RESUMO
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.
Assuntos
Síndrome Metabólica , Humanos , Camundongos , Animais , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Epigenômica , Projetos Piloto , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Dieta Hiperlipídica/efeitos adversos , Epigênese GenéticaRESUMO
BACKGROUND: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. METHODS: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit ß5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit ß1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. RESULTS: ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. CONCLUSIONS: We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.
Assuntos
Tecido Adiposo Branco , Aterosclerose , Modelos Animais de Doenças , Síndrome Metabólica , Camundongos Endogâmicos C57BL , Complexo de Endopeptidases do Proteassoma , Receptores de LDL , Animais , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Aterosclerose/genética , Aterosclerose/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/imunologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Receptores de LDL/genética , Receptores de LDL/deficiência , Complexo de Endopeptidases do Proteassoma/metabolismo , Masculino , Inibidores de Proteassoma/farmacologia , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Doenças da Aorta/prevenção & controle , Doenças da Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/enzimologia , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/imunologia , Placa Aterosclerótica , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos Knockout para ApoE , Camundongos , Metabolismo Energético/efeitos dos fármacos , OligopeptídeosRESUMO
Metabolic syndrome (MetS) has a large clinical population nowadays, usually due to excessive energy intake and lack of exercise. During MetS, excess nutrients stress the mitochondria, resulting in relative hypoxia in tissues and organs, even when blood supply is not interrupted or reduced, making mitochondrial dysfunction a central pathogenesis of cardiovascular disease in the MetS. Sodium-glucose cotransporter 2 inhibitors were designed as a hyperglycemic drug that acts on the renal tubules to block sugar reabsorption in primary urine. Recently they have been shown to have anti-inflammatory and other protective effects on cardiomyocytes in MetS, and have also been recommended in the latest heart failure guidelines as a routine therapy. Among these inhibitors, empagliflozin shows better clinical promise due to less influence from glomerular filtration rate. This review focuses on the mitochondrial mechanisms of empagliflozin, which underlie the anti-inflammatory and recover cellular functions in MetS cardiomyocytes, including stabilizing calcium concentration, mediating metabolic reprogramming, maintaining homeostasis of mitochondrial quantity and quality, stable mitochondrial DNA copy number, and repairing damaged mitochondrial DNA.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Síndrome Metabólica , Miócitos Cardíacos , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Humanos , Compostos Benzidrílicos/farmacologia , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Cálcio/metabolismo , Homeostase , Variações do Número de Cópias de DNARESUMO
Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, ß, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.
Assuntos
Resistência à Insulina , Síndrome Metabólica , Camundongos , Animais , Síndrome Metabólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Metabolismo Energético , Receptores Citoplasmáticos e Nucleares , Receptor ERRalfa Relacionado ao Estrogênio , EstrogêniosRESUMO
Cannabidiol (CBD) use has grown exponentially more popular in the last two decades, particularly among older adults (>55 yr), though very little is known about the effects of CBD use during age-associated metabolic dysfunction. In addition, synthetic analogues of CBD have generated great interest because they can offer a chemically pure product, which is free of plant-associated contaminants. To assess the effects of a synthetic analogue of CBD (H4CBD) on advanced metabolic dysfunction, a cohort of 41-wk-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were administered 200 mg H4CBD/kg by oral gavage for 4 wk. Animals were fed ad libitum and monitored alongside vehicle-treated OLETF and Long-Evans Tokushima Otsuka (LETO) rats, the lean-strain controls. An oral glucose-tolerance test (oGTT) was performed after 4 wk of treatment. When compared with vehicle-treated, OLETF rats, H4CBD decreased body mass (BM) by 15%, which was attributed to a significant loss in abdominal fat. H4CBD reduced glucose response (AUCglucose) by 29% (P < 0.001) and insulin resistance index (IRI) by 25% (P < 0.05) compared with OLETF rats. However, H4CBD did not statically reduce fasting blood glucose or plasma insulin, despite compensatory increases in skeletal muscle native insulin receptor (IR) protein expression (54%; P < 0.05). H4CBD reduced circulating adiponectin (40%; P < 0.05) and leptin (47%; P < 0.05) and increased ghrelin (75%; P < 0.01) compared with OLETF. Taken together, a chronic, high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of the profound loss of visceral adiposity.NEW & NOTEWORTHY Cannabis product use has grown in the last two decades despite the lack of research on Cannabidiol (CBD)-mediated effects on metabolism. Here, we provide seminal data on CBD effects during age-associated metabolic dysfunction. We gave 41-wk-old OLETF rats 200 mg H4CBD/kg by mouth for 4 wk and noted a high dose of H4CBD may improve glucose response, independent of static changes in insulin signaling, and these effects are likely a benefit of loss of visceral adiposity.
Assuntos
Canabidiol , Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Humanos , Ratos , Animais , Idoso , Ratos Endogâmicos OLETF , Síndrome Metabólica/tratamento farmacológico , Insulina , Glucose , Canabidiol/farmacologia , Ratos Long-Evans , Diabetes Mellitus Tipo 2/metabolismo , Glicemia/metabolismoRESUMO
BACKGROUND: Metabolic syndrome is characterized as the co-occurrence of interrelated cardiovascular risk factors, including insulin resistance, hyperinsulinemia, abdominal obesity, dyslipidemia and hypertension. Once weekly tirzepatide is approved in the US and EU for the treatment of type 2 diabetes (T2D) and obesity. In the SURPASS clinical trial program for T2D, tirzepatide demonstrated greater improvements in glycemic control, body weight reduction and other cardiometabolic risk factors versus placebo, subcutaneous semaglutide 1 mg, insulin degludec, and insulin glargine. This post hoc analysis assessed the effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome across SURPASS 1-5. METHODS: Metabolic syndrome was defined as having ≥ 3 of 5 criteria according to the US National Cholesterol Education Program: Adult Treatment Panel III. Analyses were based on on-treatment data at the primary endpoint from patients adherent to treatment (taking ≥ 75% study drug). A logistic regression model with metabolic syndrome status as the response variable, metabolic syndrome status at the baseline visit as an adjustment, and randomized treatment as fixed explanatory effect was used. The effect of tirzepatide use on the prevalence of patients meeting the criteria for metabolic syndrome by categorical weight loss, background medication and gender were assessed. RESULTS: In SURPASS, the prevalence of patients meeting the criteria for metabolic syndrome at baseline was 67-88% across treatment groups with reductions at the primary endpoint to 38-64% with tirzepatide versus 64-82% with comparators. Reductions in the prevalence of patients meeting the criteria for metabolic syndrome was significantly greater with all tirzepatide doses versus placebo, semaglutide 1 mg, insulin glargine, and insulin degludec (p < 0.001). Individual components of metabolic syndrome were also reduced to a greater extent with tirzepatide vs comparators. Greater reductions in body weight were associated with greater reductions in the prevalence of patients meeting the criteria for metabolic syndrome and its individual components. Background SGLT2i or sulfonylurea use or gender did not impact the change in prevalence of patients meeting the criteria for metabolic syndrome. CONCLUSIONS: In this post hoc analysis, tirzepatide at all doses studied was associated with a greater reduction in the prevalence of patients meeting the criteria for metabolic syndrome compared to placebo, semaglutide 1 mg, insulin degludec, and insulin glargine. Although more evidence is needed, these data would support greater potential improvement in cardiovascular risk factor profile with tirzepatide treatment in people across the continuum of T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 2 , Síndrome Metabólica , Adulto , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Prevalência , Insulina Glargina , Polipeptídeo Inibidor Gástrico , Obesidade , Peso Corporal , Hipoglicemiantes/efeitos adversosRESUMO
Metabolic syndrome (MetS) is largely coupled with chronic kidney disease (CKD). Glycogen synthase kinase-3ß (GSK-3ß) pathway drives tubular injury in animal models of acute kidney injury; but its contribution in CKD is still elusive. This study investigated the effect empagliflozin and/or pirfenidone against MetS-induced kidney dysfunction, and to clarify additional underpinning mechanisms particularly the GSK-3ß signaling pathway. Adult male rats received 10%w/v fructose in drinking water for 20 weeks to develop MetS, then treated with either drug vehicle, empagliflozin (30 mg/kg/day) and/or pirfenidone (100 mg/kg/day) via oral gavage for subsequent 4 weeks, concurrently with the high dietary fructose. Age-matched rats receiving normal drinking water were used as controls. After 24 weeks, blood and kidneys were harvested for subsequent analyses. Rats with MetS showed signs of kidney dysfunction, structural changes and interstitial fibrosis. Activation of GSK-3ß, decreased cyclinD1 expression and enhanced apoptotic signaling were found in kidneys of MetS rats. There was abundant alpha-smooth muscle actin (α-SMA) expression along with up-regulation of TGF-ß1/Smad3 in kidneys of MetS rats. These derangements were almost alleviated by empagliflozin or pirfenidone, with evidence that the combined therapy was more effective than either individual drug. This study emphasizes a novel mechanism underpinning the beneficial effects of empagliflozin and pirfenidone on kidney dysfunction associated with MetS through targeting GSK-3ß signaling which can mediate the regenerative capacity, anti-apoptotic effects and anti-fibrotic properties of such drugs. These findings recommend the possibility of using empagliflozin and pirfenidone as promising therapies for management of CKD in patients with MetS.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Glicogênio Sintase Quinase 3 beta , Túbulos Renais , Síndrome Metabólica , Piridonas , Animais , Piridonas/farmacologia , Masculino , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Compostos Benzidrílicos/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Ratos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/complicações , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Túbulos Renais/metabolismo , Regeneração/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Metabolic syndrome has become major health problems in recent decades, and natural compounds receive considerable attention in the management of metabolic syndrome. Among them, naringin is abundant in citrus fruits and tomatoes. Many studies have investigated the therapeutic effects of naringin in metabolic syndrome. This review discusses in vitro and in vivo studies on naringin and implications for clinical trials on metabolic syndrome such as diabetes mellitus, obesity, nonalcoholic fatty liver disease, dyslipidemia, and hypertension over the past decades, overviews the molecular mechanisms by which naringin targets metabolic syndrome, and analyzes possible correlations between the different mechanisms. This review provides a theoretical basis for the further application of naringin in the treatment of metabolic syndrome.
Assuntos
Flavanonas , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Obesidade/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológicoRESUMO
AIMS: To evaluate the clinical safety, tolerability, and pharmacokinetic and pharmacodynamic profile of the novel cannabinoid receptor-1 (CB1R) inverse agonist, INV-202, in adults with features of metabolic syndrome. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, placebo-controlled, 28-day repeat-dose (INV-202 [25 mg] or placebo, once-daily oral tablet), parallel-group study in 37 participants aged 18 to 65 years (46% female, mean age 55 years, glycated haemoglobin 5.7% [39 mmol/mol], body mass index [BMI] 38.1 kg/m2 ) with features of metabolic syndrome and glucose intolerance. An oral glucose tolerance test (OGTT) was performed at baseline and at the end of the study. Lipid profiles, weight, waist circumference and biomarkers were assessed weekly. Statistical comparisons were performed post hoc. RESULTS: INV-202 was well tolerated with no serious or severe treatment-emergent adverse events; the most common events related to known effects of CB1R blockade in the gastrointestinal tract. INV-202 produced a significant mean weight loss of 3.5 kg (3.3% compared with placebo participants who gained a mean 0.6 kg [0.5%]). INV-202 also exhibited significant reductions in waist circumference and BMI (P ≤ 0.03). There was no significant difference in OGTT 0- to 3-hour area under the curve for INV-202 versus placebo: least squares mean 29.38 versus 30.25 h*mmol/L, with an INV-202: placebo ratio of 97.1% (95% confidence interval 90.2, 105.6; P = 0.43). CONCLUSIONS: INV-202 was well tolerated, producing a signal for rapid weight loss with improvements in other metabolic syndrome markers in this population. These findings support further exploration and long-term assessment of cardiometabolic effects.
Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Síndrome Metabólica/tratamento farmacológico , Agonismo Inverso de Drogas , Hemoglobinas Glicadas , Teste de Tolerância a Glucose , Método Duplo-Cego , Redução de Peso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resultado do TratamentoRESUMO
AIM: This study evaluated the safety and efficacy of a moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with metabolic syndrome (MetS) and atherosclerotic cardiovascular disease. MATERIALS AND METHODS: In this post-hoc subgroup analysis of the RACING trial, patients were analysed based on the presence of MetS. MetS was defined as meeting at least three of the five following criteria: (a) elevated waist circumference; (b) elevated triglycerides; (c) reduced high-density lipoprotein cholesterol; (d) elevated blood pressure; and (e) elevated fasting glucose. The primary outcome was a 3-year composite of cardiovascular death, major cardiovascular events, or non-fatal stroke. RESULTS: Of the 3780 patients enrolled in the RACING trial, 1703 (45.1%) had MetS at baseline. The primary outcome rate was 10.1% and 10.3% in patients with MetS receiving ezetimibe combination therapy versus high-intensity statin monotherapy (hazard ratio = 0.97; 95% confidence interval = 0.72-1.32; p = .868). Lower rates of intolerance-related drug discontinuation or dose reduction (3.9% vs. 8.0%; p < .001) and lower low-density lipoprotein cholesterol levels (57 vs. 65 mg/dl; p < .001) were observed with ezetimibe combination therapy versus high-intensity statin monotherapy. Furthermore, the rate of new-onset diabetes was 18.5% and 19.1% in each group (p = .822). There were no significant interactions between MetS and therapy regarding study outcomes in the total population. CONCLUSIONS: In patients with MetS and atherosclerotic cardiovascular disease, a moderate-intensity statin with ezetimibe combination therapy had comparable cardiovascular benefits with those of high-intensity statin monotherapy. Meanwhile, ezetimibe combination therapy was associated with lower drug intolerance and low-density lipoprotein cholesterol levels, but there was no apparent between-group difference in new-onset diabetes.
Assuntos
Anticolesterolemiantes , Aterosclerose , Doenças Cardiovasculares , Diabetes Mellitus , Inibidores de Hidroximetilglutaril-CoA Redutases , Síndrome Metabólica , Humanos , Anticolesterolemiantes/efeitos adversos , Aterosclerose/complicações , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol , Diabetes Mellitus/tratamento farmacológico , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Resultado do TratamentoRESUMO
AIMS: To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS). MATERIALS AND METHODS: A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU. We focused on men who were not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) as these could affect HOMA-IR. Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks), whilst intra-group comparison was carried out on men provided TU during the RCT and open-label phases (study cohort) and men given placebo during the RCT and then switched to TU during the open-label phase (confirmatory cohort). Regression analysis was performed to identify factors associated with change in HOMA-IR (∆HOMA-IR). RESULTS: The median HOMA-IR was significantly reduced at almost every time point (after 18 weeks) compared to baseline in men receiving TU in both the study and confirmatory cohorts. There was a significant decrease in median values of fasting glucose (30 weeks: -2.1%; 138 weeks: -4.9%) and insulin (30 weeks: -10.5%; 138 weeks: -35.5%) after TU treatment. Placebo was not associated with significant ∆HOMA-IR. The only consistent predictor of HOMA-IR decrease following TU treatment was baseline HOMA-IR (r2 ≥ 0.64). CONCLUSIONS: Baseline HOMA-IR predicted ΔHOMA-IR, with a greater percentage change in insulin than in fasting glucose. In men with MetS/type 2 diabetes (T2DM) not on antiglycaemic therapy, improvements in HOMA-IR may be greater than suggested by change in fasting glucose. Our results suggest that hypogonadism screening be included in the management of men with MetS/T2DM.
Assuntos
Hipogonadismo , Resistência à Insulina , Síndrome Metabólica , Testosterona , Humanos , Masculino , Síndrome Metabólica/tratamento farmacológico , Testosterona/uso terapêutico , Testosterona/sangue , Testosterona/deficiência , Testosterona/análogos & derivados , Método Duplo-Cego , Pessoa de Meia-Idade , Adulto , Hipogonadismo/tratamento farmacológico , Hipogonadismo/sangue , Terapia de Reposição Hormonal/métodos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Glicemia/análise , IdosoRESUMO
BACKGROUND: Metabolic syndrome (MetS), which can be induced or exacerbated by the current class of antipsychotic drugs, is highly prevalent in patients with schizophrenia and presents significant challenges to lifetime disease management. Supported by initial clinical results, trace amine-associated receptor 1 (TAAR1) agonists have emerged as potential novel treatments for schizophrenia. Notably, non-clinical studies have also shown weight-lowering and glucoregulatory effects of TAAR1 agonists, including the investigational agent ulotaront. However, the translatability of these findings to humans has not been adequately assessed. Given that delayed gastric emptying (GE) was identified as a potential mechanism contributing to the metabolic benefits of TAAR1 agonists in rodents, the aim of this study was to evaluate the effect of ulotaront on GE in patients with schizophrenia and concurrent MetS with prediabetes. METHODS: Patients with schizophrenia were randomized to receive a single oral dose of ulotaront (150 mg) and their previous antipsychotic (PA) in an open-label, crossover, two-sequence design (NCT05402111). Eligible participants fulfilled at least three of five MetS criteria and had prediabetes defined by elevated glycated haemoglobin (5.7-6.4%) and/or fasting homeostatic model assessment of insulin resistance (i.e. ≥2.22). Following an overnight fast and 4 h post-dose, participants ingested a 99mTc-sulphur colloid radiolabelled egg meal (320 kcal, 30% fat). GE was measured by scintigraphy over 4 h. Endpoints included GE of solids half-time (T1/2) and percentage gastric retention at 1, 2 and 4 h. RESULTS: Thirty-one adults were randomized and 27 completed the study. Ulotaront significantly delayed GE of solids [median GE T1/2 ulotaront at 139 min (119, 182) vs. the participant's PA of 124 min (109, 132), p = .006]. A significant increase in gastric retention was seen in the ulotaront versus the PA group at 1 h (80% vs. 75%, p = .015), 2 h (61% vs. 50%, p = .023) and 4 h (17% vs. 7%, p = .002) post-meal. CONCLUSION: Ulotaront delayed the GE of solids in patients with schizophrenia and concurrent MetS with prediabetes. Additional studies are needed to assess whether treatment with TAAR1 agonists is associated with weight loss and glucoregulatory improvement.
Assuntos
Antipsicóticos , Estudos Cross-Over , Esvaziamento Gástrico , Síndrome Metabólica , Naltrexona/análogos & derivados , Estado Pré-Diabético , Receptores Acoplados a Proteínas G , Esquizofrenia , Humanos , Esvaziamento Gástrico/efeitos dos fármacos , Masculino , Feminino , Esquizofrenia/tratamento farmacológico , Esquizofrenia/complicações , Adulto , Pessoa de Meia-Idade , Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Estado Pré-Diabético/complicações , Estado Pré-Diabético/tratamento farmacológico , Antipsicóticos/uso terapêutico , Antipsicóticos/efeitos adversos , Receptores Acoplados a Proteínas G/agonistas , Tetra-Hidronaftalenos/uso terapêutico , Tetra-Hidronaftalenos/farmacologiaRESUMO
Midlife metabolic syndrome (MetS) is associated with cognitive impairment in late life. The mechanism of delayed MetS-related cognitive dysfunction (MetSCD) is not clear, but it has been linked to systemic inflammation and chronic cerebral microangiopathy. Currently there is no treatment for late life MetSCD other than early risk factor modification. We investigated the effect of soluble epoxide hydrolase (sEH) inhibitor 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (t-AUCB) on cognitive performance, cerebral blood flow (CBF), and central and peripheral inflammation in the high-fat diet (HFD) model of MetS in mice. At 6 weeks of age, male mice were randomly assigned to receive either HFD or standard chow (STD) for 6 months. Mice received either t-AUCB or vehicle for 4 weeks. Cognitive performance was evaluated, followed by CBF measurement using magnetic resonance imaging (MRI). At the end of the study, blood was collected for measurement of eicosanoids and inflammatory cytokines. The brains were then analyzed by immunohistochemistry for glial activation markers. The HFD caused a significant impairment in novel object recognition. Treatment with t-AUCB increased plasma levels of 14,15-EET, prevented this cognitive impairment and modified hippocampal glial activation and plasma cytokine levels, without affecting CBF in mice on HFD. In conclusion, sEH inhibition for four weeks prevents cognitive deficits in mice on chronic HFD by modulating inflammatory processes without affecting CBF.
Assuntos
Disfunção Cognitiva , Modelos Animais de Doenças , Epóxido Hidrolases , Inflamação , Síndrome Metabólica , Animais , Masculino , Camundongos , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Circulação Cerebrovascular/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/metabolismo , Dieta Hiperlipídica/efeitos adversos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Epóxido Hidrolases/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/complicações , Síndrome Metabólica/patologia , Camundongos Endogâmicos C57BLRESUMO
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARß/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARß/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.
Assuntos
Síndrome Metabólica , Quinolinas , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Relação Estrutura-Atividade , Humanos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Estrutura Molecular , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Relação Dose-Resposta a Droga , Benzopiranos/farmacologia , Benzopiranos/síntese química , Benzopiranos/química , Animais , CamundongosRESUMO
BACKGROUND: The prevalence of medical illnesses is high among patients with psychiatric disorders. The current study aimed to investigate multi-comorbidity in patients with psychiatric disorders in comparison to the general population. Secondary aims were to investigate factors associated with metabolic syndrome and treatment appropriateness of mental disorders. METHODS: The sample included 54,826 subjects (64.73% females; 34.15% males; 1.11% nonbinary gender) from 40 countries (COMET-G study). The analysis was based on the registration of previous history that could serve as a fair approximation for the lifetime prevalence of various medical conditions. RESULTS: About 24.5% reported a history of somatic and 26.14% of mental disorders. Mental disorders were by far the most prevalent group of medical conditions. Comorbidity of any somatic with any mental disorder was reported by 8.21%. One-third to almost two-thirds of somatic patients were also suffering from a mental disorder depending on the severity and multicomorbidity. Bipolar and psychotic patients and to a lesser extent depressives, manifested an earlier (15-20 years) manifestation of somatic multicomorbidity, severe disability, and probably earlier death. The overwhelming majority of patients with mental disorders were not receiving treatment or were being treated in a way that was not recommended. Antipsychotics and antidepressants were not related to the development of metabolic syndrome. CONCLUSIONS: The finding that one-third to almost two-thirds of somatic patients also suffered from a mental disorder strongly suggests that psychiatry is the field with the most trans-specialty and interdisciplinary value and application points to the importance of teaching psychiatry and mental health in medical schools and also to the need for more technocratically oriented training of psychiatric residents.
Assuntos
Antipsicóticos , Transtornos Mentais , Síndrome Metabólica , Masculino , Feminino , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/tratamento farmacológico , Transtornos Mentais/epidemiologia , Transtornos Mentais/tratamento farmacológico , Antipsicóticos/uso terapêutico , Saúde Mental , ComorbidadeRESUMO
This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.
Assuntos
Benzoxazóis , Butiratos , Doença da Artéria Coronariana , Estudos Cross-Over , Hipertrigliceridemia , Resistência à Insulina , Síndrome Metabólica , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/complicações , Síndrome Metabólica/diagnóstico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/complicações , Hipertrigliceridemia/diagnóstico , Pessoa de Meia-Idade , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Benzoxazóis/uso terapêutico , Benzoxazóis/farmacologia , Butiratos/uso terapêutico , Butiratos/farmacologia , Resultado do Tratamento , Idoso , Triglicerídeos/sangue , Hipolipemiantes/uso terapêutico , Hipolipemiantes/farmacologia , Biomarcadores/sangue , PPAR alfa/agonistas , Bezafibrato/uso terapêutico , Bezafibrato/farmacologiaRESUMO
The metabolic syndrome (MetS) refers to the co-occurrence of risk factors, including hyperglycaemia, increased body weight, hypertension and dyslipidemia, which eventually lead to diabetes and cardiovascular disease, a common health problem worldwide. Recently, there has been an increasing interest in the use of plant-based products for the management of MetS, because of their less detrimental and more beneficial effects. Moringa oleifera (Moringaceae), commonly known as drumstick, is cultivated worldwide for its nutritional and medicinal properties. This review focuses on the in vivo and human studies concerning the potential of M. oleifera in the alleviation of MetS and its comorbidities. The search for relevant articles was carried out in PubMed and Google Scholar databases. Randomised controlled and clinical trials from the PubMed database were included in this review. The results suggested that the administration of M. oleifera, in vivo, shows clear signs of improvement in MetS indices. Despite fewer human studies, the existing data documented convincing results that uphold the potential of M. oleifera against MetS. Therefore, future research discussing the probable mechanism of action is much needed which could further assure the usage of M. oleifera in the treatment regimen of MetS.
Assuntos
Hiperglicemia , Síndrome Metabólica , Moringa oleifera , Humanos , Síndrome Metabólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
The prevalence of metabolic syndrome is increasing globally due to behavioral and environmental changes. There are many therapeutic agents available for the treatment of chronic metabolic diseases, such as obesity and diabetes, but the data on their efficacy and safety are lacking. Through a pilot study by our group, Zingiber officinale rhizomes used as a spice and functional food were selected as an anti-obesity candidate. In this study, steam-processed ginger extract (GGE) was used and we compared its efficacy at alleviating metabolic syndrome-related symptoms with that of conventional ginger extract (GE). Compared with GE, GGE (25-100 µg/mL) had an increased antioxidant capacity and α-glucosidase inhibitory activity in vitro. GGE was better at suppressing the differentiation of 3T3-L1 adipocytes and lipid accumulation in HepG2 cells and promoting glucose utilization in C2C12 cells than GE. In 16-week high-fat-diet (HFD)-fed mice, GGE (100 and 200 mg/kg) improved biochemical profiles, including lipid status and liver function, to a greater extent than GE (200 mg/kg). The supplementation of HFD-fed mice with GGE (200 mg/kg) resulted in the downregulation of SREBP-1c and FAS gene expression in the liver. Collectively, our results indicate that GGE is a promising therapeutic for the treatment of obesity and metabolic syndrome.
Assuntos
Fármacos Antiobesidade , Síndrome Metabólica , Zingiber officinale , Camundongos , Animais , Vapor , Síndrome Metabólica/tratamento farmacológico , Projetos Piloto , Tecido Adiposo/metabolismo , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Dieta Hiperlipídica , Fármacos Antiobesidade/farmacologia , Lipídeos/farmacologia , Camundongos Endogâmicos C57BL , Células 3T3-L1 , AdipogeniaRESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, is a steatotic liver disease associated with metabolic syndrome (MetS), especially obesity, hypertension, diabetes, hyperlipidemia, and hypertriglyceridemia. MASLD in 43-44% of patients can progress to metabolic dysfunction-associated steatohepatitis (MASH), and 7-30% of these cases will progress to liver scarring (cirrhosis). To date, the mechanism of MASLD and its progression is not completely understood and there were no therapeutic strategies specifically tailored for MASLD/MASH until March 2024. The conventional antiobesity and antidiabetic pharmacological approaches used to reduce the progression of MASLD demonstrated favorable peripheral outcomes but insignificant effects on liver histology. Alternatively, phyto-synthesized metal-based nanoparticles (MNPs) are now being explored in the treatment of various liver diseases due to their unique bioactivities and reduced bystander effects. Although phytonanotherapy has not been explored in the clinical treatment of MASLD/MASH, MNPs such as gold NPs (AuNPs) and silver NPs (AgNPs) have been reported to improve metabolic processes by reducing blood glucose levels, body fat, and inflammation. Therefore, these actions suggest that MNPs can potentially be used in the treatment of MASLD/MASH and related metabolic diseases. Further studies are warranted to investigate the feasibility and efficacy of phytonanomedicine before clinical application.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Fitoterapia , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fitoterapia/métodos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Animais , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Síndrome Metabólica/complicações , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismoRESUMO
This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of ß-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.