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2.
World J Gastroenterol ; 29(20): 3103-3118, 2023 May 28.
Article in English | MEDLINE | ID: mdl-37346154

ABSTRACT

BACKGROUND: The transforming growth factor ß (TGFß) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFß type II receptor (TGFßR2), followed by the recruitment of TGFßR1 finally triggering downstream signaling pathway. AIM: To find drugs targeting TGFßR2 that inhibit TGFßR1/TGFßR2 complex formation, theoretically inhibit TGFß signaling pathway, and thereby ameliorate liver fibrosis. METHODS: Food and Drug Administration-approved drugs were screened for binding affinity with TGFßR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect. RESULTS: We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFß induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFßR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFßR2 disrupted the binding of TGFßR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson's trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver. CONCLUSION: DHE alleviates liver fibrosis by binding to TGFßR2 thereby suppressing TGFß signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.


Subject(s)
Dihydroergotamine , Liver Cirrhosis , Mice , Animals , Receptor, Transforming Growth Factor-beta Type II , Dihydroergotamine/adverse effects , Molecular Docking Simulation , Liver Cirrhosis/drug therapy , Liver Cirrhosis/prevention & control , Liver Cirrhosis/chemically induced , Fibrosis , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1 , Receptors, Transforming Growth Factor beta/genetics
3.
Front Physiol ; 13: 950619, 2022.
Article in English | MEDLINE | ID: mdl-36051914

ABSTRACT

The intermittent fasting regimen (IFR) has been certified as an effective strategy for improving metabolism. But the underlying mechanism is still obscure. Beige induction in white adipose tissue (WAT) by IFR may account for this. It has been demonstrated that the erupting of pregnancy zone protein (PZP) from the liver coincides with membrane translocation of grp78 in brown adipocytes during IFR to activate brown adipose tissue (BAT), which may partly explain the metabolic benefits of IFR. Liver-derived PZP appears to be responsible for all metabolic regulatory functions; the effect of boosting energy expenditure disappeared in liver-deficient mice. To verify whether any liver-specific modification was essential for functional PZP, we used the PZP adipose tissue-specific overexpression mice model (PZP TG). We found that the metabolic disorders induced by high-fat diet were improved in PZP TG mice under IFR. Additionally, in addition to the activation of BAT, UCP1 protein and angiogenesis were increased in WAT, as well as the expression of genes associated with glucose utilization. These results demonstrate that PZP fat-specific TG increased the energy conversion of WAT, indicating that WAT may be another direct target for PZP during IFR.

4.
Br J Pharmacol ; 179(18): 4563-4574, 2022 09.
Article in English | MEDLINE | ID: mdl-35751868

ABSTRACT

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.


Subject(s)
Ginsenosides , Polycystic Ovary Syndrome , Adipose Tissue, Brown/metabolism , Animals , Dehydroepiandrosterone/adverse effects , Disease Models, Animal , Female , Ginsenosides/pharmacology , Ginsenosides/therapeutic use , Humans , Mice , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/drug therapy , Rats
5.
Am J Physiol Endocrinol Metab ; 323(1): E69-E79, 2022 07 01.
Article in English | MEDLINE | ID: mdl-35575231

ABSTRACT

Brown adipose tissue (BAT) is the primary site of adaptive thermogenesis, which is involved in energy expenditure and has received much attention in the field of obesity treatment. By screening a small-molecule compound library of drugs approved by the Food and Drug Administration, pantothenic acid was identified as being able to significantly upregulate the expression of uncoupling protein 1 (UCP1), a key thermogenic protein found in BAT. Pantothenate (PA) treatment decreased adiposity, reversed hepatic steatosis, and improved glucose homeostasis by increasing energy expenditure in C57BL/6J mice fed a high-fat diet. PA also significantly increased BAT activity and induced beige adipocytes formation. Mechanistically, the beneficial effects were mediated by UCP1 because PA treatment was unable to ameliorate obesity in UCP1 knockout mice. In conclusion, we identified PA as an effective BAT activator that can prevent obesity and may represent a promising strategy for the clinical treatment of obesity and related metabolic diseases.NEW & NOTEWORTHY PA treatment effectively and safely protected against obesity via the BAT-UCP1 axis. PA has therapeutic potential for treating obesity and type II diabetes.


Subject(s)
Adipose Tissue, Brown , Diabetes Mellitus, Type 2 , Adipose Tissue, Brown/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Energy Metabolism , Mice , Mice, Inbred C57BL , Obesity/metabolism , Thermogenesis , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
6.
Zool Res ; 43(2): 275-284, 2022 Mar 18.
Article in English | MEDLINE | ID: mdl-35238185

ABSTRACT

Environmental temperature serves as a major driver of adaptive changes in wild organisms. To discover the mechanisms underpinning cold tolerance in domestic animals, we sequenced the genomes of 28 cattle from warm and cold areas across China. By characterizing the population structure and demographic history, we identified two genetic clusters, i.e., northern and southern groups, as well as a common historic population peak at 30 kilo years ago. Genomic scan of cold-tolerant breeds determined potential candidate genes in the thermogenesis-related pathways that were under selection. Specifically, functional analysis identified a substitution of PRDM16 (p.P779L) in northern cattle, which maintains brown adipocyte formation by boosting thermogenesis-related gene expression, indicating a vital role of this gene in cold tolerance. These findings provide a basis for genetic variation in domestic cattle shaped by environmental temperature and highlight the role of reverse mutation in livestock species.


Subject(s)
Metagenomics , Thermogenesis , Animals , Cattle/genetics , China , Cold Temperature , Genome , Thermogenesis/genetics
7.
Int J Biol Macromol ; 194: 556-562, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-34822828

ABSTRACT

TGFß1 signaling pathway is associated with many diseases, which can induce the activation of hepatic stellate cells (HSCs) and induce liver fibrosis. Studies have shown that 20S-protopanaxadiol (PPD) has a therapeutic effect on liver fibrosis, but the target is unknown. In this study, we confirmed that PPD reduced the mRNA expression of downstream genes of the TGFß1 pathway, which suggesting PPD is associated with the TGFß1 pathway. The protein dissociation temperature and dissociation constant (Kd) of PPD on TGFßR1 and TGFßR2 were determined, which showed that PPD combined with TGFßR1 (Kd = 1.54 µM). The docking and simulation methods were used to find their binding sites. Site mutations, protein expression and in vitro binding experiments were performed to demonstrated these sites. In particular, these sites of TGFßR1 were also the active sites of TGFßR2. Therefore, we speculated that PPD blocked the combination of TGFßR1 and TGFßR2 by binding to the D57, R58, P59, and N78 of the TGFßR1 extracellular domain. Thus, PPD could block the transmission of TGFß1 pathway and inhibit the activation of HSCs, and treating fibrosis. Our studies showed that PPD has the potential to treat diseases related to the TGFß1 pathway and broadens its clinical application.


Subject(s)
Ginsenosides/pharmacology , Hepatic Stellate Cells/drug effects , Liver Cirrhosis/drug therapy , Sapogenins/pharmacology , Transforming Growth Factor beta1/metabolism , Cell Line , Hepatic Stellate Cells/pathology , Humans
8.
Front Endocrinol (Lausanne) ; 12: 744628, 2021.
Article in English | MEDLINE | ID: mdl-34721298

ABSTRACT

Polycystic ovary syndrome (PCOS) is a common endocrine disease accompanied by energetic metabolic imbalance. Because the etiology of PCOS is complex and remains unclear, there is no effective and specific treatment for PCOS. It is often accompanied by various metabolic disorders such as obesity, insulin resistances, and others. Activated brown adipose tissue (BAT) consumes excess energy via thermogenesis, which has positive effects on energy metabolism. Our previous research and that of others indicates that BAT activity is decreased in PCOS patients, and exogenous BAT transplantation can improve PCOS rodents. Notably however, it is difficult to apply this therapeutic strategy in clinical practice. Therapeutic strategies of enhancing endogenous BAT activity and restoring whole-body endocrine homeostasis may be more meaningful for PCOS treatment. In the current study, the dehydroepiandrosterone-induced PCOS rat was exposed to low temperature for 20 days. The results show that cold treatment could reverse acyclicity of the estrous cycle and reduce circulating testosterone and luteinizing hormone in PCOS rats by activating endogenous BAT. It also significantly reduced the expression of steroidogenic enzymes as well as inflammatory factors in the ovaries of PCOS rats. Histological investigations revealed that cold treatment could significantly reduce ovary cystic follicles and increase corpus luteum, indicating that ovulation was recovered to a normal level. Concordant with these results, cold treatment also improved fertility in PCOS rats. Collectively, these findings suggest that cold treatment could be a novel therapeutic strategy for PCOS.


Subject(s)
Adipose Tissue, Brown/physiopathology , Cold Temperature , Polycystic Ovary Syndrome/physiopathology , Polycystic Ovary Syndrome/therapy , Adipose Tissue, White , Animals , Corpus Luteum , Dehydroepiandrosterone , Estrous Cycle , Female , Fertility , Homeostasis , Infertility, Female/therapy , Luteinizing Hormone/blood , Ovarian Follicle , Ovulation , Polycystic Ovary Syndrome/chemically induced , Rats , Rats, Sprague-Dawley , Testosterone/blood
9.
Adv Sci (Weinh) ; 8(21): e2101991, 2021 11.
Article in English | MEDLINE | ID: mdl-34514733

ABSTRACT

Intermittent fasting (IF), as a dietary intervention for weight loss, takes effects primarily through increasing energy expenditure. However, whether inter-organ systems play a key role in IF remains unclear. Here, a novel hepatokine, pregnancy zone protein (PZP) is identified, which has significant induction during the refeeding stage of IF. Further, loss of function studies and protein therapeutic experiment in mice revealed that PZP promotes diet-induced thermogenesis through activating brown adipose tissue (BAT). Mechanistically, circulating PZP can bind to cell surface glucose-regulated protein of 78 kDa (GRP78) to promote uncoupling protein 1 (UCP1) expression via a p38 MAPK-ATF2 signaling pathway in BAT. These studies illuminate a systemic regulation in which the IF promotes BAT thermogenesis through the endocrinal system and provide a novel potential target for treating obesity and related disorders.


Subject(s)
Adipose Tissue, Brown/metabolism , Diet, High-Fat , Obesity/pathology , Pregnancy Proteins/metabolism , Thermogenesis/physiology , Adult , Animals , Endoplasmic Reticulum Chaperone BiP/antagonists & inhibitors , Endoplasmic Reticulum Chaperone BiP/genetics , Endoplasmic Reticulum Chaperone BiP/metabolism , Female , Glucose Tolerance Test , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Obesity/metabolism , Pregnancy Proteins/blood , Pregnancy Proteins/genetics , RNA Interference , RNA, Small Interfering/metabolism , Signal Transduction , Uncoupling Protein 1/deficiency , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
10.
Appl Microbiol Biotechnol ; 105(14-15): 6007-6018, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34390354

ABSTRACT

Liver fibrosis is caused by the accumulation of extracellular matrix proteins on the surface of hepatocytes and results from chronic liver injury. TGFß1 is one of the most important promoters of hepatic fibrosis, which accelerates the transformation of hepatic stellate cells to myofibroblasts and collagen expression. It is well-known that TGFß1 binds to TGFßR2 to mediate its downstream signal cascades to regulate target gene transcription. Therefore, the TGFßR2 blocker might be a prominent drug candidate. We constructed TGFßR2 extracellular domain into living biotherapeutics Lactococcus lactis to reduce hepatic fibrosis in CCl4 treated mice in the present study. We found that the culture supernatant of the recombinant bacteria can inhibit the TGFß1-induced collagen synthesis in the hepatic stellate cells at the cellular level. In addition, results of in vivo study showed that the recombinant bacteria significantly reduced the degree of liver fibrosis in CCl4-treated mice. Furthermore, flow cytometry results indicated that the recombinant bacteria treatment significantly reduced the CD11b+ Kupffer cells compared with the empty vector bacteria group. Consistently, fibrosis-related gene and protein expression were significantly reduced upon recombinant bacteria treatment. Finally, the subchronic toxicity test results showed that this bacteria strain did not have any significant side effects. In conclusion, our recombinant Lactococcus lactis shows tremendous therapeutic potential in liver fibrosis. KEY POINTS: • The supernatant of L. lactis expressing TGFßR2 inhibits the activation of myofibroblast. • The oral recombinant strain reduced the degree of liver fibrosis and inflammation in mice. • The recombinant strain was safe in subchronic toxicity test in mice.


Subject(s)
Lactococcus lactis , Animals , Collagen , Hepatocytes , Lactococcus lactis/genetics , Liver Cirrhosis/prevention & control , Mice
11.
J Mol Endocrinol ; 65(3): 97-107, 2020 10.
Article in English | MEDLINE | ID: mdl-32755999

ABSTRACT

White adipose tissue (WAT) browning may have beneficial effects for treating metabolic syndrome. miRNA are important regulators of the differentiation, development, and function of brown and beige adipocytes. Here, we found that the cold-inducible miRNA17-92 cluster is enriched in brown adipose tissue (BAT) compared with WAT. Overexpression of the miR17-92 cluster in C3H10T1/2 cells, a mouse mesenchymal stem cell line, enhanced the thermogenic capacity of adipocytes. Furthermore, we observed a significant reduction in adiposity in adipose tissue-specific miR17-92 cluster transgenic (TG) mice. This finding is partly explained by dramatic increases in white fat browning and energy expenditure. Interestingly, the miR17-92 cluster stimulated WAT browning without altering BAT activity in mice. In addition, when we removed the intrascapular BAT (iBAT), the TG mice could maintain their body temperature well under cold exposure. At the molecular level, we found that the miR17-92 cluster targets Rb1, a beige cell repressor in WAT. The present study reveals a critical role for the miR17-92 cluster in regulating WAT browning. These results may be helpful for better understanding the function of beige fat, which could compensate for the lack of BAT in humans, and may open new avenues for combatting metabolic syndrome.


Subject(s)
Adipocytes, Brown/physiology , Adipocytes, White/physiology , Cell Transdifferentiation/genetics , MicroRNAs/genetics , 3T3-L1 Cells , Adipocytes, Beige/physiology , Adipose Tissue, Brown/physiology , Adipose Tissue, White/physiology , Animals , Cells, Cultured , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Multigene Family/physiology , Thermogenesis/genetics
12.
Gut ; 69(7): 1239-1247, 2020 07.
Article in English | MEDLINE | ID: mdl-31744910

ABSTRACT

OBJECTIVE: Dietary 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. DESIGN: Db/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. RESULTS: We 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. CONCLUSIONS: Our 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.


Subject(s)
Adipose Tissue, Brown/metabolism , Enterococcus faecalis/metabolism , Fatty Acids, Monounsaturated/metabolism , Obesity/metabolism , Animals , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/genetics , Male , Mice , Mice, Inbred C57BL , Panax , Plant Extracts/pharmacology , RNA, Ribosomal, 16S/genetics
13.
Int J Mol Sci ; 20(7)2019 Apr 01.
Article in English | MEDLINE | ID: mdl-30939798

ABSTRACT

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.


Subject(s)
Adipose Tissue, Brown/drug effects , Anti-Obesity Agents/therapeutic use , Fluvastatin/therapeutic use , Obesity/drug therapy , Adipose Tissue, Brown/metabolism , Animals , Anti-Obesity Agents/pharmacology , Cells, Cultured , Energy Metabolism , Fluvastatin/pharmacology , Humans , Male , Mice , Mice, Inbred C57BL , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
15.
J Nutr Biochem ; 47: 21-28, 2017 09.
Article in English | MEDLINE | ID: mdl-28501702

ABSTRACT

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, 3ß-HSD, 17ß-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.


Subject(s)
Adipose Tissue, Brown/metabolism , Disease Models, Animal , Insulin Resistance , Ovary/physiopathology , Polycystic Ovary Syndrome/diet therapy , Rutin/therapeutic use , Thermogenesis , Adipose Tissue, Brown/pathology , Animals , Anovulation/etiology , Anovulation/prevention & control , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Anti-Obesity Agents/therapeutic use , Biomarkers/blood , Biomarkers/metabolism , Congenital Abnormalities/etiology , Congenital Abnormalities/prevention & control , Dehydroepiandrosterone , Enzyme Induction , Female , Infertility, Female/etiology , Infertility, Female/prevention & control , Luteinizing Hormone/antagonists & inhibitors , Luteinizing Hormone/blood , Ovary/metabolism , Ovary/pathology , Phosphoproteins/agonists , Phosphoproteins/genetics , Phosphoproteins/metabolism , Polycystic Ovary Syndrome/metabolism , Polycystic Ovary Syndrome/pathology , Polycystic Ovary Syndrome/physiopathology , Rats, Sprague-Dawley , Thermography , Whole Body Imaging
16.
FASEB J ; 31(1): 333-345, 2017 01.
Article in English | MEDLINE | ID: mdl-28049156

ABSTRACT

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.


Subject(s)
Adipose Tissue, Brown/physiology , Diet, High-Fat/adverse effects , Energy Metabolism/drug effects , Obesity/drug therapy , Rutin/pharmacology , Animals , Body Temperature Regulation/drug effects , Body Temperature Regulation/physiology , Cold Temperature , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Glucose Tolerance Test , HEK293 Cells , High Mobility Group Proteins/genetics , High Mobility Group Proteins/metabolism , Humans , Mice , Mice, Obese , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Sirtuin 1/genetics , Sirtuin 1/metabolism , Uncoupling Protein 1/genetics , Uncoupling Protein 1/metabolism
17.
Proc Natl Acad Sci U S A ; 113(10): 2708-13, 2016 Mar 08.
Article in English | MEDLINE | ID: mdl-26903641

ABSTRACT

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.


Subject(s)
Adipose Tissue, Brown/transplantation , Infertility, Female/surgery , Insulin Resistance , Polycystic Ovary Syndrome/surgery , Adiponectin/blood , Adiponectin/pharmacology , Adult , Analysis of Variance , Animals , Blood Glucose/metabolism , Dehydroepiandrosterone , Energy Metabolism/drug effects , Estrous Cycle/drug effects , Female , Humans , Insulin/blood , Male , Polycystic Ovary Syndrome/chemically induced , Polycystic Ovary Syndrome/metabolism , Rats, Sprague-Dawley , Treatment Outcome
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