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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.

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.

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.

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)

Aims Activation of brown adipose tissue (BAT) thermogenesis could contribute to energy expenditure, which is critical for the treatment of obesity and type 2 diabetes mellitus (T2DM). In the present study, we aimed to systematically investigate whether traditional Chinese medication Jinlida (JLD) granules could improve metabolic disorders and activate BAT thermogenesis in C57BL/6 J mice fed with a high-fat diet (HFD). Methods In the present study, JLD (3.8 g/kg) in 0.5% of carboxymethyl cellulose (CMC) solution was administrated daily by oral gavage to HFD-induced mice for 15 weeks. The body weight, biochemical analysis, histology analysis, intraperitoneal glucose and insulin tolerance (OGTT and ITT) tests were measured to explore metabolic disorders. Cold tolerance test, real-time PCR (qRT-PCR), immunohistochemistry, and western blot were performed to evaluate BAT function. Results As results, JLD treatment significantly ameliorated HFD-induced obesity and fat mass gain, maintained glucose and lipid homeostasis, and improved hepatic steatosis and inflammation. More importantly, we observed that JLD markedly activated BAT thermogenesis in HFD-induced obese mice. Moreover, our data confirmed that JLD promoted mitochondrial biogenesis and fatty acid oxidation metabolism in BAT. Conclusions These data suggested that JLD could improve metabolic disorders in associated with activation of BAT thermogenesis via enhancement of mitochondrial biogenesis and fatty acid oxidation metabolism, thus providing a new pharmacological evidence for the clinical usage of JLD in T2DM treatment.

ObjectiveDietary fibre has beneficial effects on energy metabolism, and the majority of studies have focused on short-chain fatty acids produced by gut microbiota. Ginseng has been reported to aid in body weight management, however, its mechanism of action is not yet clear. In this study, we focused on the potential modulating effect of ginseng on gut microbiota, aiming to identify specific strains and their metabolites, especially long-chain fatty acids (LCFA), which mediate the anti-obesity effects of ginseng.DesignDb/db mice were gavaged with ginseng extract (GE) and the effects of GE on gut microbiota were evaluated using 16S rDNA-based high throughput sequencing. To confirm the candidate fatty acids, untargeted metabolomics analyses of the serum and medium samples were performed.ResultsWe demonstrated that GE can induce Enterococcus faecalis, which can produce an unsaturated LCFA, myristoleic acid (MA). Our results indicate that E. faecalis and its metabolite MA can reduce adiposity by brown adipose tissue (BAT) activation and beige fat formation. In addition, the gene of E. faecalis encoding Acyl-CoA thioesterases (ACOTs) exhibited the biosynthetic potential to synthesise MA, as knockdown (KD) of the ACOT gene by CRISPR-dCas9 significantly reduced MA production. Furthermore, exogenous treatment with KD E. faecalis could not reproduce the beneficial effects of wild type E. faecalis, which work by augmenting the circulating MA levels.ConclusionsOur results demonstrated that the gut microbiota-LCFA-BAT axis plays an important role in host metabolism, which may provide a strategic advantage for the next generation of anti-obesity drug development.

With rapid economic development, the prevalence of obesity has increased remarkably worldwide. Obesity can induce a variety of metabolic diseases, such as atherosclerosis, diabetes, hypertension and coronary heart disease, which significantly endanger the health and welfare of individuals. Brown and beige fat tissues play an important role in thermogenesis in mammals. Recent studies have shown that follistatin (FST) can potentially induce the browning of white adipose tissue (WAT). In this study, high-fat diet-induced obese mice were injected with follistatin for one week to explore the effects of follistatin on browning and metabolism and to determine the mechanism. The results showed that follistatin suppressed obesity caused by a high-fat diet and increased insulin sensitivity, energy expenditure, and subcutaneous fat browning. The beneficial effects remained even after a period of withdrawal. Follistatin promoted secretion of irisin from subcutaneous fat via the AMPK-PGC1α-irisin signal pathway, which induces browning of WAT, and activated the insulin pathway in beige fat thereby promoting metabolism.

A prognostic model was obtained for LC. Several critical genes were unveiled. They could be potentially applied for LC recurrence prediction.Gene expression data of laryngeal cancer (LC) were analyzed to identify critical genes associated with recurrence.Two gene expression datasets were downloaded from the Gene Expression Omnibus. Dataset GSE27020 is used as the training set, containing 75 non-recurred LC cases and 34 recurred LC cases.A total of 725 DEGs were identified from the training set. A total of 4126 gene pairs showed significant correlations in non-recurred LC only, corresponding to 533 genes. A total of 7235 gene pairs showed significant correlations in recurred LC only, corresponding to 608 genes. Besides, 1694 gene pairs showed significant correlations in both non-recurred and recurred LC, corresponding to 322 genes. Functional enrichment analysis was performed for the three groups of DEGs. Seven overlapping biological functions were revealed: positive regulation of chondrocyte differentiation, autoimmune thyroid disease, focal adhesion, linoleic acid metabolism, drug metabolism, organic cation transport, and ECM-receptor interaction. Eight feature genes (PDIA3, MYH11, PDK1, SDC3, RPE65, LAMC3, BTK, and UPK1B) were identified. Their prognostic effect was validated by independent test set as well as survival analysis.

Increasing energy expenditure through activation of brown adipose tissue (BAT) is a critical approach to treating obesity and diabetes. In this study, rutin, a natural compound extracted from mulberry and a drug used as a capillary stabilizer clinically for many years without any side effects, regulated whole-body energy metabolism by enhancing BAT activity. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both genetically obese (Db/Db) and diet-induced obesity (DIO) mice. Rutin also induced brown-like adipocyte (beige) formation in subcutaneous adipose tissue in both obesity mouse models. Mechanistically, we found that rutin directly bound to and stabilized SIRT1, leading to hypoacetylation of peroxisome proliferator-activated receptor γ coactivator-1α protein, which stimulated Tfam transactivation and eventually augmented the number of mitochondria and UCP1 activity in BAT. These findings reveal that rutin is a novel small molecule that activates BAT and may provide a novel therapeutic approach to the treatment of metabolic disorders.-Yuan, X., Wei, G., You, Y., Huang, Y., Lee, H. J., Dong, M., Lin, J., Hu, T., Zhang, H., Zhang, C., Zhou, H., Ye, R., Qi, X., Zhai, B., Huang, W., Liu, S., Xie, W., Liu, Q., Liu, X., Cui, C., Li, D., Zhan, J., Cheng, J., Yuan, Z., Jin, W. Rutin ameliorates obesity through brown fat activation.

Summary Brown adipose tissue (BAT) is a promising potential therapeutic target for the treatment of obesity and related metabolic diseases. Allicin, a natural product in garlic, has multiple biological and pharmacological functions. However, the role of allicin in the regulation of metabolic organs, particularly BAT activation, has not been well studied. Here, we show that allicin imparts a significant effect by inhibiting body weight gain, decreasing adiposity, maintaining glucose homeostasis, improving insulin resistance, and ameliorating hepatic steatosis in obese mice. These observations strongly correlate with the activation of BAT. Notably, allicin plays a role in BAT activation, which may partly contribute to the Sirt1-PGC1α-Tfam pathway. In addition, allicin can significantly increase the succinylation levels of UCP1 in BAT by inhibiting sirt5, whereas excess allicin induces autophagy/mitophagy and mitochondrial dysfunction. Thus, our findings point to allicin as a promising therapeutic approach for the treatment of obesity and metabolic disorders., Graphical Abstract, Highlights • Allicin reduces adiposity and maintains glucose homeostasis • Allicin activates the brown adipocytes and increases the energy expenditure • Allicin enhances BAT activity partly through SIRT1-PGC1a-Tfam signaling pathway • Allicin regulates mitophagy via suppressed sirt5-mediated succinylation accumulation, Biological Sciences; Human Physiology; Molecular Physiology

Mulberry leaf garners much attention from researchers because of its hypoglycemic effect. This study’s objective was to determine the impact of mulberry leaf aqueous extract (MLAE) on decreasing blood glucose and promoting energy expenditure in obese C57BL/6J mice (induced by a high-fat diet). The mice were fed with high fat diet and treated with MLAE for 12 weeks. The results showed that MLAE significantly ameliorated the hyperglycemia and insulin resistance in mice that were induced by their high-fat diet. The improved blood glucose metabolism accompanied by elevated energy expenditure was found. Abundant flavonoids, polyphenols, and alkaloids in MLAE may have contributed to the above results. Also, MLAE restored gut microbiota imbalance in obese mice and was beneficial to their liver and kidney functioning. Together, these results suggest MLAE may be a potent ingredient in dietetics and can serve as a safe hypoglycemic ingredient in health product development.

Gestational diabetes mellitus (GDM) is a type of diabetes and occurs during pregnancy. Brown adipose tissue (BAT) improves glucose homeostasis and mitigates insulin resistance, however, its activity is reduced in GDM. Placenta growth factor (PlGF) is an angiogenic factor produced by placental trophoblasts. Nevertheless, whether and how PlGF could affect BAT function in GDM are not defined. To investigate this question, 91 non-diabetic pregnant participants and 73 GDM patients were recruited to Gynaecology and Obstetrics Centre in Lu He hospital. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by far infrared thermography in the supraclavicular region where classical BATs were located. The direct effect of PlGF on BAT function was explored using the established human preadipocyte differentiation system. Thereby, we demonstrated that serum levels of PlGF were lower in GDM patients compared with controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR and western blot, mRNA and protein expression of UCP1 and OXPHOS were elevated in differentiated adipocytes treated with PlGF. PlGF stimulated mitochondrion transcription and increased copy number of mitochondrial. When subjected for respirometry, PlGF-treated differentiated adipocytes showed higher oxygen consumption rates than controls. PlGF induced AMPK phosphorylation and blockade of AMPK phosphorylation blunted UCP1 and OXPHOS expression in differentiated adipocytes. PlGF administration reduced cholesterol and triglyceride content in the liver and improved insulin sensitivity in db mice compared with control. In Conclusion, PlGF could activate BAT function. Downregulation of PlGF might contribute to the reduced BAT activity in GDM.

Brown adipose tissue (BAT) plays an important role in maintain body temperature, treating obesity and diabetes. However, the amount and activity of BAT in adults (a-BAT) is very low, while the BAT in infant (i-BAT) is abundant and with strong activation. The a-BAT and i-BAT vary greatly in activation, but the characteristics and differences at the molecular level have not yet been fully revealed. We examined the changes in the mRNA expression of UCP1 and thermogenic genes genes such as PRDM16, PGC1α, CPT1α and CPT1β in a-BAT and i-BAT of mouse. We found that, compared with i-BAT, both UCP1 and thermogenic genes were significantly decreased in a-BAT. Western blot data further confirmed the result. Transmission electron microscope (TEM) and scanning electron microscopy (SEM) also showed a clear distinction in a-BAT and i-BAT. Compared with a-BAT, the lipid droplet is less and mitochondrial density is higher in i-BAT. In addition, the characteristics and differences of a-BAT and i-BAT were comprehensively analyzed by mRNA, microRNA, LncRNA, circRNA, DNA methylation and proteome. Thousands of signifcantly changed lncRNAs and mRNAs as well as proteins were identifed. Compared with i-BAT, we found hyper 383 and hypo 503 DMR related genes in a-BAT by differentially methylated region (DMR) analysis. What’s more, we found 1221 new circRNA in i-BAT and 1991 new circRNA in a-BAT and there were significant higher expression of circRNA in a-BAT compared with i-BAT. Furthermore, we constructed correlated expression networks circRNA-mRNA-lncRNA-methylation with bioinformatics methods. Co-expression analysis showed lnc-NONMMUG024827 and lnc-NONMMUG020075 expression is correlated with Fatty acid metabolism genes, including FASN and ACADA. Taken together, these results provide a better understanding of BAT function and development, and show a novel perspective roles of i-BAT or making a-BAT achieve the better activation and dynamic state just like i-BAT through the epigenetic modification. Disclosure C. Zhang: None. R. Yin: None. Y. Sheng: None. C. Yang: None. X. He: None. W. Xu: None. K. Huang: None.

Background: Gestational diabetes mellitus (GDM) is a type of metabolic disorders. Browning adipose tissue (BAT) activity is reduced which strengthens insulin resistance in GDM. Placenta growth factor (PlGF) is one of the main factors produced by placenta during pregnancy. Once secreted into circulation, it participates in angiogenesis in peripheral tissues. However, whether and how PlGF modulates BAT function is yet unknown. Methods: We recruited 91 nondiabetic pregnant participants and 73 GDM patients. Serum levels of PlGF were quantified by ELISA. Skin temperature was measured by Far infrared thermography in the supraclavicular region where classical BAT was located. Primary human preadipocytes isolated from intercapsular BAT were differentiated under different concentrations of PlGF in vitro. Terminally differentiated adipocytes were characterized by qPCR, western blot and oxygen consumption rates by respirometry. Phosphorylation signaling pathways in differentiated cells were dissected using Bio-Plex target assay (Bio-Rad). Cells were exposed with 1 ng PlGF in the presence or absence of 1 nM AMPK inhibitor Compound C to assess UCP-1 expression. Results: Serum levels of PlGF were lower in GDM patients than non GDM controls, which was accompanied by decreased skin temperature in the supraclavicular region. By qPCR, PlGF dose-dependently induced BAT marker expression in differentiated brown adipocytes (BAC) and peaked at 1 ng as evidenced by the increased mRNA expression of UCP-1 and Oxphos. The increased BAT marker expression was further confirmed by western blot in differentiated BAC exposed to 1 ng PlGF. Accordingly, PlGF-exposed BAC showed higher oxygen consumption rates than control and stimulated AMPK phosphorylation. Blockade of AMPK phosphorylation abrogated UCP-1 and Oxphos expression in BAC induced by PlGF. Conclusions: Physically, PlGF improves preadipocyte differentiation into active BAC. Decreased PlGF levels might contribute to the reduced BAC activity in GDM. Disclosure R. Yin: None. J. Zhou: None. C. Zhang: None. C. Yan: None. W. Ma: None. N. Wu: None. D. Zhao: None. Y. Feng: None.

Alliin (S-allyl cysteine sulfoxide) is a bioactive sulfoxide compound derived from garlic. To evaluate the preventive effect of alliin against metabolic risk factors in diet induced obese (DIO) mice, we treated the C57BL/6J DIO mice with drinking water with or without alliin (0.1 mg/ml) for 8 weeks. Results showed that alliin had no significant effect on the body weight, adiposity or energy balance. However, alliin treatment enhanced glucose homeostasis, increased insulin sensitivity and improved the lipid profile in the DIO mice. This was, at least partly, attributable to alliin induced modulation of the intestinal microbiota composition, typically decreased Lachnospiraceae and increased Ruminococcaceae. From above, we conclude that alliin has nutraceutical or even medicinal potential in prevention of diabetes and lipid metabolic disorders.

Improvement of hyperglycemia through dietotherapy/herbal remedy is an effective approach to treating diabetes. In this study, mulberry leaf, famous for silkworm’s special food and therapeutic value without any side effects, alleviated diabetes by attenuating NEFA signaling and modulating intestinal microflora. Mulberry leaf treatment significantly reduce fasting blood-glucose and HbA1c, ameliorate the blood lipid profile and improve insulin resistance in streptozotocin-induced diabetic rats. Mechanistically, we found that mulberry leaf inhibited NEFA signaling by reducing downstream signaling in the NEFA pathway, further verified by reduced PKC and improved cellular energy homeostasis based on restored expression of PGC-1α, AK2, OXPHOS and adiponectin. Mulberry leaf treatment also restored the phyla Bacteroidetes and Proteobacteria and class Clostridia, which were associated with insulin resistance and diabetes. Our findings reveal that mulberry leaf is an edible with therapeutic potential for diabetes and may provide a novel dietotherapy/herbal remedy to the treatment of diabetes.

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy that is characterized by anovulation, hyperandrogenism and polycystic ovary. However, there is a lack of effective treatment for PCOS at present because the pathologic cause of PCOS has not been elucidated. Although it has been known that brown adipose tissue transplantation ameliorates PCOS by activating endogenous BAT, BAT transplantation is not applicable in clinic. Therefore, BAT activation with natural compound could be an effective treatment strategy for PCOS patients. Here, we found that 3 weeks of rutin (a novel compound for BAT activation) treatment increased BAT activation, thereby it improved thermogenesis and systemic insulin sensitivity in dehydroepiandrosterone (DHEA)-induced PCOS rat. In addition, the expression levels of ovarian steroidogenic enzymes such as P450C17, aromatase, 3β-HSD, 17β-HSD and STAR were up-regulated in rutin-treated PCOS rat. Furthermore, acyclicity and the serum level of luteinizing hormone were normalized, and a large number of mature ovulated follicle with a reduction of cystic formation were observed in PCOS rat after rutin treatment. Finally, rutin treatment surprisingly improved fertility and birth defect in PCOS rat. Collectively, our results indicate that rutin treatment significantly improves systemic insulin resistance and ovarian malfunction in PCOS, and our findings in this study provide a novel therapeutic option for the treatment of PCOS by activating BAT with rutin.

Background & Aims Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of HCV core-encoding sequences (hepatitis C virus (HCV) genotypes 3a and 1b) significantly induces intra-cellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed. Methods To investigate whether Sirt1 is involved in HCV-mediated hepatic steatosis, the overexpression of HCV core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment, liver-specific Sirt1 KO mice with lentivirus-mediated HCV core 1b overexpression were studied. Results Our results show that HCV core 1b protein overexpression led to the accumulation of triglycerides in HEPG2 cells. Notably, the expression of PPARγ2 was dramatically increased at both the mRNA and protein levels by HCV core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARγ2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARγ2 de-acetylation. In vivo studies showed that HCV core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARγ2 expression. Conclusions Sirt1 mediate HCV core protein 1b-induced hepatic steatosis by regulation of PPARγ2 expression. This article is protected by copyright. All rights reserved.

Brown adipose tissue (BAT), an organ that burns energy through uncoupling thermogenesis, is a promising therapeutic target for obesity. However, there are still no safe anti-obesity drugs that target BAT in the market. In the current study, we performed large scale screening of 636 compounds which were approved by Food and Drug Administration (FDA) to find drugs that could significantly increase uncoupling protein 1 (UCP1) mRNA expression by real-time PCR. Among those UCP1 activators, most of them were antibiotics or carcinogenic compounds. We paid particular attention to fluvastatin sodium (FS), because as an inhibitor of the cellular hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, FS has already been approved for treatment of hypercholesteremia. We found that in the cellular levels, FS treatment significantly increased UCP1 expression and BAT activity in human brown adipocytes. Consistently, the expression of oxidative phosphorylation-related genes was significantly increased upon FS treatment without differences in adipogenic gene expression. Furthermore, FS treatment resisted to high-fat diet (HFD)-induced body weight gain by activating BAT in the mice model. In addition, administration of FS significantly increased energy expenditure, improved glucose homeostasis and ameliorated hepatic steatosis. Furthermore, we reveal that FS induced browning in subcutaneous white adipose tissue (sWAT) known to have a beneficial effect on energy metabolism. Taken together, our results clearly demonstrate that as an effective BAT activator, FS may have great potential for treatment of obesity and related metabolic disorders.

As a thermogenic organ, brown adipose tissue (BAT) has received a great attention in treating obesity and related diseases. It has been reported that brown adipocyte was derived from engrailed-1 (EN1) positive central dermomyotome. However, functions of EN1 in brown adipogenesis are largely unknown. Here we demonstrated that EN1 overexpression increased while EN1 knockdown decreased lipid accumulation and the expressions of key adipogenic genes including PPARγ2 and C/EBPαand mitochondrial OXPHOS as well as BAT specific marker UCP1. Taken together, our findings clearly indicate that EN1 is a positive regulator of brown adipogenesis.

Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS.

Increasing evidence indicates that brown adipose tissue (BAT) transplantation enhances whole-body energy metabolism in a mouse model of diet-induced obesity. However, it remains unclear whether BAT also has such beneficial effects on genetically obese mice. To address this issue, we transplanted BAT from C57/BL6 mice into the dorsal subcutaneous region of age- and sex-matched leptin deficient Ob/Ob mice. Interestingly, BAT transplantation led to a significant reduction of body weight gain with increased oxygen consumption and decreased total body fat mass, resulting in improvement of insulin resistance and liver steatosis. In addition, BAT transplantation increased the level of circulating adiponectin, whereas it reduced the levels of circulating free T3 and T4, which regulate thyroid hormone sensitivity in peripheral tissues. BAT transplantation also increased β3-adrenergic receptor and fatty acid oxidation related gene expression in subcutaneous and epididymal (EP) white adipose tissue. Accordingly, BAT transplantation increased whole-body thermogenesis. Taken together our results demonstrate that BAT transplantation may reduce obesity and its related diseases by activating endogenous BAT.