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Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.

It is confirmed that tandem-blade configurations have potential to enlarge the flow turning in two-dimension (2D) studies. However, the potential of tandem blades to enlarge the design space for highly loaded axial compressors was rarely investigated in open literatures. The present work aims to show the capability of tandem blades to break the loading limit of conventional blades for highly loaded compressors. The 2D models of the maximum static pressure rise derived in previous work were validated by a large amount experimental data, which showed a good agreement. An E parameter was defined to evaluate the stall margin of compressor based on the theoretical models, which indicated that the tandem blade was able to increase the loading limit of axial compressors. A single-blade stage with a loading coefficient of 0.46 (based on the blade tip rotating speed) was designed as the baseline case under the guidance of the E parameter. A tandem-blade stage was then designed by ensuring that the velocity triangles were similar to the single-blade stage. The performances of both stages were investigated experimentally. The results showed that the maximum efficiency of the tandem-blade stage was 92.8%, 1% higher than the single; the stall margin increased from 16.9% to 22.3%. Besides, the maximum pressure rise of tandem rotors was beyond the loading limit of 2D single-blade cascades, which confirmed the potential of tandem blades to break the loading limit of axial compressors.

BACKGROUND The aim of this study was to assess the effect of indocyanine green (ICG) fluorescence imaging combined with laparoscopic ultrasound in laparoscopic microwave ablation of liver cancer. MATERIAL AND METHODS This study retrospectively analyzed 61 patients who underwent laparoscopic microwave ablation of liver cancer, including laparoscopic microwave ablation with and without ICG fluoroscopy. RESULTS The operative times, ablation times, postoperative hospital stay, postoperative complication rate, hospitalization cost, postoperative liver function changes, and postoperative overall survival were similar between the 2 groups, but there was a statistically significant difference in recurrence-free survival (P0.05). A total of 5 lesions were found in the fluorescence laparoscopy group that were not found by preoperative imaging, while no new lesions were found in the ordinary laparoscopy group. Fluorescence laparoscopy has obvious advantages over ordinary laparoscopy in finding small lesions that were not found before surgery. In terms of complete ablation rate, 3 patients in the ordinary laparoscopy group and 1 patient in the fluorescence laparoscopy group were judged to be incompletely ablated and were ablated again at 1 month after the operation. CONCLUSIONS For small hepatocellular carcinoma with severe liver cirrhosis and located on the liver surface, fluorescence laparoscopy can better reveal the location and boundary of the tumor, and fluorescence laparoscopy can detect tiny lesions that cannot be detected by preoperative imaging. The combination of fluorescence laparoscopy and microwave ablation has a good effect on the treatment of small hepatocellular carcinoma located on the surface of the liver that is difficult to distinguish.

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disease affecting women of reproductive age. Due to its complex aetiology, there is no currently effective cure for PCOS. Brown adipose tissue (BAT) activity is significantly decreased in PCOS patients, and BAT activation has beneficial effects in animal models of PCOS. Here, we investigated the effect of ginsenoside compound K (CK) in an animal model of PCOS and its mechanism of BAT activation.Primary brown adipocytes, Db/Db mice and dehydroepiandrosterone (DHEA)-induced PCOS rats were used. The core body temperature, oxygen consumption, energy metabolism related gene and protein expression were assessed to identify the effect of CK on overall energy metabolism. Oestrous cycle, serum sex hormone, ovarian steroidogenic enzyme gene expression and ovarian morphology were also evaluated following CK treatment.Our results indicated that CK treatment could significantly protect against body weight gain in Db/Db mice via BAT activation. Furthermore, we found that CK treatment could normalize hyperandrogenism, oestrous cyclicity, normalize steroidogenic enzyme expression and decrease the number of cystic follicles in PCOS rats. Interestingly, as a potential endocrine intermediate, C-X-C motif chemokine ligand-14 protein (CXCL14) was significantly up-regulated following CK administration. In addition, exogenous CXC14 supplementation was found to reverse DHEA-induced PCOS in a phenotypically similar manner to CK treatment.In summary, CK treatment significantly activates BAT, increases CXCL14 expression and ameliorates PCOS. These findings suggest that CK might be a potential drug candidate for PCOS treatment.

Allicin (diallylthiosulfinate) is a natural food compound with multiple biological and pharmacological functions. However, the mechanism of beneficial role of Allicin on energy homeostasis is not well studied. Gut microbiota (GM) profoundly affects host metabolism via microbiota-host interactions and coevolution. Here, we investigated the interventions of beneficial microbiome induced by Allicin on energy homeostasis, particularly obesity, and related complications. Interestingly, Allicin treatment significantly improved GM composition and induced the most significant alteration enrichment of Bifidobacterium and Lactobacillus. Importantly, transplantation of the Allicin-induced GM to HFD mice (AGMT) played a remarkable role in decreasing adiposity, maintaining glucose homeostasis, and ameliorating hepatic steatosis. Furthermore, AGMT was effective in modulating lipid metabolism, activated brown adipose tissues (BATs), induced browning in sWAT, reduced inflammation, and inhibited the degradation of intestinal villi. Mechanically, AGMT significantly increased Blautia [short-chain fatty acids (SCFAs)-producing microbiota] and Bifidobacterium in HFD mice, also increased the SCFAs in the cecum, which has been proved many beneficial effects on energy homeostasis. Our study highlights that Allicin-induced host-gut microbe interactions plays an important role in regulating energy homeostasis, which provides a promising potential therapy for obesity and metabolic disorders based on host-microbe interactions.

Inter-organellar contact sites facilitate material exchanges between membrane-bound intracellular compartments and sustain the structural and functional integrity of organelles1-3. The endoplasmic reticulum (ER)-lipid droplet (LD) contact sites contribute to LD biogenesis and lipid transfer between the ER and LDs4-11. LDs in adipocytes are significantly larger than in non-adipocytes and crucial for energy storage and mobilization in response to body needs12-14. How adipocytes employ cell type-specific mechanisms to suppress unregulated lipolysis while remaining responsive to catecholamine-induced lipolysis is incompletely understood. Here we show that the mammalian adipocyte-specific protein Calsyntenin 3β (CLSTN3B) works at the ER/LD interface to enhance LD functionality. We found that CLSTN3B harbors an N-terminal LD-targeting and a C-terminal ER transmembrane domain linked by an arginine-rich segment, promoting a tight association between the ER and LDs. CLSTN3B-deficient LDs have reduced surface phospholipids density and decreased binding of LD-targeting proteins, hence more prone to leakage of free fatty acids (FFA) and less responsive to catecholamine-induced lipolysis than wild-type (WT) LDs. Furthermore, clstn3b knockout (clstn3b-/-) mice are more susceptible to high fat diet-induced metabolic complications than adiposity-matched WT mice, consistent with impaired LD functionality and compromised lipid-storing capacity of adipocytes. Our results demonstrate how CLSTN3B-mediated inter-organellar communication shapes LD functionality and translates into physiological significance at the animal level15

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. Ace2 knockout mice (Ace2-/y) and Mas1 knockout mice (Mas1-/-) displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from Mas1-/- display metabolic abnormalities consistent with those seen in the Ace2 and Mas1 knockout mice. In contrast, impaired thermogenesis of Leprdb/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of Ace2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids, and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.

Traditional Chinese medicine (TCM) has been long time used in China and gains ever-increasing worldwide acceptance. Er Miao San (EMS), a TCM formula, has been extensively used to treat inflammatory diseases, while its bioactive components and therapeutic mechanisms remain unclear. In this study, we conducted an integrative approach of network pharmacology and experimental study to elucidate the underlying mechanisms of EMS in treating human rheumatoid arthritis (RA) and other inflammatory conditions. Quercetin, wogonin and rutaecarpine were probably the main active compounds of EMS in RA treatment as they affected the most RA-related targets, and TNF-α, IL-6 and IL-1β were considered to be the core target proteins. The main compounds in EMS bound to these core proteins, which was further confirmed by molecular docking and bio-layer interferometry (BLI) analysis. Moreover, the potential molecular mechanisms of EMS predicted from network pharmacology analysis, were validated in vivo and in vitro experiments. EMS was found to inhibit the production of NO, TNF-α and IL-6 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells; reduce xylene-induced mouse ear edema; and decrease the incidence of carrageenan-induced rat paw edema. The carrageenan-induced up-regulation of TNF-α, IL-6 and IL-1β mRNA expression in rat paws was down-regulated by EMS, consistent with the network pharmacology results. This study provides evidence that EMS plays a critical role in anti-inflammation via suppressing inflammatory cytokines, indicating that EMS is a candidate herbal drug for further investigation in treating inflammatory and arthritic conditions.

This study aimed to introduce a modified Huang's method to perform laparoscopic intracorporeal Pringle manoeuvre. Zhang's modified method is a simple, safe and reliable way for laparoscopic hepatectomy that is associated with favourable perioperative outcomes and low risk of conversion.

Intermittent fasting, which can effectively reduce obesity and improve the related metabolic syndrome has become an exciting research area in recent years. Adipose tissue is pivotal in regulating the metabolism and determining the occurrence of obesity. In the current study, we aimed to investigate the effects of acute fasting (AF) on fat tissue. Mice were subjected to AF for 36 h, receiving normal chow (low-fat diet [LFD]) or a high-fat diet (HFD), with free ad libitum access to drinking water, and those fed on free-diet counterparts without fasting serveding as controls. We found that AF obviously reshaped the morphology of fat tissue (WAT) and promoted the beiging of white adipose tissue in both LFD- and HFD-fed mice. AF principally improved the lipid metabolism, and increased the M2- polarization of macrophages in WAT white fat tissue of HFD-fed mice. Interestingly, we found that AF dramatically upregulated Sirt5 expression levels and fat tissue succinylation, suggesting that AF-induced beneficial effects on fat might occur via the regulation of Sirt5 levels and altered succinylation in fatty tissues. Our study clearly showed the remodeling function of adipose tissue during AF; in terms of mechanism, the regulation of succinylation levels by AF might provide new insights into the mechanism(s) underlying the improvement in fat metabolism by energy restriction.

Caffeic acid (CFA), a natural polyphenolic compound which exists in coffee, fruits and certain traditional Chinese medicine, is one promising anti-obesity agent with a variety of pharmacological activities. The objective of the current study was to determine the mechanism of anti-obesity effect of CFA, and the relationship between its anti-obesity effect and gut microbiota change in high fat diet induced obese (DIO) mice. The DIO mice were administrated CFA by daily gavage at 50 mg/kg body weight for 12 weeks. The results showed that CFA significantly ameliorated high fat diet induced obesity. Specifically CFA reduced body weight and fat accumulation, improved lipid profile and increased energy expenditure in DIO mice. Moreover, CFA restored gut microbiota imbalance and increased the abundance of anti-obesity related bacteria and butyrate-producing bacteria in DIO mice. We conclude that CFA is effective to reduce metabolic risks possibly by regulating gut microbiota.

This paper examines the effects of futures trading on the jump risk in the Bitcoin market. We use a nonparametric method to detect Levy-type jumps in Bitcoin prices and obtain jump risk measures (jump intensity and jump size) of big and small jumps by using 5-minute high-frequency data, and document that Bitcoin has obvious features of Levy jumps, i.e., prices include both big jumps and small jumps, and the jump risk is time-varying. We then investigate the changes of these jump risk measures before and after the introduction of the Bitcoin futures, and we find that the jump size of big and small jumps decreases after the introduction of Bitcoin futures, while the big jump intensity increases. Further, we examine whether greater futures-trading activity (volume and open interest) is associated with greater Bitcoin jump risk and document that, on the one hand, there exists bidirectional causality between unexpected volume and jump intensity and size of Bitcoin and the impulse response function analysis show that the shocks have temporary increasing effects, and the speculative trading in the futures market will increase the jump risk. On the other hand, unexpected open interest Granger causes jump risk but the inverse is not true, indicating that investors are unlikely to hedge jump risk by using Bitcoin futures. These findings disclose the fact that the hedging function of the Bitcoin futures does not work well and the functions of Bitcoin futures need to be further improved.

Brown adipose tissue (BAT) plays an essential role in maintaining body temperature and in treating obesity and diabetes. The adult BAT (aBAT) and neonatal BAT (neBAT) vary greatly in capacity, but the characteristics and differences between them on the molecular level, as well as the related features of BAT as it develops post-delivery, have not yet been fully determined. In this study, we examined the morphological features of aBAT and neBAT of mice by using hematoxylin-eosin (H&amp, E) staining, transmission electron microscopy (TEM), and scanning electron microscopy (SEM). We found that neBAT contains a smaller number and size of lipid droplets, as well as more abundant mitochondria, compared with aBAT. The dynamic morphological changes revealed that the number and size of lipid droplets increase, but the number of mitochondria gradually decrease during the post-delivery development, which consisted of some differences in RNA or protein expression levels, such as gradually decreased uncoupling protein 1 (UCP1) expression levels and mitochondrial genes, such as mitochondrial transcription factor A (Tfam). The adipocyte differentiation-related genes, such as transcription factor CCAAT enhancer-binding protein &beta, (CEBP&beta, ), were also continuously upregulated. Additionally, the different features of aBAT and neBAT were analyzed from the global transcription (RNA-Seq) level, which included messenger RNA (mRNA), microRNA, long non-coding RNA (lncRNA), circRNA, and DNA methylation, as well as proteins (proteomics). Differentially methylated region (DMR) analysis identified 383 hyper- and 503 hypo-methylated genes, as well as 1221 new circRNA in ne-BAT and 1991 new circRNA in a-BAT, with significantly higher expression of circRNA in aBAT compared with neBAT. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that mitochondrial activity, protein synthesis, and cell life activity levels were higher in neBAT, and pathways related to ribosomes, spliceosomes, and metabolism were significantly activated in neBAT compared to aBAT. Collectively, this study describes the dynamic changes occurring throughout post-delivery development from the morphological, molecular and omics perspectives. Our study provides information that may be utilized in improving BAT functional activity through gene regulation and/or epigenetic regulation.

This paper develops the asymptotic theory of the threshold pre-averaged multi-power variation estimation in the simultaneous presence of jumps and market microstructure noise and then proposes an improved estimator for integrated volatility of an Ito semi-martingale based on the obtained theory. This new class of estimation is based on the joint use of pre-averaging multi-power variation estimation in a noisy diffusion setting and the threshold technique, which serve to remove microstructure noise and jumps, respectively. Asymptotic properties of the proposed integrated volatility estimator, such as consistency and associated central limit theorems are also provided. Monte Carlo simulations show that the estimator is robust to both Levy jumps and microstructure noise and it provides less biased estimation, compared to existing estimators, of the continuous variation in finite samples. We also apply our estimator to some real high frequency financial data-sets.

Diabetic nephropathy (DN) is the leading cause of the end-stage renal disease worldwide and an independent risk factor for cardiovascular mortalities in diabetic patients. We evaluated the anti-hyperglycemic and anti-chronic renal damage effect of mulberry leaf tea, a potential functional food material. Mulberry leaf tea significantly alleviated symptoms of DN rats including reducing blood glucose level, improving insulin sensibility and ameliorating blood lipid profile and chronic renal damages. The abundant pharmacologically compounds in mulberry leaf tea such as 1-DNJ, flavonoids, polyphenols and polysaccharides were likely responsible for its beneficial effects. Furthermore, we found that mulberry leaf tea alleviated DN by reducing DAG-PKC cascades including regulating energy metabolism, improving insulin sensibility and reducing inflammatory response. Mulberry leaf tea also modulated the community structure of the intestinal flora which were closely associated with diabetes and its complications. Mulberry leaf tea provides a novel dietotherapy for DN.

Background/Aims: Brown and beige adipocytes are widely recognized as potential therapeutic targets to treat obesity and related metabolic disorders, and the recruitment of brown and beige adipocytes is an essential aspect that requires attention. Although many methods of activating brown adipocytes or generating beige adipocytes have been reported, the limited number and sources are the biggest challenges. The number of white adipocytes is much greater than the number of brown adipocytes, both in human adults and fetuses. Unfortunately, human adult white adipose tissue-derived stem cell (aWAsc) has little beige adipogenic potential. However, the characteristics and beige adipogenic potential of human embryo-derived white adipose stem cells (eWAsc) still need to be investigated. Methods: To analyze the characteristics and functionality of eWAsc, we analyzed the markers of adipose precursor cells by flow cytometry. Then, differentiation and browning/beiging were induced, and the identifying markers were analyzed by real-time PCR and immunoblot. In addition, more in-depth exploration was performed using RNA-SEQ on eWAsc and aWAsc. Results: eWAsc was isolated from human embryonic white adipose tissue, and aWAsc was isolated from adult white adipose tissue by collagenase treatment. eWAsc has extreme advantages in adipogenesis capacity and browning/beiging ability in comparison to aWAsc, indicating that eWAsc may possess some special regulatory factors to promote the generation of functional brown/beige adipocytes. Greater exploration was enabled by RNA-SEQ, revealing a large number of differences at the transcriptional levels, including 1263 differentially expressed genes, 657 down- and 605 upregulated, in eWAsc compared to aWAsc. Pathway analysis revealed enrichment in cell cycle, TGF-β signaling pathway, DNA replication, and Hippo signaling pathways. Interestingly, the expression levels of C/EBPα, FGF1 and FST gene, which are related to the maturation of adipocytes, Hippo signaling pathway and TGF-β signaling pathway, were significantly higher in eWAsc than in aWAsc. These may be potential candidates and possible regulatory targets for recruiting beige adipocytes in human adipose tissue. Conclusion: Overall, we have demonstrated the molecular characteristics and excellent beige adipogenic potential of eWAsc, providing a new reference for studying human adipocytes.

Obesity is associated with disrupted energy homeostasis and intestinal dysbiosis. Caulis Spatholobi, traditional Chinese medicine for herbal therapy, contains a wide range of bioactive compounds and has a specific pharmacological function. However, its effects on obesity and related metabolic disorder have remained largely unexplored. In this study, we showed that the water extract of Caulis Spatholobi (WECS) has a significant effect in inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, reducing insulin resistance and improving hepatic steatosis in diet-introduced obesity (DIO) mice. Besides, the administration of WECS significantly increased the expression levels of genes involved in the brown adipose tissue (BAT) activation and thermogenesis in DIO mice. Also, the activation of BAT treated with WECS was also confirmed in BAT primary cells. Mechanisms, the improvement of glucose homeostasis and insulin resistance may be related to the upregulated MAPK and AMPK pathways in white adipose tissue (WAT) and BAT. Notably, WECS also improved the obesity-induced gut microbiota dysbiosis, which induced an increase of anti-obesity and anti-diabetes related bacteria genus. In conclusion, Caulis Spatholobi can ameliorate obesity through activating brown adipose tissue and modulating the composition of gut microbiota. Our findings provide a novel perspective on Chinese medicine applications and provide a promising therapeutic approach for the treatment of obesity and metabolic disorders.

Methylation of DNA and RNA has become a research hotspot because of its diverse regulation of biological function and processes. In particular, posttranscriptional modifications in RNA, including methylation of the N6 positions in adenine (m6A), N1 positions in adenine (m1A) and methylation of carbon 5 in cytosine (m5C). However, information about the transcriptome-wide distribution and possible functions of m5C in different cell types, tissues, and organisms is still extremely limited. Brown adipose tissue is a functional organ for thermogenesis and an important potential target for the treatment of obesity and diabetes. The insights into possible functions of m5C modification and implications in BAT are significant and urgent to be revealed. In our study, we performed an unbiased global analysis of m5C in total and Ribo-minus RNA of brown adipose tissue from mouse after thermoneutrality (29?-30?) and/or cold stimulation (4?) for 1 day. We identified total 8153 sites in mRNA, 570 sites in CircRNA, and 991 sites in LncRNA, with respect to the degree of methylation, functional classification of methylated transcripts, and position bias within the transcript. Interestingly, there are intriguing differences in BAT after thermoneutrality and/or cold stimulation, which may provide us with new ideas to activate or enhance functionality of BAT. Our findings show the first comprehensive picture of m5C in the BAT from the mouse. These data establish and provide an important resource for future studies of function and biological significance of m5C in Ribo-minus RNA in brown adipose tissue. Disclosure C. Zhang: None. R. Yin: None. J. Wang: None. W. Quanwei: None. Funding National Natural Science Foundation of China (81700684 to C.Z.), (31402075), (31572403)