, with a positive trend of 29.62 °C days per decade—over twice the average global trend (12.37 °C days per decade), which is further confirmed by its first empirical orthogonal function mode. The strengthening trend in MHWs may be explained by oceanic dynamics rather than atmospheric forcing, and may result in increased surface latent heat flux from the ocean to the atmosphere.
The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or ...20% fat. Contrasting the expectation, very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.
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•Very low protein caused decreased body fat and improved glucose tolerance•Fatty acid and amino acid metabolism were changed by dietary low protein•The 1% protein group did not show hyperphagia despite the hunger pathway being activated•The effect of 1% protein on food intake was linked to hypothalamic mTOR signaling
Wu et al. investigated how very low levels of dietary protein affect energy balance by exposing mice to diets containing 1%–20% protein. Very low protein caused decreased food intake despite activated hunger signaling and led to decreased body weight, partially due to inhibited hypothalamic mTOR signaling but not eIF2a, TRPML1, and FGF21 signaling.
Gut microbiota deficient mice demonstrate accelerated glucose clearance. However, which tissues are responsible for the upregulated glucose uptake remains unresolved, with different studies ...suggesting that browning of white adipose tissue, or modulated hepatic gluconeogenesis, may be related to enhanced glucose clearance when the gut microbiota is absent. Here, we investigate glucose uptake in 22 different tissues in 3 different mouse models. We find that gut microbiota depletion via treatment with antibiotic cocktails (ABX) promotes glucose uptake in brown adipose tissue (BAT) and cecum. Nevertheless, the adaptive thermogenesis and the expression of uncoupling protein 1 (UCP1) are dispensable for the increased glucose uptake and clearance. Deletion of Ucp1 expressing cells blunts the improvement of glucose clearance in ABX-treated mice. Our results indicate that BAT and cecum, but not white adipose tissue (WAT) or liver, contribute to the glucose uptake in the gut microbiota depleted mouse model and this response is dissociated from adaptive thermogenesis.
Naphthyridine derivatives are a widely-used class of heterocycles due to their pharmacological activities. A novel compound (10-Methoxy-1,2,3,4-tetrahydrobenzo(
)(1,3) ...diazepino(1,2-a)-(1,8)naphthyridin-6-yl)(phenyl) methanone (named 3u), showed good anticancer activity in the human malignant melanoma cell line A375 via Thiazolyl Blue Tetrazolium Bromide (MTT) assay. After Western blotting confirmed, we found that 3u induces necroptosis at low concentrations and apoptosis at high concentrations via the upregulation of death receptors and scaffold protein in A375 cells. Furthermore, by combining 3u with the caspase inhibitor zVAD-fmk or Receptor Interacting Serine/Threonine Kinase 1 (RIP1) kinase inhibitor Necrostatin-1 (Nec-1), we found that the activity of caspase-8 was the crucial factor that determined whether either apoptosis or necroptosis occurred. The results indicate that 3u should be considered as a potential chemical substance for melanoma treatment.
Maternal overnutrition during lactation predisposes offspring to develop metabolic diseases and exacerbates the relevant syndromes in males more than females in later life. The hypothalamus is a ...heterogenous brain region that regulates energy balance. Here we combined metabolic trait quantification of mother and offspring mice under low and high fat diet (HFD) feeding during lactation, with single nucleus transcriptomic profiling of their offspring hypothalamus at peak lacation to understand the cellular and molecular alterations in response to maternal dietary pertubation. We found significant expansion in neuronal subpopulations including histaminergic (Hdc), arginine vasopressin/retinoic acid receptor-related orphan receptor β (Avp/Rorb) and agouti-related peptide/neuropeptide Y (AgRP/Npy) in male offspring when their mothers were fed HFD, and increased Npy-astrocyte interactions in offspring responding to maternal overnutrition. Our study provides a comprehensive offspring hypothalamus map at the peak lactation and reveals how the cellular subpopulations respond to maternal dietary fat in a sex-specific manner during development.
Sutures separate the flat bones of the skull and enable coordinated growth of the brain and overlying cranium. The coronal suture is most commonly fused in monogenic craniosynostosis, yet the unique ...aspects of its development remain incompletely understood. To uncover the cellular diversity within the murine embryonic coronal suture, we generated single-cell transcriptomes and performed extensive expression validation. We find distinct pre-osteoblast signatures between the bone fronts and periosteum, a ligament-like population above the suture that persists into adulthood, and a chondrogenic-like population in the dura mater underlying the suture. Lineage tracing reveals an embryonic Six2+ osteoprogenitor population that contributes to the postnatal suture mesenchyme, with these progenitors being preferentially affected in a Twist1+/-; Tcf12+/- mouse model of Saethre-Chotzen Syndrome. This single-cell atlas provides a resource for understanding the development of the coronal suture and the mechanisms for its loss in craniosynostosis.
The discovery of the TRAIL protein and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer ...therapies has yet to be established, as most cancer cells are TRAIL-resistant. In this report, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of c-FLIP expression and simultaneous inhibition of IAPs activity using AT406, a pan-antagonist of IAPs. Combined triple actions of the TRAIL, the IAPs inhibitor, AT406, and the c-FLIP expression inhibitor, rocaglamide (ART), markedly improve TRAIL-induced apoptotic effects in most solid cancer cell lines through the activation of an extrinsic apoptosis pathway. Furthermore, this ART combination does not harm normal cells. Among the 18 TRAIL-resistant cancer cell lines used, 15 cell lines become sensitive or highly sensitive to ART, and two out of three glioma cell lines exhibit high resistance to ART treatment due to very low levels of procaspase-8. This study provides a rationale for the development of TRAIL-induced apoptosis-based cancer therapies.
This study presents the development and testing of a global navigation satellite system (GNSS) buoy designed for measuring the sea surface elevation and tide level. The precision-point-positioning ...(PPP) technology is adopted for precise observation. The design of the buoy body is optimized by stability and hydrodynamic calculations. A high-performance embedded data acquisition system with big storage and high-frequency sampling is developed for long-term observation. The GNSS buoy is deployed in a wind farm approximately 70 km offshore of China, and undergoes a 60-day ocean test. A comparison of the sea level elevations obtained from the GNSS buoy and the pressure sensor shows that there is a strong correlation between them, with a correlation coefficient of 0.99. A harmonic analysis is applied to derive the harmonic constants for four key tidal components (M2, S2, O1, and K1). The amplitude differences are −1.2 cm, 1.4 cm, −0.6 cm, and −1.2 cm, respectively, and the phase differences are 1.8°, 2.2°, −1.3°, and −2.9°, respectively. The strong correlation between the measurements of the GNSS buoy and the pressure sensor and the relatively small differences of the amplitude and phase of the main tidal components indicate that the compact GNSS buoy demonstrates a capability to continuously measure the sea surface elevation and tide level with an elevation reference in the open sea.
Physical activity (PA) is widely acknowledged to be beneficial to health and wellbeing, and is potentially influenced by a variety of environmental factors such as ambient temperature, weather ...conditions and air pollution levels. Since these factors vary seasonally, physical activity participation may also respond seasonally. Current population studies to profile physical activity often sample individuals only once, and this may result in biased estimates if there is strong seasonal variation.
We conducted a study of 40 Han Chinese adults living in Beijing using GT3X accelerometers. We measured PA levels every two months across a complete year, while simultaneously monitoring ambient temperatures and air pollution levels. Average hourly vector magnitude (VM) and percentage time spent at each PA intensity (sedentary to light, moderate, vigorous and very vigorous) were measured. General Linear models (GLMs) were used to explore the effects of time of day, temperature and PM 2.5 levels on PA. One way ANOVA was used to test whether there were seasonal differences in body weight and body fatness.
The main factors influencing activity levels were the time of day and individual characteristics including age and body fatness, but there was no significant difference between the months. In addition, there was no significant impact of either ambient temperature or air pollution levels (PM2.5). There were also no significant differences over the year in the time spent at sedentary-light, moderate and very vigorous PA levels, but for vigorous PA level which occupied less than 0.5% daily physical activity, both month and individual were significant factors.
The relatively constant pattern of urban daily life, independent of time of year, may override the potential impacts of environmental factors that would be anticipated to impact PA levels. These subjects did not specifically avoid activity coincident with elevated air pollution levels (PM2.5). Single week long measurements of physical activity could provide a representative measurement of the physical active levels in this population.
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