RESUMO
BACKGROUND: The pericoronary fat attenuation index (FAI) has emerged as a novel and sensitive biomarker reflecting the degree of coronary artery inflammation. Semaglutide has been demonstrated to exert a cardiovascular protective effect independent of hypoglycemia; however, its impact on coronary artery inflammation remains elusive. This study aimed to investigate the association between semaglutide treatment and coronary artery inflammation based on FAI in patients with type 2 diabetes mellitus (T2DM). METHODS: This study enrolled 497 T2DM patients who underwent coronary computed tomography angiography (CCTA) at Hebei General Hospital, of whom 93 treated with semaglutide (Sema+) and 404 did not (Sema-). Clinical data, laboratory indicators, and CCTA parameters were collected and compared between the two groups at baseline. Propensity score matching (PSM) was used to adjust for confounders, and pericoronary FAI was compared. Multivariate linear regression models were used to analyze the association between semaglutide treatment and pericoronary FAI. RESULTS: Before PSM, pericoronary FAI of the LAD and LCX was lower in patients treated with semaglutide than those without semaglutide treatment. The results of the PSM analysis revealed a lower FAI in all three major coronary arteries in the Sema + group compared to the Sema- group. Multivariate linear regression analyses revealed an independent association between semaglutide treatment and reduced FAI in all three major coronary arteries. This association varied across T2DM patients of differing profiles. CONCLUSION: Semaglutide treatment may be associated with lower coronary artery inflammation in patients with T2DM, which might partially explain its cardiovascular protective mechanism.
Assuntos
Angiografia Coronária , Doença da Artéria Coronariana , Diabetes Mellitus Tipo 2 , Peptídeos Semelhantes ao Glucagon , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Idoso , Resultado do Tratamento , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Angiografia por Tomografia Computadorizada , Adiposidade/efeitos dos fármacos , China/epidemiologia , Medição de Risco , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo EpicárdicoRESUMO
BACKGROUND/OBJECTIVES: Capsinoids are potential antioxidant agents capable of reducing oxidative damage and the resulting complications triggered by obesity. Thus, this study aimed to investigate the effects of capsinoids on adiposity and biomarkers of cardiac oxidative stress in obese rats induced by a high-fat diet. METHODS: Male Wistar rats were exposed to a high-fat diet for 27 consecutive weeks. After the characterization of obesity (week 19), some of the obese animals began to receive capsinoids (10 mg/kg/day) by orogastric gavage. Adiposity and comorbidities were assessed. In the heart, remodeling, injury, and biomarkers of oxidative stress were determined. RESULTS: The treatment did not reduce obesity-induced adiposity but was efficient in reducing cholesterol levels. Capsinoid treatment did not cause a difference in heart and LV mass, despite having reduced troponin I concentrations. Furthermore, capsinoids did not reduce the increase in the advanced oxidation of protein products and carbonylated proteins caused by obesity in cardiac tissue. In addition, obese rats treated with capsinoids presented high levels of malondialdehyde and greater antioxidant enzyme activity compared to untreated obese rats. CONCLUSIONS: In conclusion, treatment with capsinoids increases antioxidative enzyme activity and prevents obesity-induced cardiac injury without positively modulating body fat accumulation and cardiac oxidative biomarkers.
Assuntos
Adiposidade , Antioxidantes , Biomarcadores , Dieta Hiperlipídica , Obesidade , Estresse Oxidativo , Ratos Wistar , Animais , Masculino , Obesidade/complicações , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Biomarcadores/sangue , Biomarcadores/metabolismo , Antioxidantes/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ratos , Adiposidade/efeitos dos fármacos , Miocárdio/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Extratos Vegetais/farmacologia , Traumatismos Cardíacos/prevenção & controle , Traumatismos Cardíacos/metabolismo , Traumatismos Cardíacos/etiologia , Malondialdeído/metabolismoRESUMO
Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain (fourth ventricular [4V]) administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT, a surrogate measure of increased EE) in DIO mice. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to increase TIBAT and elicit weight loss in DIO mice. We first determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1-, 6- and 7-weeks post-denervation by 95.9 ± 2.0, 77.4 ± 12.7 and 93.6 ± 4.6% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas or liver. We subsequently measured the effects of acute 4V OT (1, 5 µg ≈ 0.99, 4.96 nmol) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) elevated TIBAT similarly in sham mice as in denervated mice. We subsequently measured the effects of chronic 4V OT (16 nmol/day over 29 days) or vehicle infusions on body weight, adiposity and food intake in DIO mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.7 ± 2.23% and 6.6 ± 1.4% in sham and denervated mice (P<0.05), respectively, and this effect was similar between groups (P=NS). OT produced corresponding reductions in whole body fat mass (P<0.05). Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and reductions of body weight and adiposity in male DIO mice.
Assuntos
Tecido Adiposo Marrom , Adiposidade , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Ocitocina , Sistema Nervoso Simpático , Animais , Ocitocina/farmacologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/inervação , Masculino , Camundongos , Obesidade/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Adiposidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Camundongos Obesos , Metabolismo Energético/efeitos dos fármacos , Norepinefrina/metabolismoRESUMO
Tributyltin (TBT) is an organotin compound that has several adverse health effects, including the development of obesity. Although obesity is strongly associated with adipose redox imbalance, there is a lack of information on whether TBT promotes a pro-oxidative environment in WAT. Thus, adult male Wistar rats were randomly exposed to either vehicle (ethanol 0.4%) or TBT (1000 ng/kg) for 30 days. Body and fat pad masses, visceral fat morphology, lipid peroxidation, protein carbonylation, redox status markers, and catalase activity were evaluated. TBT promoted increased adiposity and visceral fat, with hypertrophic adipocytes, but did not alter body mass and subcutaneous fat. ROS production and lipid peroxidation were elevated in TBT group, as well as catalase protein expression and activity, although protein oxidation and glutathione peroxidase protein expression remained unchanged. In conclusion, this is the first study to demonstrate that subacute TBT administration leads to visceral adipose redox imbalance, with increased oxidative stress. This enlights the understanding of the metabolic toxic outcomes of continuous exposure to TBT in mammals.
Assuntos
Adiposidade , Catalase , Gordura Intra-Abdominal , Peroxidação de Lipídeos , Oxirredução , Estresse Oxidativo , Ratos Wistar , Compostos de Trialquitina , Animais , Masculino , Compostos de Trialquitina/toxicidade , Oxirredução/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Adiposidade/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Catalase/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Carbonilação Proteica/efeitos dos fármacos , Glutationa Peroxidase/metabolismoRESUMO
The current study aimed to determine whether Strongylocentrotus intermedius (S. intermedius) extract (SIE) exerts anti-obesity potentials employing 3T3-L1 cells as in vitro model. Herein we reported that treatment of SIE for 6 days reduced lipid accretion and triglyceride content whereas it increased the release of free glycerol. The inhibited lipid accumulation and induced lipolysis were evidenced by the downregulation of lipogenesis proteins, such as fatty acid synthase and lipoprotein lipase, and the upregulation of hormone-sensitive lipase expression. Furthermore, the downregulation of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α, and sterol regulatory element-binding protein 1, highlights that reduced lipid accumulation is supported by lowering adipocyte differentiation. Additionally, treatment activates brown adipocyte phenotype in 3T3-L1 cells by inducing expression of brown adipose tissue-specific proteins, such as uncoupling protein 1 and peroxisome proliferator-activated receptor-γ coactivator 1α. Moreover, SIE induced the phosphorylation of AMP-activated protein kinase (AMPK). The pharmacological approach using AMPK inhibitor revealed that the restraining effect of SIE on adipogenesis and promotion of adipocyte browning were blocked. In GC-MS analysis, SIE was mainly composed of cholest-5-en-3-ol (36.71%) along with saturated and unsaturated fatty acids which have favorable anti-obesity potentials. These results reveal that SIE has the possibility as a lipid-lowering agent for the intervention of obesity.
Assuntos
Células 3T3-L1 , Proteínas Quinases Ativadas por AMP , Adipogenia , Animais , Adipogenia/efeitos dos fármacos , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Lipólise/efeitos dos fármacos , PPAR gama/metabolismo , PPAR gama/genética , Adiposidade/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Adipócitos Marrons/efeitos dos fármacos , Adipócitos Marrons/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Triglicerídeos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacosRESUMO
Research on antidepressant-related weight changes over more than 12 months is scarce and adjustment for the effects of depressive episodes has rarely been applied. Accordingly, our aim was to assess the associations of the use of any antidepressants, subclasses of antidepressant and specific compounds prior to baseline and during a 5.5-year follow-up with changes in adiposity markers, and the effect of sex on these associations, with adjustment for multiple confounders including the effects of depressive episodes and their severity. Data stemmed from a prospective cohort study including 2479 randomly selected 35-66 year-old residents of an urban area (mean age 49.9 years, 53.3% women) who underwent physical and psychiatric evaluations at baseline and follow-up. Weight, height, waist circumference, and body fat were measured by trained nurses and information on diagnosis and antidepressant use prior to baseline and during follow-up was collected through standardized interviews. In the fully adjusted models, the number of antidepressants, mainly SSRIs and TCAs, used prior to baseline, was associated with a lower increase of body-mass index (BMI, ß (95%CI) = -0.12 (-0.19, -0.05)) and waist circumference (ß = -0.28 (-0.56, -0.01)), whereas participants treated with antidepressants during the follow-up had a steeper increase in BMI (ß = 0.32 (0.13, 0.50)) and waist circumference (ß = 1.23 (0.44, 2.01)). Within the class of SSRIs, the use of fluoxetine, sertraline or escitalopram during follow-up was associated with a steeper increase in adiposity markers. The associations of SSRIs with BMI and waist circumference were only observed when the SSRIs were used during the second period of the follow-up. Sex did not moderate these associations. Our findings suggest an increase of adiposity markers during sustained treatment with TCAs and SSRIs, which however return to normal levels after cessation of treatment. Hence, the benefit of long-term administration of these antidepressants should be carefully weighed against the potential risk of weight gain.
Assuntos
Adiposidade , Antidepressivos , Índice de Massa Corporal , Circunferência da Cintura , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adiposidade/efeitos dos fármacos , Antidepressivos/uso terapêutico , Adulto , Idoso , Estudos Prospectivos , Seguimentos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Many women have sought alternative therapies to address menopause. Recently, a multi-ingredient supplement (MIS) containing L-histidine, L-carnosine, L-serine, and L-cysteine has been shown to be effective at ameliorating hepatic steatosis (HS) in ovariectomized (OVX) rats, a postmenopausal oestrogen deficiency model. Considering that HS frequently accompanies obesity, which often occurs during menopause, we aimed to investigate the effects of this MIS for 8 weeks in OVX rats. Twenty OVX rats were orally supplemented with either MIS (OVX-MIS) or vehicle (OVX). Ten OVX rats received vehicle orally along with subcutaneous injections of 17ß-oestradiol (OVX-E2), whereas 10 rats underwent a sham operation and received oral and injected vehicles (control group). MIS consumption partly counteracted the fat mass accretion observed in OVX animals, leading to decreased total fat mass, adiposity index and retroperitoneal white adipose tissue (RWAT) adipocyte hypertrophy. OVX-MIS rats also displayed increased lean mass and lean/fat ratio, suggesting a healthier body composition, similar to the results reported for OVX-E2 animals. MIS consumption decreased the circulating levels of the proinflammatory marker CRP, the total cholesterol-to-HDL-cholesterol ratio and the leptin-to-adiponectin ratio, a biomarker of diabetes risk and metabolic syndrome. RWAT transcriptomics indicated that MIS favourably regulated genes involved in adipocyte structure and morphology, cell fate determination and differentiation, glucose/insulin homeostasis, inflammation, response to stress and oxidative phosphorylation, which may be mechanisms underlying the beneficial effects described for OVX-MIS rats. Our results pave the way for using this MIS formulation to improve the body composition and immunometabolic health of menopausal women.
Assuntos
Tecido Adiposo , Adiposidade , Carnosina , Cisteína , Histidina , Ovariectomia , Serina , Animais , Feminino , Adiposidade/efeitos dos fármacos , Carnosina/farmacologia , Histidina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Ratos , Cisteína/farmacologia , Serina/farmacologia , Serina/metabolismo , Ratos Wistar , Suplementos NutricionaisRESUMO
Romosozumab, a humanized monoclonal antibody that binds and inhibits sclerostin, produces a marked increase in bone formation with a concomitant decreased bone resorption. This transient rise in bone formation in the first 2 months of treatment is mainly due to an increased modeling-based bone formation. This requires the recruitment and differentiation of osteoblasts, one possibility being a preferential switch in commitment of precursors to osteoblasts over adipocytes. The purpose of this study was to analyze the marrow adiposity in transiliac bone biopsies at months 2 or 12 from the FRAME biopsy sub-study in patients receiving romosozumab or placebo. The total adipocyte area, number, and density were measured on the total cancellous bone area. The size and shape at the individual adipocyte level were assessed including the mean adipocyte area, perimeter, min and max diameters, and aspect ratio. No significant difference in total adipocyte area, number, or density between placebo and romosozumab groups was observed at months 2 and 12, and no difference was observed between 2 and 12 months. After 2 or 12 months, romosozumab did not modify the size or shape of the adipocytes. No relationship between the adipocyte parameters and the dynamic parameters of bone formation could be evidenced. In conclusion, based on the analysis of a small number of biopsies, no effect of romosozumab on bone marrow adiposity of iliac crest was identified after 2 and 12 months suggesting that the modeling-based formation observed at month 2 was not due to a preferential commitment of the precursor to osteoblast over adipocyte cell lines but may result from a reactivation of bone lining cells and from a progenitor pool independent of the marrow adipocyte population.
Osteoporosis is characterized by bone loss resulting from an imbalance between the bone resorption and the bone formation in favor of the resorption. Romosozumab, a new medication to treat osteoporosis, has been shown to induce an early transient increase in bone formation that requires the differentiation of new bone forming cells called osteoblasts. Osteoblasts and fat-containing cells known as adipocytes present in the bone marrow originate from a common precursor cell. Thus, a preferential switch of this precursor to osteoblast over adipocyte is thought to be a possible cause for the increase in bone formation. The purpose of this study was to analyze the bone marrow adipocytes on bone biopsies from the pelvis in osteoporotic patients treated with romosozumab in order to evaluate that possibility. After treatment, the proportion of adipocytes, their size and shape, did not change when compared with untreated patients. In conclusion, no effect of romosozumab on bone marrow adipocytes was identified suggesting that the increased bone formation induced by romosozumab was not due to a preferential differentiation of precursor cells to osteoblasts over adipocytes.
Assuntos
Adiposidade , Anticorpos Monoclonais , Medula Óssea , Osteoporose Pós-Menopausa , Humanos , Feminino , Medula Óssea/patologia , Medula Óssea/efeitos dos fármacos , Biópsia , Adiposidade/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Idoso , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/patologia , Pessoa de Meia-Idade , Adipócitos/patologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismoRESUMO
GPR55 is a receptor for lysophosphatidylinositols (LPIs) in digestive metabolites. Overnutrition leads to obesity, insulin resistance, and increased LPI levels in the plasma. The involvement of LPIs and GPR55 in adiposity, hepatic steatosis, and atherosclerosis has been previously elucidated. However, the therapeutic efficacy of GPR55 antagonists against obesity-induced airway inflammation has not been studied. The present study investigated whether CID16020046, a selective antagonist of GPR55, could modulate obesity-induced airway inflammation caused by a high-fat diet (HFD) in C57BL/6 mice. Administration of CID16020046 (1 mg/kg) inhibits HFD-induced adiposity and glucose intolerance. Analysis of immune cells in BALF showed that CID16020046 inhibited HFD-induced increase in immune cell infiltration. Histological analysis revealed the HFD induced hypersecretion of mucus and extensive fibrosis in the lungs. CID16020046 inhibited these HFD-induced pathological features. qRT-PCR revealed the HFD-induced increase in the expression of Ifn-γ, Tnf-α, Il-6, Il-13, Il-17A, Il-1ß, Nlrp3, and Mpo mRNAs in the lungs. CID16020046 inhibited the HFD-induced increases in these genes. The expression levels of adipokines were regulated by the HFD and CID16020046. AdipoQ in the lungs and gonadal white adipose tissue was decreased by the HFD and reversed by CID16020046. In contrast, Lep was increased by the HFD and suppressed by CID16020046. The findings suggest the potential application of the GPR55 antagonist CID16020046 in obesity-induced airway inflammation.
Assuntos
Dieta Hiperlipídica , Pulmão , Camundongos Endogâmicos C57BL , Obesidade , Receptores de Canabinoides , Animais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/complicações , Camundongos , Dieta Hiperlipídica/efeitos adversos , Masculino , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Receptores de Canabinoides/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Adiposidade/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidoresRESUMO
This study addresses the increasing prevalence of obesity, especially among postmenopausal. Estrogen plays a crucial role in regulating adipose tissue in women, with its absence after menopause associated with metabolic complications. The study aimed to determine the lipolytic activity in different adipose tissue depots of ovariectomized rats submitted to a high-fat diet. Also, to analyze the expression of estrogen receptors in adipose tissues and perform histological and morphometric analyzes of these deposits. Female rats were ovariectomized (O) or sham operated (S). The animals were divided into groups: ovariectomized with high-fat diet (OF), sham-operated with high-fat diet (SF), ovariectomized with control diet (OC) or sham-operated with control diet as the control group (SC). After 24 weeks of consuming the diets, rats were killed and adipose tissue deposits were removed. Polymerase chain reaction was performed to analyze the expression of estrogen receptors in adipose tissues, lipolysis assay and histological analysis. Both the high-fat diet and ovariectomy increased body weight and adiposity. There was hypertrophy of adipocytes. Estrogen replacement therapy modulate lipolytic activity in different adipose depots, with different responses in relation to estrogen receptors. Estrogen receptor expression varied between fat depots. Mesenteric adipose tissue showed greater sensitivity to estrogen compared with others. Estrogen increased lipolytic activity in some fat depots, reducing in others. Expression of ERs depends of hormonal status and adipose tissue location, which may explain distinct actions of estrogen on the metabolism of adipose tissue and on the production of adipokines by them.
Assuntos
Tecido Adiposo , Dieta Hiperlipídica , Lipólise , Ovariectomia , Ratos Wistar , Receptores de Estrogênio , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo/metabolismo , Receptores de Estrogênio/metabolismo , Ratos , Peso Corporal , Adiposidade/efeitos dos fármacos , Adipócitos/metabolismo , Estrogênios/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Bisphenols and phthalates are two classes of endocrine-disrupting chemicals (EDCs) thought to influence weight and adiposity. Limited research has investigated their influence on maternal weight changes, and no prior work has examined maternal fat mass. We examined the associations between exposure to these chemicals during pregnancy and multiple maternal weight and fat mass outcomes. METHODS: This study included a sample of 318 women enrolled in a Canadian prospective pregnancy cohort. Second trimester urinary concentrations of 2 bisphenols and 12 phthalate metabolites were quantified. Self-reported and measured maternal weights and measured skinfold thicknesses were used to calculate gestational weight gain, 3-months and 3- to 5-years postpartum weight retention, late pregnancy fat mass gain, total postpartum fat mass loss, and late postpartum fat mass retention. Adjusted robust regressions examined associations between chemicals and outcomes in the entire study population and sub-groups stratified by pre-pregnancy body mass index (BMI). Bayesian kernel machine regression examined chemical mixture effects. RESULTS: Among women with underweight or normal pre-pregnancy BMIs, MBzP was negatively associated with weight retention at 3- to 5-years postpartum (B = -0.04, 95%CI: -0.07, -0.01). Among women with overweight or obese pre-pregnancy BMIs, MEHP and MMP were positively associated with weight retention at 3-months and 3- to 5-years postpartum, respectively (B's = 0.12 to 0.63, 95%CIs: 0.02, 1.07). DEHP metabolites and MCNP were positively associated with late pregnancy fat mass gain and late postpartum fat mass retention (B's = 0.04 to 0.18, 95%CIs: 0.001, 0.32). Further, the mixture of EDCs was positively associated with late pregnancy fat mass gain. CONCLUSION: In this cohort, pre-pregnancy BMI was a key determinant of the associations between second trimester exposure to bisphenols and phthalates and maternal weight changes and fat accumulation. Investigations of underlying physiological mechanisms, windows of susceptibility, and impacts on maternal and infant health are needed.
Assuntos
Compostos Benzidrílicos , Índice de Massa Corporal , Fenóis , Ácidos Ftálicos , Humanos , Feminino , Fenóis/urina , Fenóis/efeitos adversos , Ácidos Ftálicos/urina , Gravidez , Adulto , Compostos Benzidrílicos/urina , Compostos Benzidrílicos/efeitos adversos , Estudos Prospectivos , Exposição Materna/efeitos adversos , Poluentes Ambientais/urina , Disruptores Endócrinos/urina , Adulto Jovem , Adiposidade/efeitos dos fármacos , CanadáRESUMO
Thyroid hormone (TH) plays a crucial role in regulating the functions of both bone and adipose tissue. Given that TH exerts its cholesterol-lowering effects in hepatic tissue through the TH receptor-ß (TRß), we hypothesized that TRß agonist therapy using MGL3196 (MGL) would be effective in treating increased adiposity and bone loss in response to a 12-week high-fat diet (HFD) in adult C57BL/6J mice. Transcriptional and serum profiling revealed that HFD-induced leptin promoted weight gain in both males and females, but MGL only suppressed leptin induction and weight gain in males. In vitro studies suggest that estrogen suppresses MGL activity in adipocytes, indicating that estrogen might interfere with MGL-TRß function. Compared to systemic adiposity, HFD reduced bone mass in male but not female mice. Paradoxically, MGL treatment reversed macroscopic bone mineral density loss in appendicular bones, but micro-CT revealed that MGL exacerbated HFD-induced trabecular bone loss, and reduced bone strength. In studies on the mechanisms for HFD effects on bone, we found that HFD induced Rankl expression in male femurs that was blocked by MGL. By ex vivo assays, we found that RANKL indirectly represses osteoblast lineage allocation of osteoprogenitors by induction of inflammatory cytokines TNFα, IL-1ß, and CCL2. Finally, we found that MGL functions in both systemic adiposity and bone by nongenomic TRß signaling, as HFD-mediated phenotypes were not rescued in TRß147F knockout mice with normal genomic but defective nongenomic TRß signaling. Our findings demonstrate that the negative effects of HFD on body fat and bone phenotypes are impacted by MGL in a gender-specific manner.
Assuntos
Dieta Hiperlipídica , Transdução de Sinais , Receptores beta dos Hormônios Tireóideos , Animais , Feminino , Masculino , Camundongos , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Leptina/metabolismo , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Osteoblastos/efeitos dos fármacos , Ligante RANK/metabolismo , Ligante RANK/genética , Caracteres Sexuais , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Receptores beta dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Aumento de Peso/efeitos dos fármacosRESUMO
Obesity is a complex disease associated with augmented risk of metabolic disorder development and cellular dysfunction in various species. The goal of the present study was to investigate the impacts of obesity on the metabolic health of old mares as well as test the ability of diet supplementation with either a complex blend of nutrients designed to improve equine metabolism and gastrointestinal health or L-carnitine alone to mitigate negative effects of obesity. Mares (n = 19, 17.9 ± 3.7 years) were placed into one of three group: normal-weight (NW, n = 6), obese (OB, n = 7) or obese fed a complex diet supplement for 12 weeks (OBD, n = 6). After 12 weeks and completion of sample collections, OB mares received L-carnitine alone for an additional 6 weeks. Obesity in mares was significantly associated with insulin dysregulation, reduced muscle mitochondrial function, and decreased skeletal muscle oxidative capacity with greater ROS production when compared to NW. Obese mares fed the complex diet supplement had better insulin sensivity, greater cell lipid metabolism, and higher muscle oxidative capacity with reduced ROS production than OB. L-carnitine supplementation alone did not significantly alter insulin signaling, but improved lipid metabolism and muscle oxidative capacity with reduced ROS. In conclusion, obesity is associated with insulin dysregulation and altered skeletal muscle metabolism in older mares. However, dietary interventions are an effective strategy to improve metabolic status and skeletal muscle mitochondrial function in older mares.
Assuntos
Adiposidade , Carnitina , Suplementos Nutricionais , Insulina , Obesidade , Animais , Cavalos , Feminino , Insulina/metabolismo , Insulina/sangue , Carnitina/metabolismo , Carnitina/farmacologia , Obesidade/metabolismo , Obesidade/dietoterapia , Adiposidade/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças dos Cavalos/metabolismo , Doenças dos Cavalos/dietoterapia , Doenças dos Cavalos/etiologia , Resistência à Insulina , Espécies Reativas de Oxigênio/metabolismoRESUMO
Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.
Assuntos
Corticosterona , Dinoprostona , Epinefrina , Fatores de Crescimento de Fibroblastos , Glucagon , Ácidos Linoleicos Conjugados , Camundongos Transgênicos , Animais , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Camundongos , Ácidos Linoleicos Conjugados/farmacologia , Ácidos Linoleicos Conjugados/metabolismo , Corticosterona/metabolismo , Dinoprostona/metabolismo , Glucagon/metabolismo , Epinefrina/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética , Masculino , Metabolismo dos Lipídeos/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Fígado Gorduroso/genética , Lipólise/efeitos dos fármacos , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/genética , Adiposidade/efeitos dos fármacosRESUMO
OBJECTIVE.: Motivation for the study. Most research supports a negative association between metabolic syndrome and bone health, although there is an overall lack of consensus. Therefore, there is a need for research in this area to develop a better understanding. Main findings. Metabolic syndrome induced by a fructose-rich diet increases the adipogenic predisposition of bone marrow progenitor cells and femoral medullary adiposity in rats. Furthermore, this can be partially prevented by co-treatment with metformin. Implications. Experimental metabolic syndrome has negative effects on bone tissue and can be prevented by oral treatment with metformin as a normoglycemic drug. To determine the effect of metformin (MET) treatment on adipogenic predisposition of bone marrow progenitor cells (BMPC), bone marrow adiposity and bone biomechanical properties. MATERIALS AND METHODS.: 20 young adult male Wistar rats were sorted into four groups. Each of the groups received the following in drinking water: 100% water (C); 20% fructose (F); metformin 100 mg/kg wt/day (M); or fructose plus metformin (FM). After five weeks the animals were sacrificed. Both humeri were dissected to obtain BMPC, and both femurs were dissected to evaluate medullary adiposity (histomorphometry) and biomechanical properties (3-point bending). BMPC were cultured in vitro in adipogenic medium to evaluate RUNX2, PPAR-γ and RAGE expression by RT-PCR, lipase activity and triglyceride accumulation. RESULTS.: The fructose-rich diet (group F) caused an increase in both triglycerides in vitro, and medullary adiposity in vivo; being partially or totally prevented by co-treatment with metformin (group FM). No differences were found in femoral biomechanical tests in vivo, nor in lipase activity and RUNX2/PPAR-γ ratio in vitro. DRF increased RAGE expression in BMPC, being prevented by co-treatment with MET. CONCLUSIONS.: Metabolic syndrome induced by a fructose-rich diet increases femoral medullary adiposity and, in part, the adipogenic predisposition of BMPC. In turn, this can be totally or partially prevented by oral co-treatment with MET.
OBJETIVO.: Motivación para realizar el estudio. La mayoría de las investigaciones respaldan una asociación negativa entre el síndrome metabólico y la salud ósea, aunque existe una falta de consenso general. Por lo tanto, es necesario realizar investigaciones en esta área que permitan desarrollar un mejor conocimiento. Principales hallazgos. El síndrome metabólico inducido por una dieta rica en fructosa incrementa la predisposición adipogénica de células progenitoras de médula ósea y la adiposidad medular femoral en ratas. Además, esto puede prevenirse parcialmente mediante un co-tratamiento con metformina. Implicancias. El síndrome metabólico experimental posee efectos negativos sobre el tejido óseo, pudiendo ser prevenidos mediante un tratamiento oral de metformina como fármaco normoglucemiante. Determinar el efecto de un tratamiento con metformina (MET) sobre la predisposición adipogénica de células progenitoras de médula ósea (CPMO), adiposidad de la médula ósea y propiedades biomecánicas óseas. MATERIALES Y MÉTODOS.: 20 ratas Wistar machos adultos jóvenes fueron separados en cuatro grupos, recibiendo en agua de bebida: 100% agua (C); 20% de fructosa (F); metformina 100 mg/kg peso/día (M); o fructosa más metformina (FM). Tras cinco semanas se sacrificaron los animales, se diseccionaron ambos húmeros para obtener CPMO, y ambos fémures para evaluar adiposidad medular (histomorfometría) y propiedades biomecánicas (flexión a 3 puntos). Las CPMO se cultivaron in vitro en medio adipogénico para evaluar expresión de RUNX2, PPAR-γ y RAGE por RT-PCR, actividad de lipasa y acumulación de triglicéridos. RESULTADOS.: La dieta rica en fructosa (grupo F) produjo un aumento tanto de triglicéridos in vitro, como de la adiposidad medular in vivo; siendo parcial o totalmente prevenido por un co-tratamiento con metformina (grupo FM). No se observaron diferencias en las pruebas biomecánicas femorales in vivo, ni en actividad de lipasa y relación RUNX2/PPAR-γ in vitro. La DRF aumentó la expresión de RAGE en CPMO, siendo prevenido por co-tratamiento con MET. CONCLUSIONES.: El síndrome metabólico inducido por una dieta rica en fructosa aumenta la adiposidad medular femoral y, en parte, la predisposición adipogénica de las CPMO. A su vez, esto puede ser prevenido total o parcialmente por un co-tratamiento oral con MET.
Assuntos
Adiposidade , Fêmur , Síndrome Metabólica , Metformina , Ratos Wistar , Animais , Metformina/farmacologia , Síndrome Metabólica/etiologia , Masculino , Ratos , Adiposidade/efeitos dos fármacos , Fêmur/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Hipoglicemiantes/farmacologiaRESUMO
Hyperlipidemia-induced osteoporosis is marked by increased bone marrow adiposity, and treatment with statins for hyperlipidemia often leads to new-onset osteoporosis. Endosome-associated trafficking regulator 1 (ENTR1) has been found to interact with different proteins in pathophysiology, but its exact role in adipogenesis is not yet understood. This research aimed to explore the role of ENTR1 in adipogenesis and to discover a new small molecule that targets ENTR1 for evaluating its effectiveness in treating hyperlipidemia-induced osteoporosis. We found that ENTR1 expression increased during the adipogenesis of bone marrow mesenchymal cells (BMSCs). ENTR1 gain- and loss-of-function assays significantly enhanced lipid droplets formation. Mechanistically, ENTR1 binds peroxisome proliferator-activated receptor γ (PPARγ) and enhances its expression, thereby elevating adipogenic markers including C/EBPα and LDLR. Therapeutically, AN698/40746067 attenuated adipogenesis by targeting ENTR1 to suppress PPARγ. In vivo, AN698/40746067 reduced bone marrow adiposity and bone loss, as well as prevented lipogenesis-related obesity, inflammation, steatohepatitis, and abnormal serum lipid levels during hyperlipidemia. Together, these findings suggest that ENTR1 facilitates adipogenesis by PPARγ involved in BMSCs' differentiation, and targeted inhibition of ENTR1 by AN698/40746067 may offer a promising therapy for addressing lipogenesis-related challenges and alleviating osteoporosis following hyperlipidemia.
Assuntos
Adipogenia , Medula Óssea , Hiperlipidemias , Células-Tronco Mesenquimais , Osteoporose , PPAR gama , Animais , Masculino , Camundongos , Adipogenia/efeitos dos fármacos , Adiposidade/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/efeitos dos fármacos , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos Endogâmicos C57BL , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/etiologia , Osteoporose/prevenção & controle , PPAR gama/metabolismoRESUMO
In recent years many women have looked for alternative therapies to address menopause. Hesperidin, phytosterols and curcumin are bioactive compounds that can ameliorate some cardiovascular risk factors associated with menopause, although there are no data concerning the effects of their combined supplementation. We used ovariectomized (OVX) rats, a postmenopausal model with oestrogen deficiency, to evaluate whether supplementation with a multi-ingredient (MI) including hesperidin, phytosterols and curcumin for 57 days would display beneficial effects against fat mass accretion and metabolic disturbances associated with menopause. Twenty OVX rats were orally supplemented with either MI (OVX-MI) or vehicle (OVX). Furthermore, 10 OVX rats orally received the vehicle along with subcutaneous injections of 17ß-oestradiol biweekly (OVX-E2), whereas 10 rats were sham operated and received oral and injected vehicles (control group; SH). MI supplementation partly counteracted the fat mass accretion observed in OVX animals, which was evidenced by decreased total fat mass, adiposity index, the weight of retroperitoneal, inguinal and mesenteric white adipose tissue (MWAT) depots and MWAT adipocyte hypertrophy. These effects were accompanied by a significant decrease in the circulating levels of leptin and the mRNA levels of the fatty acid uptake-related genes Lpl and Cd36 in MWAT. These results were very similar to those observed in OVX-E2 animals. OVX-MI rats also displayed a higher lean body mass, lean/fat mass ratio, adiponectin-to-leptin ratio and insulin sensitivity than their OVX counterparts. Our findings can pave the way for using this MI formulation as an alternative therapy to manage obesity and to improve the cardiometabolic health of menopausal women.
Assuntos
Adiposidade , Curcumina , Suplementos Nutricionais , Hesperidina , Ovariectomia , Fitosteróis , Animais , Feminino , Hesperidina/farmacologia , Hesperidina/administração & dosagem , Fitosteróis/farmacologia , Fitosteróis/administração & dosagem , Ratos , Curcumina/farmacologia , Curcumina/administração & dosagem , Adiposidade/efeitos dos fármacos , Leptina/sangue , Ratos Sprague-Dawley , Humanos , Ratos WistarRESUMO
BACKGROUND: Glucocorticoids and sclerostin act as inhibitors of the Wnt signaling pathway, thereby hindering bone formation. Given the pathway's intricate association with mesenchymal stem cells, the hypothesis suggests that heightened sclerostin levels may be intricately linked to an augmentation in marrow adiposity induced by glucocorticoids. This study endeavored to delve into the nuanced relationship between circulating sclerostin and bone marrow adipose tissue in postmenopausal women grappling with glucocorticoid-induced osteoporosis (GIO). METHODS: In this cross-sectional study, 103 patients with autoimmune-associated diseases underwent glucocorticoid treatment, boasting an average age of 61.3 years (standard deviation 7.1 years). The investigation encompassed a thorough assessment, incorporating medical history, anthropometric data, biochemical analysis, and dual-energy X-ray absorptiometry measurements of lumbar and femoral bone mineral density (BMD). Osteoporosis criteria were established at a T-score of -2.5 or lower. Additionally, MR spectroscopy quantified the vertebral marrow fat fraction. RESULTS: BMD at the femoral neck, total hip, and lumbar spine showcased an inverse correlation with marrow fat fraction (r = -0.511 to - 0.647, P < 0.001). Serum sclerostin levels exhibited a positive correlation with BMD at various skeletal sites (r = 0.476 to 0.589, P < 0.001). A noteworthy correlation emerged between circulating sclerostin and marrow fat fraction at the lumbar spine (r = -0.731, 95% CI, -0.810 to -0.627, P < 0.001). Multivariate analysis brought to light that vertebral marrow fat fraction significantly contributed to sclerostin serum concentrations (standardized regression coefficient ß = 0.462, P < 0.001). Even after adjusting for age, body mass index, physical activity, renal function, BMD, and the duration and doses of glucocorticoid treatment, serum sclerostin levels maintained a significant correlation with marrow fat fraction. CONCLUSIONS: Circulating sclerostin levels exhibited a noteworthy association with marrow adiposity in postmenopausal women grappling with GIO.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Adiposidade , Densidade Óssea , Medula Óssea , Glucocorticoides , Pós-Menopausa , Humanos , Feminino , Pessoa de Meia-Idade , Glucocorticoides/efeitos adversos , Estudos Transversais , Adiposidade/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Idoso , Marcadores Genéticos , Biomarcadores/sangue , Biomarcadores/análise , Osteoporose Pós-Menopausa/sangue , Absorciometria de FótonRESUMO
Obese asthma is recognized to have different asthma phenotypes. N-3 polyunsaturated fatty acids (PUFAs) have shown beneficial effects in obesity and metabolic syndrome. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFAs. In the present study, we investigated whether FFA4 activation ameliorates high-fat diet (HFD)-induced obese asthma. We investigated whether FFA4 activation ameliorates obese asthma using an FFA4 agonist, compound A (CpdA), in combination with FFA4 wild-type (WT) and knock-out (KO) mice. Administration of an FFA4 agonist, compound A (CpdA, 30â¯mg/kg), suppressed HFD-induced weight gain, adiposity, and airway hypersensitivity (AHR), and increased immune cell infiltration in an FFA4-dependent manner. Histological analysis revealed that CpdA treatment suppressed HFD-induced mucus hypersecretion, inflammation, and fibrosis in an FFA4-dependent manner. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed an HFD-induced increase in the mRNA levels of pro-inflammatory cytokines in the lungs and gonadal white adipose tissue, whereas CpdA inhibited this increase in an FFA4-dependent manner. In the fluorescence-activated cell sorting (FACS) analysis, HFD induced an increase in the lung innate lymphoid cells (ILC) ILC1, ILC2, and ILC3; however, CpdA reversed this increase. In addition, HFD induced an increase in the pro-inflammatory M1 macrophage population and a decrease in the anti-inflammatory M2 macrophage population in the lungs, whereas CpdA treatment reversed these changes. The present study suggests that FFA4 activation may have therapeutic potential in obese asthma.
Assuntos
Adiposidade , Asma , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade , Receptores Acoplados a Proteínas G , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Adiposidade/efeitos dos fármacos , Obesidade/tratamento farmacológico , Obesidade/complicações , Obesidade/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Masculino , Camundongos , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Citocinas/metabolismoRESUMO
AIM: This systematic review and meta-analysis aimed to comprehensively evaluate the impact of glucagon-like peptide 1 receptor agonists (GLP-1RAs) on visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in individuals with diabetes mellitus and non-alcoholic fatty liver disease (NAFLD) or obesity. METHODS: A search of PubMed, Embase, and Web of Science until October 2023 identified 13 Randomized Controlled Trials (RCTs) meeting the inclusion criteria. Bias risk was assessed using the Cochrane risk-of-bias instrument. Statistical analysis utilized standard mean differences (SMD) in Review Manager 5.4. Heterogeneity and publication bias were assessed. This study used the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY2023110020). RESULTS: GLP-1RA treatment significantly reduced VAT (SMD -0.55, 95 % CI [-0.90, -0.19]), SAT (SMD -0.59, 95 % CI [-0.99, -0.19]), body weight (SMD -1.07, 95 % CI [-1.67, -0.47]), and body mass index (BMI) (SMD -1.10, 95 % CI [-1.74, -0.47]) compared to controls. Heterogeneity was observed for VAT (I2 = 79 %, P < 0.01), SAT (I2 = 73 %, P < 0.01), body weight (I2 = 82 %, P < 0.01), and BMI (I2 = 82 %, P < 0.01). No publication bias was detected for VAT (P = 0.57) and SAT (P = 0.18). GLP-1RA treatment improved fasting blood glucose (FBG), postprandial glucose (PPG), hemoglobin A1c (HbA1c), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), and fibrosis-4 (FIB-4). CONCLUSIONS: This meta-analysis highlights GLP-1RAs' potential to reduce fat accumulation, body weight, and BMI and improve glycemic control in individuals with diabetes mellitus and NAFLD or obesity. These findings supported using GLP-1RAs as promising therapeutic agents to address abnormal adipose tissue distribution and metabolic dysfunction.