RESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo , Diabetes Mellitus Tipo 2 , Tejido Adiposo Pardo/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Termogénesis , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
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.
Asunto(s)
Lactococcus lactis , Animales , Colágeno , Hepatocitos , Lactococcus lactis/genética , Cirrosis Hepática/prevención & control , RatonesRESUMEN
Uncoupling protein 1 (UCP1) is localized on the inner mitochondrial membrane and generates heat by uncoupling ATP synthesis from proton transit across the inner membrane. UCP1 is a key element of nonshivering thermogenesis and is most likely important in the regulation of body adiposity. Pigs (Artiodactyl family Suidae) lack a functional UCP1 gene, resulting in poor thermoregulation and susceptibility to cold, which is an economic and pig welfare issue owing to neonatal mortality. Pigs also have a tendency toward fat accumulation, which may be linked to their lack of UCP1, and thus influences the efficiency of pig production. Here, we report application of a CRISPR/Cas9-mediated, homologous recombination (HR)-independent approach to efficiently insert mouse adiponectin-UCP1 into the porcine endogenous UCP1 locus. The resultant UCP1 knock-in (KI) pigs showed an improved ability to maintain body temperature during acute cold exposure, but they did not have alterations in physical activity levels or total daily energy expenditure (DEE). Furthermore, ectopic UCP1 expression in white adipose tissue (WAT) dramatically decreased fat deposition by 4.89% (P < 0.01), consequently increasing carcass lean percentage (CLP; P < 0.05). Mechanism studies indicated that the loss of fat upon UCP1 activation in WAT was linked to elevated lipolysis. UCP1 KI pigs are a potentially valuable resource for agricultural production through their combination of cold adaptation, which improves pig welfare and reduces economic losses, with reduced fat deposition and increased lean meat production.
Asunto(s)
Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/fisiología , Sistemas CRISPR-Cas/fisiología , Termogénesis/fisiología , Proteína Desacopladora 1/metabolismo , Adiposidad/fisiología , Animales , Temperatura Corporal/fisiología , Regulación de la Temperatura Corporal/fisiología , Frío , Metabolismo Energético/fisiología , Femenino , Lipólisis/fisiología , Masculino , Ratones , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , PorcinosRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo/trasplante , Infertilidad Femenina/cirugía , Resistencia a la Insulina , Síndrome del Ovario Poliquístico/cirugía , Adiponectina/sangre , Adiponectina/farmacología , Adulto , Análisis de Varianza , Animales , Glucemia/metabolismo , Deshidroepiandrosterona , Metabolismo Energético/efectos de los fármacos , Ciclo Estral/efectos de los fármacos , Femenino , Humanos , Insulina/sangre , Masculino , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Fármacos Antiobesidad/uso terapéutico , Fluvastatina/uso terapéutico , Obesidad/tratamiento farmacológico , Tejido Adiposo Pardo/metabolismo , Animales , Fármacos Antiobesidad/farmacología , Células Cultivadas , Metabolismo Energético , Fluvastatina/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo/fisiología , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/efectos de los fármacos , Obesidad/tratamiento farmacológico , Rutina/farmacología , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/fisiología , Frío , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Prueba de Tolerancia a la Glucosa , Células HEK293 , Proteínas del Grupo de Alta Movilidad/genética , Proteínas del Grupo de Alta Movilidad/metabolismo , Humanos , Ratones , Ratones Obesos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
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.
Asunto(s)
Dihidroergotamina , Cirrosis Hepática , Ratones , Animales , Receptor Tipo II de Factor de Crecimiento Transformador beta , Dihidroergotamina/efectos adversos , Simulación del Acoplamiento Molecular , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Cirrosis Hepática/inducido químicamente , Fibrosis , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta1 , Receptores de Factores de Crecimiento Transformadores beta/genéticaRESUMEN
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.
Asunto(s)
Ginsenósidos/farmacología , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/tratamiento farmacológico , Sapogeninas/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Línea Celular , Células Estrelladas Hepáticas/patología , HumanosRESUMEN
Brown adipose tissue (BAT), a unique tissue, plays a key role in metabolism and energy expenditure through adaptive nonshivering thermogenesis. It has recently become a therapeutic target in the treatment of obesity and metabolic diseases. The thermogenic effect of BAT occurs through uncoupling protein-1 by uncoupling adenosine triphosphate (ATP) synthesis from energy substrate oxidation. The review discusses the recent developments and progress associated with the biology, function, and activation of BAT, with a focus on its therapeutic potential for the treatment of polycystic ovary syndrome (PCOS). The endocrine activity of brown adipocytes affects the energy balance and homeostasis of glucose and lipids, thereby affecting the association of BAT activity and the metabolic profile. PCOS is a complex reproductive and metabolic disorder of reproductive-age women. Functional abnormalities of adipose tissue (AT) have been reported in patients with PCOS. Numerous studies have shown that BAT could regulate the features of PCOS and that increases in BAT mass or activity were effective in the treatment of PCOS through approaches including cold stimulation, BAT transplantation and compound activation in various animal models. Therefore, BAT may be used as a novel management strategy for the patients with PCOS to improve women's health clinically. It is highly important to identify key brown adipokines for the discovery and development of novel candidates to establish an efficacious therapeutic strategy for patients with PCOS in the future.
Asunto(s)
Tejido Adiposo Pardo , Síndrome del Ovario Poliquístico , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Femenino , Humanos , Síndrome del Ovario Poliquístico/metabolismo , Termogénesis/fisiología , Proteína Desacopladora 1/metabolismoRESUMEN
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.
RESUMEN
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.
Asunto(s)
Ginsenósidos , Síndrome del Ovario Poliquístico , Tejido Adiposo Pardo/metabolismo , Animales , Deshidroepiandrosterona/efectos adversos , Modelos Animales de Enfermedad , Femenino , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Humanos , Ratones , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/tratamiento farmacológico , RatasRESUMEN
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.
Asunto(s)
Metagenómica , Termogénesis , Animales , Bovinos/genética , China , Frío , Genoma , Termogénesis/genéticaRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo/fisiopatología , Frío , Síndrome del Ovario Poliquístico/fisiopatología , Síndrome del Ovario Poliquístico/terapia , Tejido Adiposo Blanco , Animales , Cuerpo Lúteo , Deshidroepiandrosterona , Ciclo Estral , Femenino , Fertilidad , Homeostasis , Infertilidad Femenina/terapia , Hormona Luteinizante/sangre , Folículo Ovárico , Ovulación , Síndrome del Ovario Poliquístico/inducido químicamente , Ratas , Ratas Sprague-Dawley , Testosterona/sangreRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Dieta Alta en Grasa , Obesidad/patología , Proteínas Gestacionales/metabolismo , Termogénesis/fisiología , Adulto , Animales , Chaperón BiP del Retículo Endoplásmico/antagonistas & inhibidores , Chaperón BiP del Retículo Endoplásmico/genética , Chaperón BiP del Retículo Endoplásmico/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Obesidad/metabolismo , Proteínas Gestacionales/sangre , Proteínas Gestacionales/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Proteína Desacopladora 1/deficiencia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
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.
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Adipocitos Marrones/fisiología , Adipocitos Blancos/fisiología , Transdiferenciación Celular/genética , MicroARNs/genética , Células 3T3-L1 , Adipocitos Beige/fisiología , Tejido Adiposo Pardo/fisiología , Tejido Adiposo Blanco/fisiología , Animales , Células Cultivadas , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Familia de Multigenes/fisiología , Termogénesis/genéticaRESUMEN
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.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Modelos Animales de Enfermedad , Resistencia a la Insulina , Ovario/fisiopatología , Síndrome del Ovario Poliquístico/dietoterapia , Rutina/uso terapéutico , Termogénesis , Tejido Adiposo Pardo/patología , Animales , Anovulación/etiología , Anovulación/prevención & control , Antiinflamatorios no Esteroideos/uso terapéutico , Fármacos Antiobesidad/uso terapéutico , Biomarcadores/sangre , Biomarcadores/metabolismo , Anomalías Congénitas/etiología , Anomalías Congénitas/prevención & control , Deshidroepiandrosterona , Inducción Enzimática , Femenino , Infertilidad Femenina/etiología , Infertilidad Femenina/prevención & control , Hormona Luteinizante/antagonistas & inhibidores , Hormona Luteinizante/sangre , Ovario/metabolismo , Ovario/patología , Fosfoproteínas/agonistas , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Síndrome del Ovario Poliquístico/fisiopatología , Ratas Sprague-Dawley , Termografía , Imagen de Cuerpo EnteroRESUMEN
Pigs lack functional uncoupling protein 1 (UCP1) making them susceptible to cold. Nevertheless, several pig breeds are known to be cold resistant. The molecular mechanism(s) enabling such adaptation are currently unknown. Here, we show that this resistance is not dependent on shivering, but rather depends on UCP3 and white adipose tissue (WAT) browning. In two cold-resistant breeds (Tibetan and Min), but not a cold-sensitive breed (Bama), WAT browning was induced after cold exposure. Beige adipocytes from Tibetan pigs exhibited greater oxidative capacity than those from Bama pigs. Notably, UCP3 expression was significantly increased only in cold-resistant breeds, and knockdown of UCP3 expression in Tibetan adipocytes phenocopied Bama adipocytes in culture. Moreover, the eight dominant pig breeds found across China can be classified into cold-sensitive and cold-resistant breeds based on the UCP3 cDNA sequence. This study indicates that UCP3 has contributed to the evolution of cold resistance in the pig and overturns the orthodoxy that UCP1 is the only thermogenic uncoupling protein.