RESUMEN
Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub.
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Decidua , Retardo del Crecimiento Fetal , Leptina , Placenta , Transducción de Señal , Animales , Femenino , Ratones , Embarazo , Decidua/metabolismo , Decidua/patología , Dieta Alta en Grasa/efectos adversos , Retardo del Crecimiento Fetal/metabolismo , Retardo del Crecimiento Fetal/patología , Leptina/metabolismo , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , Obesidad/patología , Placenta/metabolismo , Progesterona/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Factor de Transcripción STAT3/metabolismo , Células del Estroma/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genéticaRESUMEN
BACKGROUND: Silymarin is recognized for its excellent hepato-protective properties. Recent clinical studies have examined the effects of silymarin on metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the necessity of further exploration into optimal dosages, active components, and mechanisms of action. METHODS AND RESULTS: This study assessed the anti-inflammatory activity of the principal constituents of silymarin at the cellular level. The therapeutic effects of varying silymarin doses and components on MASLD in mouse models induced by a high-fat diet (HFD) were also examined. These findings indicate the superior efficacy of 80 mg kg-1 silymarin in mitigating liver steatosis and reducing lipid accumulation compared to 30 mg kg-1 silymarin or a combination of silybin and isosilybin A. The mechanism of silymarin involves regulating gut microbiota homeostasis and influencing the TLR4/NF-κB signalling pathway through LPS. Bile acid-targeted metabolomics analysis revealed that silymarin significantly decreases the HFD-induced increase in 7-keto-deoxycholic acid (7-KDCA). Further investigations suggested that 7-KDCA as an antagonist targeted farnesoid X receptor (FXR) and that both silybin and isosilybin A could directly interact with FXR. CONCLUSION: These findings elucidate that 80 mg kg-1 of silymarin can exert therapeutic effects on MASLD mice and offer novel insights into the mechanism of silymarin in treating MASLD. Especially, it was found that silymarin could regulate bile acid metabolism, reduce the concentration of 7-KDCA, and thus perform negative feedback regulation on FXR.
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Ácido Desoxicólico , Dieta Alta en Grasa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Receptores Citoplasmáticos y Nucleares , Silimarina , Animales , Silimarina/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Masculino , Ratones , Ácido Desoxicólico/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Silibina/farmacología , Transducción de Señal/efectos de los fármacos , Humanos , FN-kappa B/metabolismo , Ácidos y Sales Biliares/metabolismo , Hígado Graso/tratamiento farmacológico , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Receptor Toll-Like 4/metabolismo , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Células Hep G2RESUMEN
Objective: This study aims to investigate the effects of semaglutide on gut microbiota, cognitive function, and inflammation in obese mice. Method: Twenty-four C57BL/6J male mice were randomly assigned to three groups: a normal-chow diet group (NCD, n = 8), high-fat diet group (HFD, n = 8), and HFD+semaglutide group (Sema, n = 8). The mice were fed a HFD to establish an animal model of obesity and then administered with semaglutide or saline for 12 weeks. Cognitive function was assessed using the Morris water maze test. Serum pro-inflammatory cytokines were measured. 16S rRNA gene sequencing technology was used to explore gut microbiota characteristics in obese mice. Result: Obese mice showed significant cognitive impairment and inflammation. Semaglutide improved cognitive function and attenuated inflammation induced by a HFD diet. The abundance of gut microbiota was significantly changed in the HFD group, including decreased Akkermansia, Muribaculaceae, Coriobacteriaceae_UCG_002, Clostridia_UCG_014 and increased Romboutsia, Dubosiella, Enterorhabdus. Whereas semaglutide could dramatically reverse the relative abundance of these gut microbiota. Correlation analysis suggested that cognitive function was positively correlated with Muribaculaceae and Clostridia_UCG_014, and negatively associated with Romboutsia and Dubosiella. Romboutsia was positively correlated with TNFα, IL-6 and IL-1ß. While Clostridia_UCG_014 was negatively related to TNFα, IL-6 and IL-1ß. Conclusions: For the first time semaglutide displayed different regulatory effects on HFD-induced gut microbiota dysbiosis. Semaglutide could regulate the structure and composition of gut microbiota associated with cognitive function and inflammation. Thus, affecting gut microbiota might be a potential mechanism of semaglutide in attenuating cognitive function and inflammation.
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Cognición , Dieta Alta en Grasa , Microbioma Gastrointestinal , Péptidos Similares al Glucagón , Inflamación , Ratones Endogámicos C57BL , Obesidad , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Péptidos Similares al Glucagón/farmacología , Ratones , Masculino , Obesidad/microbiología , Obesidad/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Cognición/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Ratones Obesos , Modelos Animales de Enfermedad , Citocinas/metabolismo , Citocinas/sangre , Disfunción Cognitiva/tratamiento farmacológicoRESUMEN
OBJECTIVES: Obesity related glomerulopathy (ORG) is induced by obesity, but the pathogenesis remains unclear. This study aims to investigate the expression of early growth response protein 3 (EGR3) in the renal cortex tissues of ORG patients and high-fat diet-induced obese mice, and to further explore the molecular mechanism of EGR3 in inhibiting palmitic acid (PA) induced human podocyte inflammatory damage. METHODS: Renal cortex tissues were collected from ORG patients (n=6) who have been excluded from kidney damage caused by other diseases and confirmed by histopathology, and from obese mice induced by high-fat diet (n=10). Human and mouse podocytes were intervened with 150 µmol/L PA for 48 hours. EGR3 was overexpressed or silenced in human podocytes. Enzyme linked immunosorbent assay (ELISA) was used to detcet the levels of interleukin-6 (IL-6) and interleukin-1ß (IL-1ß). Real-time RT-PCR was used to detect the mRNA expressions of EGR3, podocytes molecular markers nephrosis 1 (NPHS1), nephrosis 2 (NPHS2), podocalyxin (PODXL), and podoplanin (PDPN). RNA-seq was performed to detect differentially expressed genes (DEGs) after human podocytes overexpressing EGR3 and treated with 150 µmol/L PA compared with the control group. Co-immunoprecipitation (Co-IP) combined with liquid chromatography tandem mass spectrometry (LC-MS) was used to detect potential interacting proteins of EGR3 and the intersected with the RNA-seq results. Co-IP confirmed the interaction between EGR3 and protein arginine methyltransferases 1 (PRMT1), after silencing EGR3 and PRMT1 inhibitor intervention, the secretion of IL-6 and IL-1ß in PA-induced podocytes was detected. Western blotting was used to detect the expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) after overexpression or silencing of EGR3. RESULTS: EGR3 was significantly upregulated in renal cortex tissues of ORG patients and high-fat diet-induced obese mice (both P<0.01). In addition, after treating with 150 µmol/L PA for 48 hours, the expression of EGR3 in human and mouse podocytes was significantly upregulated (both P<0.05). Overexpression or silencing of EGR3 in human podocytes inhibited or promoted the secretion of IL-6 and IL-1ß in the cell culture supernatant after PA intervention, respectively, and upregulated or downregulated the expression of NPHS1, PODXL, NPHS2,and PDPN (all P<0.05). RNA-seq showed a total of 988 DEGs, and Co-IP+LC-MS identified a total of 238 proteins that may interact with EGR3. Co-IP confirmed that PRMT1 was an interacting protein with EGR3. Furthermore, PRMT1 inhibitors could partially reduce PA-induced IL-6 and IL-1ß secretion after EGR3 silencing in human podocytes (both P<0.05). Overexpression or silencing of EGR3 negatively regulated the expression of PRMT1 and p-STAT3. CONCLUSIONS: EGR3 may reduce ORG podocyte inflammatory damage by inhibiting the PRMT1/p-STAT3 pathway.
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Proteína 3 de la Respuesta de Crecimiento Precoz , Obesidad , Podocitos , Proteína-Arginina N-Metiltransferasas , Proteínas Represoras , Factor de Transcripción STAT3 , Animales , Humanos , Masculino , Ratones , Dieta Alta en Grasa/efectos adversos , Proteína 3 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 3 de la Respuesta de Crecimiento Precoz/genética , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-6/genética , Corteza Renal/metabolismo , Corteza Renal/patología , Enfermedades Renales/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/patología , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/complicaciones , Obesidad/metabolismo , Ácido Palmítico/farmacología , Podocitos/metabolismo , Podocitos/patología , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Represoras/metabolismo , Proteínas Represoras/genética , Transducción de Señal , Factor de Transcripción STAT3/metabolismoRESUMEN
To investigate the effects of rapeseed diacylglycerol oil (RDG) intake on lipid accumulation and metabolism in C57BL/6J mice, obese mice were fed a high-fat diet in which 45% of the total energy content came from RDG (RDGM group) or rapeseed triacylglycerol oil (RTGM group). This diet intervention was conducted for 12 weeks following the establishment of the obese mouse model. By the end of the experiment, the serum glucose levels of the mice in the RTGM and RDGM groups were 13.0 ± 1.3 mmol/L and 9.7 ± 1.5 mmol/L, respectively. Meanwhile, the serum triglyceride level in the RDGM group was 26.3% lower than that in the RTGM group. The weight-loss effect in the RDGM group was accompanied by a significant decrease in the white adipose tissue (WAT) index. The RDG intervention did not significantly change the antioxidant and anti-inflammatory properties of the rapeseed oil in vivo. The RDG diet improved the liver lipid metabolism abnormalities induced by a high-fat diet, leading to decreased liver damage index values (AST and ALT). Additionally, compared to that in the RTGM group, the expression of the adipogenic genes PPAR-γ and DGAT decreased in both the liver and intestine by 21.7% and 16.7% and by 38.7% and 47.2%, respectively, in the RDGM group. Further, most lipolytic genes in BAT showed no significant change after the RDG intervention. This implies that RDG regulates lipid metabolism by altering the expression of adipogenic genes in the liver, intestine, and adipose tissue, thereby reducing the accumulation of WAT. Furthermore, the RDG diet enhanced gut flora diversity, increasing the relative levels of unclassified Muribaculaceae and decreasing the levels of Dubosiella and Faecalibaculum in the mouse gut, potentially accelerating lipid metabolism. Thus, a three-month RDG diet intervention in obese mice exhibited benefits in regulating the somatotype, serum obesity-related indices, gut flora structure, and lipid metabolism in the adipose tissue, liver, and intestine.
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Fármacos Antiobesidad , Dieta Alta en Grasa , Diglicéridos , Metabolismo de los Lípidos , Hígado , Ratones Endogámicos C57BL , Obesidad , Aceite de Brassica napus , Animales , Metabolismo de los Lípidos/efectos de los fármacos , Obesidad/metabolismo , Diglicéridos/farmacología , Dieta Alta en Grasa/efectos adversos , Masculino , Aceite de Brassica napus/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Ratones , Fármacos Antiobesidad/farmacología , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Triglicéridos/sangre , Diacilglicerol O-Acetiltransferasa/metabolismo , Diacilglicerol O-Acetiltransferasa/genética , Microbioma Gastrointestinal/efectos de los fármacos , PPAR gamma/metabolismo , Ratones ObesosRESUMEN
Obesity is associated with one-fifth of cancer deaths, and breast cancer is one of the obesity-related cancers. Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors and human epidermal growth factor receptor 2, leading to the absence of these therapeutic targets, followed by poor overall survival. We investigated if obesity could hasten TNBC progression and intermittent fasting (IF) could attenuate the progression of obesity-related TNBC. Our meta-analysis of the TNBC outcomes literature showed that obesity led to poorer overall survival in TNBC patients. Fasting-mimicking media reduced cell proliferation disrupted the cell cycle, and decreased cell migration and invasion. IF decreased body weight in obese mice but no change in normal mice. Obese mice exhibited elevated plasma glucose and cholesterol levels, increased tumor volume and weight, and enhanced macrophage accumulation in tumors. The obesity-exacerbated TNBC progression was attenuated after IF, which decreased cyclin B1 and vimentin levels and reduced the proinflammatory signature in the obesity-associated tumor microenvironment. IF attenuated obesity-induced TNBC progression through reduced obesity and tumor burdens in cell and animal experiments, supporting the potential of a cost-effective adjuvant IF therapy for TNBC through lifestyle change. Further evidence is needed of these IF benefits in TNBC, including from human clinical trials.
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Ciclo Celular , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal , Ayuno , Obesidad , Neoplasias de la Mama Triple Negativas , Animales , Obesidad/complicaciones , Femenino , Humanos , Ratones , Línea Celular Tumoral , Inflamación , Proliferación Celular , Microambiente Tumoral , Ratones Obesos , Movimiento Celular , Ayuno IntermitenteRESUMEN
Peptide-based drug discovery has surged with the development of peptide hormone-derived analogs for the treatment of diabetes and obesity. Machine learning (ML)-enabled quantitative structure-activity relationship (QSAR) approaches have shown great promise in small molecule drug discovery but have been less successful in peptide drug discovery due to limited data availability. We have developed a peptide drug discovery platform called streaMLine, enabling rigorous design, synthesis, screening, and ML-driven analysis of large peptide libraries. Using streaMLine, this study systematically explored secretin as a peptide backbone to generate potent, selective, and long-acting GLP-1R agonists with improved physicochemical properties. We synthesized and screened a total of 2688 peptides and applied ML-guided QSAR to identify multiple options for designing stable and potent GLP-1R agonists. One candidate, GUB021794, was profiled in vivo (S.C., 10 nmol/kg QD) and showed potent body weight loss in diet-induced obese mice and a half-life compatible with once-weekly dosing.
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Descubrimiento de Drogas , Receptor del Péptido 1 Similar al Glucagón , Aprendizaje Automático , Receptor del Péptido 1 Similar al Glucagón/agonistas , Animales , Ratones , Humanos , Péptidos/química , Péptidos/farmacología , Péptidos/síntesis química , Obesidad/tratamiento farmacológico , Ratones Endogámicos C57BL , Masculino , Relación Estructura-Actividad Cuantitativa , Ratones Obesos , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
Green tea polyphenols (GTP) have been shown to ameliorate lipid metabolic disorders by regulating intestinal bacteria. Given the significant role of intestinal bacteriophages in shaping the gut microbiota, this study investigates GTP's influence on gut bacteriophage-bacteria interactions and lipid metabolism using metagenomics and metabonomics. The research results indicated that GTP significantly reduced body weight, serum triglycerides, leptin, insulin resistance, interleukin-6, and TNF-α levels while increasing adiponectin in ob/ob mice fed high-fat diet, aiding intestinal repair. GTP improved gut health by decreasing Enterobacter, Siphoviridae and Enterobacteria_phage_sfv, increasing Bifidobacterium and intestinal metabolites SCFA and hippuric acid. Correlation analysis showed negative correlations between Enterobacter sp. 50,588,862 and Enterobacteria_phages, Shigella_phages with 4-hydroxyphenylpyruvate and hippuric acid. Bifidobacterium choerinum and Bifidobacterium sp. AGR2158 were positively correlated with fatty acids and bile acids. In conclusion, GTP reduced fat accumulation and inflammation, enhanced gut barrier function in obese mice, closely associated with changes in the gut bacteriophage community.
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Bacterias , Bacteriófagos , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Polifenoles , Té , Animales , Ratones , Polifenoles/farmacología , Polifenoles/administración & dosificación , Polifenoles/metabolismo , Polifenoles/química , Microbioma Gastrointestinal/efectos de los fármacos , Bacteriófagos/metabolismo , Té/química , Bacterias/genética , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/aislamiento & purificación , Masculino , Metabolismo de los Lípidos/efectos de los fármacos , Humanos , Ratones Obesos , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/fisiopatología , Obesidad/terapia , Obesidad/microbiología , Ratones Endogámicos C57BL , Intestinos/microbiología , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Dieta Alta en Grasa/efectos adversosRESUMEN
The increased incidence of obesity, which become a global health problem, requires more functional food products with minor side and excellent effects. Calebin A (CbA) is a non-curcuminoid compound, which is reported to be an effective treatment for lipid metabolism and thermogenesis. However, its ability and mechanism of action in improving obesity-associated hyperglycemia remain unclear. This study was designed to explore the effect and mechanism of CbA in hyperglycemia via improvement of inflammation and glucose metabolism in the adipose tissue and liver in high-fat diet (HFD)-fed mice. After 10 weeks fed HFD, obese mice supplemented with CbA (25 and 100 mg/kg) for another 10 weeks showed a remarkable reducing adiposity and blood glucose. CbA modulated M1/M2 macrophage polarization, ameliorated inflammatory cytokines, and restored adiponectin as well as Glut 4 expression in the adipose tissue. In the in vitro study, CbA attenuated pro-inflammatory markers while upregulated anti-inflammatory IL-10 in LPS + IFNγ-generated M1 phenotype macrophages. In the liver, CbA attenuated steatosis, inflammatory infiltration, and protein levels of inflammatory TNF-α and IL-6. Moreover, CbA markedly upregulated Adiponectin receptor 1, AMPK, and insulin downstream Akt signaling to improve glycogen content and increase Glut2 protein. These findings indicated that CbA may be a novel therapeutic approach to treat obesity and hyperglycemia phenotype targeting on adipose inflammation and hepatic insulin signaling.
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Tejido Adiposo , Dieta Alta en Grasa , Glucosa , Hiperglucemia , Inflamación , Hígado , Macrófagos , Obesidad , Animales , Dieta Alta en Grasa/efectos adversos , Ratones , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Glucosa/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Células RAW 264.7 , Ratones Obesos , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Citocinas/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.
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Compuestos de Bencidrilo , Glucósidos , Resistencia a la Insulina , Obesidad , Síndrome del Ovario Poliquístico , Animales , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/metabolismo , Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Femenino , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/complicaciones , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ratones Obesos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Metformina/farmacología , Metformina/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Ratones Endogámicos C57BL , Glucemia/efectos de los fármacos , Glucemia/metabolismoRESUMEN
OBJECTIVE: Bariatric surgery is an effective treatment to obesity, leading to weight loss and improvement in glycemia, that is characterized by hypersecretion of gastrointestinal hormones. However, weight regain and relapse of hyperglycemia are not uncommon. We set to identify mechanisms that can enhance gastrointestinal hormonal secretion following surgery to sustain weight loss. METHODS: We investigated the effect of somatostatin (Sst) inhibition on the outcomes of bariatric surgery using a mouse model of sleeve gastrectomy (SG). RESULTS: Sst knockout (sst-ko) mice fed with a calorie-rich diet gained weight normally and had a mild favorable metabolic phenotype compared to heterozygous sibling controls, including elevated plasma levels of GLP-1. Mathematical modeling of the feedback inhibition between Sst and GLP-1 showed that Sst exerts its maximal effect on GLP-1 under conditions of high hormonal stimulation, such as following SG. Obese sst-ko mice that underwent SG had higher levels of GLP-1 compared with heterozygous SG-operated controls. The SG-sst-ko mice regained less weight than controls and maintained lower glycemia months after surgery. Obese wild-type mice that underwent SG and were treated daily with a Sst receptor inhibitor for two months had higher GLP-1 levels, regained less weight, and improved metabolic profile compared to saline-treated SG-operated controls, and compared to inhibitor or saline-treated sham-operated obese mice. CONCLUSIONS: Our results suggest that inhibition of Sst signaling enhances the long-term favorable metabolic outcomes of bariatric surgery.
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Gastrectomía , Péptido 1 Similar al Glucagón , Ratones Noqueados , Obesidad , Somatostatina , Animales , Somatostatina/metabolismo , Ratones , Gastrectomía/métodos , Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón/sangre , Obesidad/metabolismo , Obesidad/cirugía , Masculino , Cirugía Bariátrica/métodos , Ratones Endogámicos C57BL , Pérdida de Peso , Glucemia/metabolismo , Ratones ObesosRESUMEN
Citrus peels contain abundant polyphenols, particularly flavonoids, and have been shown to exert lipid accumulation decreasing ability. In this study, Citrus depressa peel applied to oven drying and extracted with ethanol extract as CDEE to analyze its flavonoids compositions and investigated its effects on a high-fat diet (HFD)-induced obese mice model. CDEE contained several flavonoids such as hesperidin, sinesentin, nobiletin, tangeretin, 5-demethylnobiletin, and 5-demethyltangeretin. The mice fed an HFD, and administration of 2% CDEE to could decrease weight gain, abdominal fat weight, inguinal fat weight, and the adipocyte size, and CDEE also reduced serum total cholesterol (TCHO), triacylglycerol (TG) compared with mice fed only on HFD. CDEE hindered lipid accumulation through a decreased fatty acid synthase (FAS) protein expression via upregulation of the protein expression of AMP-activated protein kinase α (AMPKα). Moreover, CDEE modulated gut microbiota that altered by HFD through an increased abundance of Lactobacillus reuteri compared with the HFD group. The results demonstrated that CDEE helps decrease lipid accumulation through the AMPK pathway, which also indicates a prebiotic-like effect on gut microbiota.
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Citrus , Dieta Alta en Grasa , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad , Extractos Vegetales , Prebióticos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Citrus/química , Masculino , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Prebióticos/administración & dosificación , Prebióticos/análisis , Dieta Alta en Grasa/efectos adversos , Humanos , Triglicéridos/metabolismo , Triglicéridos/sangre , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Bacterias/metabolismo , Bacterias/efectos de los fármacosRESUMEN
Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic ß cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity.NEW & NOTEWORTHY Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity.
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Receptor del Péptido 1 Similar al Glucagón , Incretinas , Ratones Endogámicos C57BL , Obesidad , Animales , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Masculino , Incretinas/farmacología , Incretinas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Control Glucémico/métodos , Ratones Obesos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Humanos , Dieta Alta en Grasa/efectos adversos , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Insulina/metabolismo , Exenatida/farmacología , Transducción de Señal/efectos de los fármacos , AMP Cíclico/metabolismoRESUMEN
Obesity and overweight are multifactorial diseases affecting more than one-third of the world's population. Physical inactivity contributes to a positive energy balance and the onset of obesity. Exercise combined with a balanced diet is an effective non-pharmacological strategy to improve obesity-related disorders. Gallic acid (GA), is a natural endogenous polyphenol found in a variety of fruits, vegetables, and wines, with beneficial effects on energetic homeostasis. The present study aims to investigate the effects of exercise training on obese mice supplemented with GA. Animal experimentation was performed with male Swiss mice divided into five groups: ST (standard control), HFD (obese control), HFD + GA (GA supplement), HFD + Trained (training), and HFD + GA + Trained (GA and training). The groups are treated for eight weeks with 200 mg/kg/body weight of the feed compound and, if applicable, physical training. The main findings of the present study show that GA supplementation improves liver fat, body weight, adiposity, and plasma insulin levels. In addition, animals treated with the GA and a physical training program demonstrate reduced levels of anxiety. Gene expression analyses show that Sesn2 is activated via PGC-1α independent of the GATOR2 protein, which is activated by GA in the context of physical activity. These data are corroborated by molecular docking analysis, demonstrating the interaction of GA with GATOR2. The present study contributes to understanding the metabolic effects of GA and physical training and demonstrates a new hepatic mechanism of action via Sestrin 2 and PGC-1α.
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Ácido Gálico , Hígado , Ratones Obesos , Obesidad , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Condicionamiento Físico Animal , Animales , Ratones , Ácido Gálico/farmacología , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Obesidad/metabolismo , Obesidad/genética , Obesidad/tratamiento farmacológico , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Ansiedad/tratamiento farmacológico , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Dieta Alta en Grasa/efectos adversos , Regulación de la Expresión Génica/efectos de los fármacos , SestrinasRESUMEN
Obesity is a global public health problem and is related with fatal diseases such as cancer and cardiovascular and metabolic diseases. Medical and lifestyle-related strategies to combat obesity have their limitations. White adipose tissue (WAT) browning is a promising strategy for increasing energy expenditure in individuals with obesity. Uncoupling protein 1 (UCP1) drives WAT browning. We previously screened natural products that enable induction of Ucp1 and demonstrated that these natural products induced WAT browning and increased energy expenditure in mice with diet-induced obesity. In this study, we aimed to extensively optimise the structure of compound 1, previously shown to promote WAT browning. Compound 3 s exhibited a significantly higher ability to induce Ucp1 in white and brown adipocytes than did compound 1. A daily injection of compound 3 s at 5 mg/kg prevented weight gain by 13.6 % in high-fat diet-fed mice without any toxicological observation. In addition, compound 3 s significantly improved glucose homeostasis, decreased serum triacylglycerol levels, and reduced total cholesterol and LDL cholesterol levels, without altering dietary intake or physical activity. Pharmaceutical properties such as solubility, lipophilicity, and membrane permeability as well as metabolic stability, half-life (T1/2), and blood exposure ratio of i.p to i.v were significantly improved in compound 3 s when compared with those in compound 1. Regarding the mode of action of WAT browning, the induction of Ucp1 and Prdm4 by compounds 1 and 3 s was dependent on Akt1 in mouse embryonic fibroblasts. Therefore, this study suggests the potential of compound 3 s as a therapeutic agent for individuals with obesity and related metabolic diseases, which acts through the induction of WAT browning as well as brown adipose tissue activation.
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Dieta Alta en Grasa , Metabolismo Energético , Resistencia a la Insulina , Ratones Endogámicos C57BL , Obesidad , Proteína Desacopladora 1 , Animales , Dieta Alta en Grasa/efectos adversos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Metabolismo Energético/efectos de los fármacos , Masculino , Ratones , Proteína Desacopladora 1/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Chalconas/farmacología , Ratones Obesos , Fármacos Antiobesidad/farmacología , Células 3T3-L1RESUMEN
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2+/+/GluR-BR/R mice (wild type, WT) and ADAR2-/-/GluR-BR/R mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3ß pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.
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Adenosina Desaminasa , Dieta Alta en Grasa , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico , Proteínas de Unión al ARN , Transducción de Señal , Animales , Ratones , Adenosina Desaminasa/metabolismo , Adenosina Desaminasa/genética , Adenosina Desaminasa/deficiencia , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina , Hígado/metabolismo , Ratones Endogámicos C57BL , Ratones Obesos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/etiología , Obesidad/metabolismo , Obesidad/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genéticaRESUMEN
Lipolysis is the hydrolysis of triglycerides (TGs), commonly known as fats. Intracellular lipolysis of TG is associated with adipose triglyceride lipase (ATGL), which provides fatty acids during times of metabolic need. The aim of this study was to determine whether Coix lacryma-jobi L. var. ma-yuen Stapf (Coix) sprouts (CS) can alleviate obesity through lipolysis. Overall, we investigated the potential of CS under in vitro and in vivo conditions and confirmed the underlying mechanisms. Huh7 cells were exposed to free fatty acids (FFAs), and C57BL/6J mice were fed a 60% high-fat diet. When FFA were introduced into Huh7 cells, the intracellular TG levels increased within the Huh7 cells. However, CS treatment significantly reduced intracellular TG levels. Furthermore, CS decreased the expression of Pparγ and Srebp1c mRNA and downregulated the mutant Pnpla3 (I148M) mRNA. Notably, CS significantly upregulated ATGL expression. CS treatment at a dose of 200 mg/kg/day resulted in a significant and dose-dependent decrease in body weight gain and epididymal adipose tissue weight. Specifically, the group treated with CS (200 mg/kg/day) exhibited a significant modulation of serum lipid biomarkers. In addition, CS ameliorated histological alterations in both the liver and adipose tissues. In summary, CS efficiently inhibited lipid accumulation through the activation of the lipolytic enzyme ATGL coupled with the suppression of enzymes involved in TG synthesis. Consequently, CS show promise as a potential anti-obesity agent.
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Coix , Dieta Alta en Grasa , Lipasa , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad , Triglicéridos , Animales , Dieta Alta en Grasa/efectos adversos , Triglicéridos/metabolismo , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Ratones , Masculino , Humanos , Lipasa/metabolismo , Lipasa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Extractos Vegetales/farmacología , Lipólisis/efectos de los fármacos , PPAR gamma/metabolismo , PPAR gamma/genética , Plantones/metabolismo , Línea Celular Tumoral , Tejido Adiposo/metabolismo , Tejido Adiposo/efectos de los fármacosRESUMEN
OBJECTIVE: Pancreatic cancer (PC) originates and progresses with genetic mutations in various oncogenes and suppressor genes, notably KRAS, CDKN2A, TP53, and SMAD4, prevalent across diverse PC cells. In addition to genetic mutations/deletions, persistent exposure to high-risk factors, including obesity, induces whole-genome scale epigenetic alterations contributing to malignancy. However, the impact of obesity on DNA methylation in the presymptomatic stage, particularly in genes prone to PC mutation, remains uncharacterized. RESULTS: We analyzed the methylation levels of 197 loci in six genes (KRAS, CDKN2A, TP53, SMAD4, GNAS and RNF43) using Illumina Mouse Methylation BeadChip array (280 K) data from pancreatic exocrine cells obtained from high-fat-diet (HFD) induced obese mice. Results revealed no significant differences in methylation levels in loci between HFD- and normal-fat-diet (NFD)-fed mice, except for RNF43, a negative regulator of Wnt signaling, which showed hypermethylation in three loci. These findings indicate that, in mouse pancreatic exocrine cells, high-fat dietary obesity induced aberrant DNA methylation in RNF43 but not in other frequently mutated PC-related genes.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Animales , Ratones , Epigénesis Genética , Ratones Obesos , Mutación , Obesidad/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
G-protein coupled receptor-120 (GPR120; FFAR4) is a free fatty acid receptor, widely researched for its glucoregulatory and insulin release activities. This study aimed to investigate the metabolic advantage of FFAR4/GPR120 activation using combination therapy. C57BL/6 mice, fed a High Fat Diet (HFD) for 120 days to induce obesity-diabetes, were subsequently treated with a single daily oral dose of FFAR4/GPR120 agonist Compound A (CpdA) (0.1µmol/kg) alone or in combination with sitagliptin (50â¯mg/kg) for 21 days. After 21-days, glucose homeostasis, islet morphology, plasma hormones and lipids, tissue genes (qPCR) and protein expression (immunocytochemistry) were assessed. Oral administration of CpdA improved glucose tolerance (34% p<0.001) and increased circulating insulin (38% p<0.001). Addition of CpdA with the dipeptidyl peptidase-IV (DPP-IV) inhibitor, sitagliptin, further improved insulin release (44%) compared to sitagliptin alone and reduced fat mass (p<0.05). CpdA alone (50%) and in combination with sitagliptin (89%) induced marked reductions in LDL-cholesterol, with greater effects in combination (p<0.05). All treatment regimens restored pancreatic islet and beta-cell area and mass, complemented with significantly elevated beta-cell proliferation rates. A marked increase in circulating GLP-1 (53%) was observed, with further increases in combination (38%). With treatment, mice presented with increased Gcg (proglucagon) gene expression in the jejunum (130% increase) and ileum (120% increase), indicative of GLP-1 synthesis and secretion. These data highlight the therapeutic promise of FFAR4/GPR120 activation and the potential for combined benefit with incretin enhancing DPP-IV inhibitors in the regulation of beta cell proliferation and diabetes.
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Proliferación Celular , Dieta Alta en Grasa , Inhibidores de la Dipeptidil-Peptidasa IV , Péptido 1 Similar al Glucagón , Células Secretoras de Insulina , Obesidad , Receptores Acoplados a Proteínas G , Fosfato de Sitagliptina , Animales , Péptido 1 Similar al Glucagón/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Ratones , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Dieta Alta en Grasa/efectos adversos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Fosfato de Sitagliptina/farmacología , Proliferación Celular/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Obesidad/patología , Masculino , Dipeptidil Peptidasa 4/metabolismo , Ratones Endogámicos C57BL , Homeostasis/efectos de los fármacos , Insulina/metabolismo , Insulina/sangre , Glucosa/metabolismo , Ratones ObesosRESUMEN
Both obesity and exposure to environmental genotoxicants, such as 7,12-dimethylbenz[a]anthracene, negatively impair female reproductive health. Hyperphagic lean KK.Cg-a/a (n = 8) and obese KK.Cg-Ay/J (n = 10) mice were exposed to corn oil as vehicle control (CT) or 7,12-dimethylbenz[a]anthracene (1 mg/kg/day) for 7d intraperitoneally, followed by a recovery period. Obesity increased liver and spleen weight (P < 0.05), and 7,12-dimethylbenz[a]anthracene exposure decreased uterine weight (P < 0.05) in obese mice. Primordial follicle loss (P < 0.05) caused by 7,12-dimethylbenz[a]anthracene exposure was observed in obese mice only. Primary (lean P < 0.1; obese P < 0.05) and secondary (lean P < 0.05, obese P < 0.1) follicle loss initiated by 7,12-dimethylbenz[a]anthracene exposure continued across recovery. Reduced pre-antral follicle number in lean mice (P < 0.05), regardless of 7,12-dimethylbenz[a]anthracene exposure, was evident with no effect on antral follicles or corpora lutea number. Immunofluorescence staining of DNA damage marker, γH2AX, did not indicate ongoing DNA damage but TRP53 abundance was decreased in follicles (P < 0.05) of 7,12-dimethylbenz[a]anthracene-exposed obese mice. In contrast, increased (P < 0.05) superoxide dismutase was observed in the corpora lutea of 7,12-dimethylbenz[a]anthracene-exposed obese mice and reduced (P < 0.05) TRP53 abundance was noted in preantral and antral follicles of 7,12-dimethylbenz[a]anthracene-exposed obese mice. This study indicates that obesity influences ovotoxicity caused by a genotoxicant, potentially involving accelerated primordial follicle activation and hampering normal follicular dynamics.