Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and ...inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a-KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow-derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.
Adiponectin is an abundant adipokine with pleiotropic protective effects against a cluster of obesity-related cardiometabolic disorders. However, its role in adaptive thermogenesis has scarcely been ...explored. Here we showed that chronic cold exposure led to a markedly elevated production of adiponectin in adipocytes of subcutaneous white adipose tissue (scWAT), which in turn bound to M2 macrophages in the stromal vascular fraction. Chronic cold exposure-induced accumulation of M2 macrophages, activation of beige cells, and thermogenic program were markedly impaired in scWAT of adiponectin knockout (ADN KO) mice, whereas these impairments were reversed by replenishment with adiponectin. Mechanistically, adiponectin was recruited to the cell surface of M2 macrophages via its binding partner T-cadherin and promoted the cell proliferation by activation of Akt, consequently leading to beige cell activation. These findings uncover adiponectin as a key efferent signal for cold-induced adaptive thermogenesis by mediating the crosstalk between adipocytes and M2 macrophages in scWAT.
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•Cold exposure selectively induces adiponectin accumulation in subcutaneous WAT•Adiponectin KO mice are resistant to subcutaneous adipose browning during cold adaptation•Cold-induced M2 macrophage proliferation requires adiponectin in subcutaneous WAT•T-cadherin serves as an anchor for tethering of adiponectin to M2 macrophages
Adiponectin protects against a cluster of obesity-related metabolic complications through multiple mechanisms. This study shows that chronic cold exposure induces adiponectin accumulation in subcutaneous fat, which is indispensable for subcutaneous adipose browning via promoting M2 macrophage proliferation. These findings suggest a key role of adiponectin in mediating crosstalk between innate immunity and adaptive thermogenesis.
Abstract
Adipose tissue macrophage (ATM) inflammation is involved with meta-inflammation and pathology of metabolic complications. Here we report that in adipocytes, elevated lactate production, ...previously regarded as the waste product of glycolysis, serves as a danger signal to promote ATM polarization to an inflammatory state in the context of obesity. Adipocyte-selective deletion of lactate dehydrogenase A (
Ldha
), the enzyme converting pyruvate to lactate, protects mice from obesity-associated glucose intolerance and insulin resistance, accompanied by a lower percentage of inflammatory ATM and reduced production of pro-inflammatory cytokines such as interleukin 1β (IL-1β). Mechanistically, lactate, at its physiological concentration, fosters the activation of inflammatory macrophages by directly binding to the catalytic domain of prolyl hydroxylase domain-containing 2 (PHD2) in a competitive manner with α-ketoglutarate and stabilizes hypoxia inducible factor (HIF-1α). Lactate-induced IL-1β was abolished in PHD2-deficient macrophages. Human adipose lactate level is positively linked with local inflammatory features and insulin resistance index independent of the body mass index (BMI). Our study shows a critical function of adipocyte-derived lactate in promoting the pro-inflammatory microenvironment in adipose and identifies PHD2 as a direct sensor of lactate, which functions to connect chronic inflammation and energy metabolism.
Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and ...systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific
knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.
Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice.
Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
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•We developed PLGA microspheres featured highly porous structures with a low density.•The features of the PLGA microspheres are beneficial for pulmonary drug delivery.•We studied the ...synergistic effect of simultaneous release of doxorubicin and paclitaxel in the PLGA microspheres.•High ratio of doxorubicin to paclitaxel was required to maximize the therapeutic effect.•The sustained-release porous PLGA microspheres containing DOX and PTX have the potential for future clinical application.
PLGA porous microspheres loaded with doxorubicin (DOX) and paclitaxel (PTX) were developed for in situ treatment of metastatic lung cancer. The synergistic effect of the combined drugs was investigated against B16F10 cells to obtain the optimal prescription for in vivo studies. The combination therapy showed great synergism when DOX was the majority in the combination therapy, while they showed moderate antagonism when PTX is in major. The combination of DOX and PTX at a molar ratio of 5/1 showed the best synergistic therapeutic effect in the free form. However, the drugs exhibited more synergism in the PLGA microspheres at a molar ratio of 2/1, due to the difference in drug release rate. The in vivo study verified the synergism of DOX and PTX at the optimal molar ratio. These results suggested that dual encapsulation of DOX and PTX in porous PLGA microspheres would be a promising technology for long effective lung cancer treatment.
Accurate extraction of farmland boundaries is crucial for improving the efficiency of farmland surveys, achieving precise agricultural management, enhancing farmers’ production conditions, protecting ...the ecological environment, and promoting local economic development. Remote sensing and deep learning are feasible methods for creating large-scale farmland boundary maps. However, existing neural network models have limitations that restrict the accuracy and reliability of agricultural parcel extraction using remote sensing technology. In this study, we used high-resolution satellite images (2 m, 1 m, and 0.8 m) and the U2-Net++ model based on the RSU module, deep separable convolution, and the channel-spatial attention mechanism module to extract different types of fields. Our model exhibited significant improvements in farmland parcel extraction compared with the other models. It achieved an F1-score of 97.13%, which is a 7.36% to 17.63% improvement over older models such as U-Net and FCN and a more than 2% improvement over advanced models such as DeepLabv3+ and U2-Net. These results indicate that U2-Net++ holds the potential for widespread application in the production of large-scale farmland boundary maps.
Increasingly stringent regulations regarding vehicle emissions have contributed to the diversification of vehicle technologies, resulting in the increasing complexity of typical vehicles that make up ...a fleet. In order to investigate the real gas emissions of different typical vehicles, tests were conducted using a portable emission measurement system (PEMS) in Beijing and emission studies were conducted on eight light-duty passenger vehicles (LDPVs, including light-duty gasoline passenger vehicles and hybrid electric vehicles), eight heavy-duty passenger vehicles (HDPVs), and four light-duty trucks (LDTs). The results show that the emissions of relevant pollutants from LDPV meet the emission standard limits. The emission factors of CO2, CO, NOX, and HC of China IV and China V hybrid electric vehicles (HEVs) are much smaller than the emission standard limits and the emission factors of other vehicles, which have better emission reduction effects. Among LDPV, heavy-duty passenger vehicles (HDPVs), and LDT, the emissions of HDPV and LDT are extremely high. Emission characteristics vary on different types of roads, with the highest emission factors generally occurring on secondary roads. The micro-trip method was used to explore the influence of speed on emission factors. HEV are less sensitive to speed changes and can still maintain a low emission level at low speeds. The average speed and emission factors of HDPV in micro-trip has a strong correlation.
Thyroid hormone (TH) is a thermogenic activator with anti-obesity potential. However, systemic TH administration has no obvious clinical benefits on weight reduction. Herein we selectively delivered ...triiodothyronine (T3) to adipose tissues by encapsulating T3 in liposomes modified with an adipose homing peptide (PLT3). Systemic T3 administration failed to promote thermogenesis in brown and white adipose tissues (WAT) due to a feedback suppression of sympathetic innervation. PLT3 therapy effectively obviated this feedback suppression on adrenergic inputs, and potently induced browning and thermogenesis of WAT, leading to alleviation of obesity, glucose intolerance, insulin resistance, and fatty liver in obese mice. Furthermore, PLT3 was much more effective than systemic T3 therapy in reducing hypercholesterolemia and atherosclerosis in apoE-deficient mice. These findings uncover WAT as a viable target mediating the therapeutic benefits of TH and provide a safe and efficient therapeutic strategy for obesity and its complications by delivering TH to adipose tissue.
Neutron diffraction and total scattering are combined to investigate a series of single-phase 10-component compositionally complex fluorite-based oxides, ...(Pr0.375Nd0.375Yb0.25)2(Ti0.5Hf0.25Zr0.25)2O71-x(DyHoErNb)O7x, denoted as 10CCFBOxNb. A long-range order-disorder transition (ODT) occurs at x = 0.81 ± 0.01 from the ordered pyrochlore to disordered defect fluorite. In contrast to ternary oxides, this ODT occurs abruptly without an observable two-phase region; moreover, the phase stability in 10CCFBOs deviates from the well-established criteria for simpler oxides. Rietveld refinements of neutron diffraction patterns suggest that this ODT occurs via the migration of oxygen anions from the position 48f to 8a, with a small final jump at the ODT; however, the 8a oxygen occupancy changes gradually (without an observable discontinuous jump). We further discover diffuse scattering in Nb-rich compositions, which suggests the presence of short-range order. Using small-box modelling, four compositions near ODT (x = 0.75, 0.8, 0.85, and 1) can be better fitted by C2221 weberite ordering for the local polyhedral structure at nanoscale. Interestingly, 10CCFBO0.75Nb and 10CCFBO0.8Nb possess both long-range pyrochlore order and short-range weberite-type order, which can be understood from severe local distortion of the pyrochlore polyhedral structure. Thus, weberite-type short-range order emerges before the ODT, coexisting and interacting with long-range pyrochlore order. After the ODT, the long-range pyrochlore order vanishes but the short-range weberite-type order persists in the long-range disordered defect fluorite structure. Notably, a drop in the thermal conductivity coincides with emergence of the short-range order, instead of the long-range ODT.
A Short Text: Neutron diffraction and total scattering were used to characterize long- and short-range orders in 10-component compositionally complex ceramics. An unusual long-range order-disorder transition (ODT) from disordered defect fluorite to ordered pyrochlore occurs, which competes with emergence of weberite-type short-range ordering. Interestingly, reduced thermal conductivity coincides with the rise of short-range ordering, instead of occurrence of the long-range ODT. Display omitted
•Neutron diffraction and total scattering are combined to investigate 10-component oxides.•A long-range order-disorder transition (ODT) from pyrochlore to fluorite is observed.•This long-range ODT occurs abruptly without an observable two-phase region.•Long-range pyrochlore order and short-range weberite-type order can co-exist and interact.•A drop in the thermal conductivity is coincident with emergence of the short-range order.
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