Deletion of the mitochondrial calcium uniporter in adipose tissue promotes energy expenditure and alleviates diet-induced obesity.

OBJECTIVE: Studies have shown a correlation between obesity and mitochondrial calcium homeostasis, yet it is unclear whether and how Mcu regulates adipocyte lipid deposition. This study aims to provide new potential target for the treatment of obesity and related metabolic diseases, and to explore the function of Mcu in adipose tissue. METHODS: We firstly investigated the role of mitoxantrone, an Mcu inhibitor, in the regulation of glucose and lipid metabolism in mouse adipocytes (3T3-L1 cells). Secondly, C57BL/6J mice were used as a research model to investigate the effects of Mcu inhibitors on fat accumulation and glucose metabolism in mice on a high-fat diet (HFD), and by using CRISPR/Cas9 technology, adipose tissue-specific Mcu knockdown mice (Mcufl/+ AKO) and Mcu knockout of mice (Mcufl/fl AKO) were obtained, to further investigate the direct effects of Mcu on fat deposition, glucose tolerance and insulin sensitivity in mice on a high-fat diet. RESULTS: We found the Mcu inhibitor reduced adipocytes lipid accumulation and adipose tissues mass in mice fed an HFD. Both Mcufl/+ AKO mice and Mcufl/fl AKO mice were resistant to HFD-induced obesity, compared to control mice. Mice with Mcufl/fl AKO showed improved glucose tolerance and insulin sensitivity as well as reduced hepatic lipid accumulation. Mechanistically, inhibition of Mcu promoted mitochondrial biogenesis and adipocyte browning, increase energy expenditure and alleviates diet-induced obesity. CONCLUSIONS: Our study demonstrates a link between adipocyte lipid accumulation and mCa2+ levels, suggesting that adipose-specific Mcu deficiency alleviates HFD-induced obesity and ameliorates metabolic disorders such as insulin resistance and hepatic steatosis. These effects may be achieved by increasing mitochondrial biosynthesis, promoting white fat browning and enhancing energy metabolism.

BATF relieves hepatic steatosis by inhibiting PD1 and promoting energy metabolism.

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) has become a global health threat that needs to be addressed urgently. Basic leucine zipper ATF-like transcription factor (BATF) is commonly thought to be involved in immunity, but its effect on lipid metabolism is not clear. Here, we investigated the function of BATF in hepatic lipid metabolism. BATF alleviated high-fat diet (HFD)-induced hepatic steatosis and inhibited elevated programmed cell death protein (PD)1 expression induced by HFD. A mechanistic study confirmed that BATF regulated fat accumulation by inhibiting PD1 expression and promoting energy metabolism. PD1 antibodies alleviated hepatic lipid deposition. In conclusion, we identified the regulatory role of BATF in hepatic lipid metabolism and that PD1 is a target for alleviation of NAFLD. This study provides new insights into the relationship between BATF, PD1, and NAFLD.

Anti-Parity-Time Symmetry in a Su-Schrieffer-Heeger Sonic Lattice.

The Su-Schrieffer-Heeger (SSH) model is an important cornerstone in modern condensed-matter topology, yet it is the simplest one-dimensional (1D) tight binding approach to dwell into the characteristics of spinless electrons in chains of staggered bonds. Moreover, the chiral symmetry assures that its surface-confining states pin to zero energy, i.e., they reside midgap in the energy dispersion. Symmetry is also an attribute related to artificial media that are subject to parity P and time-reversal T operations. This non-Hermitian family has been thoroughly nourished in a wave-based context, where anti-PT (APT) symmetric systems are the youngest belonging members, permitting refractionless optics, inverse PT-symmetry breaking transition, and asymmetric mode switching. Here, we report the first extension of APT symmetry in an acoustic setting by endowing a SSH lattice with gain and loss components. We show that the in-gap topological defect state hinges on the non-Hermitian phase, in that the broken symmetry suppresses it, yet when PT or APT symmetry is intact, it is observed with either damped or evanescent decay, respectively. Our experiments showcase how the non-Hermitian SSH lattice serves as a utile platform to investigate topological properties across various PT symmetric phases using sound.

Echinocystic acid prevents obesity and fatty liver via interacting with FABP1.

Long-term high-fat diet (HFD) will lead to obesity and their complications. Echinocystic acid (EA), a triterpene, shows anti-inflammatory and antioxidant effects. We predict that EA supplementation can prevent obesity, diabetes, and nonalcoholic steatohepatitis. To test our hypothesis, we investigated the effects of EA supplementation on mice with HFD-induced obesity in vivo and in vitro by adding EA to the diet of mice and the medium of HepG2 cells, the protein target of EA was analyzed by molecular docking. The results showed that EA ameliorated obesity and inhibited blood triglyceride and liver triglyceride concentrations than those in the HFD groups. The data on molecular docking indicated that FABP1 was a potential target of EA. Further experimental results confirmed that EA affected the triglyceride level by regulating the function of FABP1. This study may provide a new potential inhibitor for FABP1 and a new strategy for the treatment of obesity.

The Roles of Natural Alkaloids and Polyphenols in Lipid Metabolism: Therapeutic Implications and Potential Targets in Metabolic Diseases.

The prevalence of obesity and its associated diseases has increased dramatically, and they are major threats to human health worldwide. A variety of approaches, such as physical training and drug therapy, can be used to reduce weight and reverse associated diseases; however, the efficacy and the prognosis are often unsatisfactory. It has been reported that natural food-based small molecules can prevent obesity and its associated diseases. Among them, alkaloids and polyphenols have been demonstrated to regulate lipid metabolism by enhancing energy metabolism, promoting lipid phagocytosis, inhibiting adipocyte proliferation and differentiation, and enhancing the intestinal microbial community to alleviate obesity. This review summarizes the regulatory mechanisms and metabolic pathways of these natural small molecules and reveals that the binding targets of most of these molecules are still undefined, which limits the study of their regulatory mechanisms and prevents their further application. In this review, we describe the use of Discovery Studio for the reverse docking of related small molecules and provide new insights for target protein prediction, scaffold hopping, and mechanistic studies in the future. These studies will provide a theoretical basis for the modernization of anti-obesity drugs and promote the discovery of novel drugs.

Maximum Decentral Projection Margin Classifier for High Dimension and Low Sample Size problems.

Compared with relatively easy feature creation or generation in data analysis, manual data labeling needs a lot of time and effort in most cases. Even if automated data labeling​ seems to make it better in some cases, the labeling results still need to be checked and verified by manual. The High Dimension and Low Sample Size (HDLSS) data are therefore very common in data mining and machine learning. For classification problems with the HDLSS data, due to data piling and approximate equidistance between any two input points in high-dimension space, some traditional classifiers often give poor predictive performance. In this paper, we propose a Maximum Decentral Projection Margin Classifier (MDPMC) in the framework of a Support Vector Classifier (SVC). In the MDPMC model, the constraints of maximizing the projection distance between decentralized input points and their supporting hyperplane are integrated into the SVC model in addition to maximizing the margin of two supporting hyperplanes. On ten real HDLSS datasets, the experiment results show that the proposed MDPMC approach can deal well with data piling and approximate equidistance problems. Compared with SVC with Linear Kernel (SVC-LK) and Radial Basis Function Kernel (SVC-RBFK), Distance Weighted Discrimination (DWD), weighted DWD (wDWD), Distance-Weighted Support Vector Machine (DWSVM), Population-Guided Large Margin Classifier (PGLMC), and Data Maximum Dispersion Classifier (DMDC), MDPMC obtains better predictive accuracy and lower classification errors than the other seven classifiers on the HDLSS data.

Structured sonic tube with carbon nanotube-like topological edge states.

A single-wall carbon nanotube can be viewed as a one-dimensional material created by rolling up a sheet of graphene. Its electronic band structure depends on the chirality, i.e., how the sheet has been rolled up, yet synthesizing the symmetry at will is rather challenging. We structure an artificial honeycomb lattice in both a zigzag and an armchair tube and explore their topological features for sound. Our findings reveal how armchair tubes remain gapless, whereas the zigzag counterparts host nontrivial edge states of non-zero quantized Zak phase, which are dictated by the circumferential number of units. Unlike man-made planar lattices whose underling symmetry must be broken to harvest quantum Hall and pseudospin phases, interestingly, the structured tubular lattice symmetry remains intact, while its nontrivial phase alone is governed by the chirality and the tube diameter. We foresee that our results, not only for sound, but also in photonics, mechanics and electronics will broaden future avenues for fundamental and applied sciences.

A New lncRNA, lnc-LLMA, Regulates Lipid Metabolism in Pig Hepatocytes.

A large variety of long noncoding RNAs (lncRNAs) have been discovered through high-throughput sequencing technology and some have been demonstrated to play important roles in lipid metabolism regulation. In our study, we found a highly expressed lncRNA (lnc-LLMA, liver lipid metabolism-associated lncRNA) in the liver of Duroc pigs, which was enriched in the nucleus. It displays potent tissue specificity among different pig breeds. Overexpression of lnc-LLMA can cause a decline in intracellular triglyceride (TG) levels and increases in ATP and mitochondrial DNA levels in pig primary hepatocytes and HepG2 cells. In addition, the expression levels of MTTP, APOB, CPT1α, and other genes were increased by overexpression of lnc-LLMA. It downregulated expression of G6Pase and SREBP1 genes. Chromatin isolation by RNA purification (ChRIP) experiments demonstrated that microsomal triglyceride transfer protein (MTTP) and glycogen synthase 2 (GYS2) were the potential interacting proteins of lnc-LLMA. The overexpression of the GYS2 gene rescued the decreasing intracellular TG levels caused by the increase of lnc-LLMA. Similarly, overexpression of MTTP was also able to save the lnc-LLMA-induced decrease in intracellular TG. Our study demonstrated that this novel lncRNA was closely related to lipid metabolism and affected lipid transport and mitochondrial function through MTTP and GYS2. Our results provided a new direction for further studying the effect of lncRNA on lipid metabolism regulation.

Ruthenium 360 and mitoxantrone inhibit mitochondrial calcium uniporter channel to prevent liver steatosis induced by high-fat diet.

BACKGROUND AND PURPOSE: Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population and lacks an effective treatment. Recent evidence implicates disrupted mitochondrial calcium homeostasis in the pathogenesis of hepatic steatosis. EXPERIMENTAL APPROACH: In this study, mitochondrial calcium uniporter (MCU) was inhibited through classical genetic approaches, viral vectors or small molecule inhibitors in vivo to study its role in hepatic steatosis induced by high-fat diet (HFD). In vitro, MCU was overexpressed or inhibited to change mitochondrial calcium homeostasis, endoplasmic reticulum-mitochondrial linker was adopted to increase mitochondria-associated membranes (MAMs) and MICU1-EF hand mutant was used to decrease the sensitivity of mitochondrial calcium uptake 1 (MICU1) to calcium and block MCU channel. KEY RESULTS: Here, we found that inhibition of liver MCU by AAV virus and classical genetic approaches can prevent HFD-induced liver steatosis. MCU regulates mitochondrial calcium homeostasis and affects lipid accumulation in liver cells. In addition, a HFD in mice enlarged the MAM. The high-calcium environment produced by MAM invalidated the function of MICU1 and led to persistent open of MCU channels. Therefore, it caused mitochondrial calcium overload and liver fat deposition. Inhibition of MAM and MCU alleviated HFD-induced hepatic steatosis. MCU inhibitors (Ru360 and mitoxantrone) can block MCU channels and reduce mitochondrial calcium levels. Intraperitoneal injection of MCU inhibitors (0.01-µM·kg-1 bodyweight) can alleviate HFD-induced hepatic steatosis. CONCLUSION AND IMPLICATIONS: These findings provide molecular insights into the way HFD disrupts mitochondrial calcium homeostasis and identify MCU as a promising drug target for the treatment of hepatic steatosis.

Non-Hermitian topological whispering gallery.

In 1878, Lord Rayleigh observed the highly celebrated phenomenon of sound waves that creep around the curved gallery of St Paul's Cathedral in London1,2. These whispering-gallery waves scatter efficiently with little diffraction around an enclosure and have since found applications in ultrasonic fatigue and crack testing, and in the optical sensing of nanoparticles or molecules using silica microscale toroids. Recently, intense research efforts have focused on exploring non-Hermitian systems with cleverly matched gain and loss, facilitating unidirectional invisibility and exotic characteristics of exceptional points3,4. Likewise, the surge in physics using topological insulators comprising non-trivial symmetry-protected phases has laid the groundwork in reshaping highly unconventional avenues for robust and reflection-free guiding and steering of both sound and light5,6. Here we construct a topological gallery insulator using sonic crystals made of thermoplastic rods that are decorated with carbon nanotube films, which act as a sonic gain medium by virtue of electro-thermoacoustic coupling. By engineering specific non-Hermiticity textures to the activated rods, we are able to break the chiral symmetry of the whispering-gallery modes, which enables the out-coupling of topological 'audio lasing' modes with the desired handedness. We foresee that these findings will stimulate progress in non-destructive testing and acoustic sensing.

Dietary calcium supplementation promotes the accumulation of intramuscular fat.

BACKGROUND: In the livestock industry, intramuscular fat content is a key factor affecting meat quality. Many studies have shown that dietary calcium supplementation is closely related to lipid metabolism. However, few studies have examined the relationship between dietary calcium supplementation and intramuscular fat accumulation. METHODS: Here, we used C2C12 cells, C57BL/6 mice (n = 8) and three-way cross-breeding pigs (Duroc×Landrace×Large white) (n = 10) to study the effect of calcium addition on intramuscular fat accumulation. In vitro, we used calcium chloride to adjust the calcium levels in the medium (2 mmol/L or 3 mmol/L). Then we measured various indicators. In vivo, calcium carbonate was used to regulate calcium levels in feeds (Mice: 0.5% calcium or 1.2% calcium) (Pigs: 0.9% calcium or 1.5% calcium). Then we tested the mice gastrocnemius muscle triglyceride content, pig longissimus dorsi muscle meat quality and lipidomics. RESULTS: In vitro, calcium addition (3 mmol/L) had no significant effect on cell proliferation, but promoted the differentiation of C2C12 cells into slow-twitch fibers. Calcium supplementation increased triglyceride accumulation in C2C12 cells. Calcium addition increased the number of mitochondria and also increased the calcium level in the mitochondria and reduced the of key enzymes activity involved in ß-oxidation such as acyl-coenzyme A dehydrogenase. Decreasing mitochondrial calcium level can alleviate lipid accumulation induced by calcium addition. In addition, calcium addition also reduced the glycolytic capacity and glycolytic conversion rate of C2C12 cells. In vivo, dietary calcium supplementation (1.2%) promoted the accumulation of triglycerides in the gastrocnemius muscle of mice. Dietary calcium supplementation (1.5%) had no effect on pig weight, but significantly improved the flesh color of the longissimus dorsi muscle, reduced the backfat thickness and increased intramuscular fat content in pigs. Besides, calcium addition had no effect on longissimus dorsi pH, electrical conductivity and shear force. CONCLUSIONS: These results suggest that calcium addition promotes intramuscular fat accumulation by inhibiting the oxidation of fatty acids. These findings provide a new tool for increasing intramuscular fat content and an economical strategy for improving meat quality.

Lipidomic and Transcriptomic Analysis of the Longissimus Muscle of Luchuan and Duroc Pigs.

Meat is an essential food, and pork is the largest consumer meat product in China and the world. Intramuscular fat has always been the basis for people to select and judge meat products. Therefore, we selected the Duroc, a western lean pig breed, and the Luchuan, a Chinese obese pig breed, as models, and used the longissimus dorsi muscle for lipidomics testing and transcriptomics sequencing. The purpose of the study was to determine the differences in intramuscular fat between the two breeds and identify the reasons for the differences. We found that the intramuscular fat content of Luchuan pigs was significantly higher than that of Duroc pigs. The triglycerides and diglycerides related to flavor were higher in Luchuan pigs compared to Duroc pigs. This phenotype may be caused by the difference in the expression of key genes in the glycerolipid metabolism signaling pathway.

Calcium supplementation relieves high-fat diet-induced liver steatosis by reducing energy metabolism and promoting lipolysis.

Nonalcoholic fatty liver disease (NAFLD) is a chronic disease affecting the health of many people worldwide. Previous studies have shown that dietary calcium supplementation may alleviate NAFLD, but the underlying mechanism is not clear. In this study investigating the effect of calcium on hepatic lipid metabolism, 8-week-old male C57BL/6J mice were divided into four groups (n = 6): (1) mice given a normal chow containing 0.5% calcium (CN0.5), (2) mice given a normal chow containing 1.2% calcium (CN1.2), (3) mice given a high-fat diet (HFD) containing 0.5% calcium (HFD0.5), and (4) mice fed a HFD containing 1.2% calcium (HFD1.2). To understand the underlying mechanism, cells were treated with oleic acid and palmitic acid to mimic the HFD conditions in vitro. The results showed that calcium alleviated the increase in triglyceride accumulation induced by oleic acid and/or palmitic acid in HepG2, AML12, and primary hepatocyte cells. Our data demonstrated that calcium supplementation alleviated HFD-induced hepatic steatosis through increased liver lipase activity, proving calcium is involved in the regulation of hepatic lipid metabolism. Moreover, calcium also increased the level of glycogen in the liver, and at the same time had the effect of reducing glycolysis and promoting glucose absorption. Calcium addition increased calcium levels in the mitochondria and cytoplasm. Taken together, we concluded that calcium supplementation could relieve HFD-induced hepatic steatosis by changing energy metabolism and lipase activity.

Effects of lycopene on skeletal muscle-fiber type and high-fat diet-induced oxidative stress.

Increasing studies report that many natural products can participate in formation of muscle fibers. This study aimed to investigate the effect of lycopene on skeletal muscle-fiber type in vivo and in vitro. C2C12 myoblasts were used in vitro study, and the concentration of lycopene was 10 µM. In vivo, 8-week-old male C57/BL6 mice were used and divided into four groups (n=8): (1) ND: normal-fat diet; (2) ND+Lyc: normal-fat diet mixed with 0.33% w/w lycopene; (3) HFD: high-fat diet; and (4) HFD+Lyc: high-fat diet mixed with 0.33% w/w lycopene. The mice tissue samples were collected after 8 weeks feeding. We found that lycopene supplementation enhanced the protein expression of slow-twitch fiber, succinate dehydrogenase, and malic dehydrogenase enzyme activities, whereas lycopene reduced the protein expression of fast-twitch fibers, lactate dehydrogenase, pyruvate kinase enzyme activities. Moreover, lycopene can promote skeletal muscle triglyceride deposition, enhanced the mRNA expression of genes related to lipid synthesis, reduced the mRNA expression of genes related to lipolysis. And high-fat diet-induced dyslipidemia and oxidative stress were attenuated after lycopene supplementation. Additionally, lycopene supplementation reduced the glycolytic reserve but enhanced mitochondrial ATP production in C2C12 cells. These results demonstrated that lycopene affects the activities of metabolic enzymes in muscle fibers, promotes the expression of slow-twitch fibers, and enhanced mitochondrial respiratory capacity. We speculated that lycopene affects the muscle-fiber type through aerobic oxidation, suggesting that lycopene exerts potential beneficial effects on skeletal muscle metabolism.

Comprehensive analysis of the translatome reveals the relationship between the translational and transcriptional control in high fat diet-induced liver steatosis.

Translational regulation plays a critical role in gene expression. However, there are few genome-wide studies on translational regulation in non-alcoholic fatty liver disease (NAFLD), which is a severe non-communicable epidemic worldwide. In this study, we performed RNC-mRNA (mRNAs bound to ribosome-nascent chain complex) sequencing and mRNA sequencing to probe the translation status of high-fat-diet (HFD) induced mouse fatty liver. Generally, in the HFD group compared to the control group, changes of translation ratios and changes in mRNA abundance had a negative correlation. The relative abundance of RNC-mRNAs and mRNAs were positively correlated, yet the former changed more slowly than the latter. However, the rate of change became more balanced when it came to the livers of mice that were fed the HFD plus lycopene, an antioxidant. This indicated relatively independent roles of translational modulation and transcriptional regulation. Furthermore, many genes were differentially regulated at the transcriptional or translational levels, suggesting a new screening strategy for functional genes. In conclusion, our analysis revealed the different and correlated role of translational control with transcriptional regulation in the HFD-induced mouse fatty liver relative to the control, which indicates critical roles of translational control for liver steatosis; thus, adding a new dimension towards a better understanding and improvement of treatment for NAFLD.

Effect of Tai Chi Training on Plantar Loads during Walking in Individuals with Knee Osteoarthritis.

Tai Chi is an available method for the treatment of knee osteoarthritis (KOA). The impacts of Tai Chi on plantar loads of individuals with KOA are not fully understood. 46 participants with knee osteoarthritis were randomly assigned into the Tai Chi group (n = 23) or the control group (n = 23). The Tai Chi group attended a 6-month Tai Chi program, and the control group participated in a wellness education program. Novel Pedar-X system was used to collect the peak pressure (PP) and maximum force (MF) during walking before and 6 months after the intervention. Significant higher peak pressure and maximum force were observed in the 4th and 5th metatarsophalangeal joints in the Tai Chi group. However, there were significant declines in the peak pressure of the whole foot and the 2nd and 3rd metatarsophalangeal joints and maximum force of the heel in the control group. These results suggested that individuals with KOA might change the pattern of plantar loads during walking through Tai Chi, and plantar loads would be useful as a parameter to assess the effect of Tai Chi on knee osteoarthritis. This trial is registered with Clinical Trials: CHiCTR-TRC-13003264.

Zinc Supplementation Alleviates Lipid and Glucose Metabolic Disorders Induced by a High-Fat Diet.

Zinc deficiency is a risk factor for the development of obesity and diabetes. Studies have shown lower serum zinc levels in obese individuals and those with diabetes. We speculate that zinc supplementation can alleviate obesity and diabetes and, to some extent, their complications. To test our hypothesis, we investigated the effects of zinc supplementation on mice with high-fat diet (HFD)-induced hepatic steatosis in vivo and in vitro by adding zinc to the diet of mice and the medium of HepG2 cells. Both results showed that high levels of zinc could alleviate the glucose and lipid metabolic disorders induced by a HFD. High zinc can reduce glucose production, promote glucose absorption, reduce lipid deposition, improve HFD-induced liver injury, and regulate energy metabolism. This study provides novel insight into the treatment of non-alcoholic fatty liver disease and glucose metabolic disorder.

Deep-Subwavelength Holey Acoustic Second-Order Topological Insulators.

Higher-order topological insulators (HOTIs) belong to a new class of materials with unusual topological phases. They have garnered considerable attention due to their capabilities in confining energy at the hinges and corners, which is entirely protected by the topology, and have thus become attractive structures for acoustic wave studies and control. However, for most practical applications at audible and low frequencies, compact and subwavelength implementations are desirable in addition to providing robust guiding of sound beyond a single-frequency operation. Here, a holey HOTI capable of sustaining deeply confined corner states 50 times smaller than the wavelength is proposed. A remarkable resilience of these surface-confined acoustic states against defects is experimentally observed, and topologically protected sound is demonstrated in three different frequency regimes. Concerning this matter, the findings will thus have the capability to push forward exciting applications for robust acoustic imaging way beyond the diffraction limit.

Subwavelength Acoustic Valley-Hall Topological Insulators Using Soda Cans Honeycomb Lattices.

Topological valley-contrasting physics has attracted great attention in exploring the use of the valley degree of freedom as a promising carrier of information. Recently, this concept has been extended to acoustic systems to obtain nonbackscattering sound propagations. However, previous demonstrations are limited by the cut-off frequency of 2D waveguides and lattice-scale size restrictions since the topological edge states originate from Bragg interference. Here we engineer topologically valley-projected edge states in the form of spoof surface acoustic waves that confine along the surface of a subwavelength honeycomb lattice composed of 330-mL soda cans. The inversion symmetry is broken through injecting a certain amount of water into one of the two cans in each unit cell, which gaps the Dirac cone and ultimately leads to the topological valley-Hall phase transition. Dual-frequency ranges of the valley-projected edge states below the sound line are observed, which originate from the first-order and second-order resonances, respectively. These results have the potential to enable promising routes to design integrated acoustic devices based on valley-contrasting physics.