RESUMO
OBJECTIVE: This study aims to investigate whether antidepressant users display differences in fat distribution and muscle composition relative to non-users and to explore risk factors for developing cardiovascular disease (CVD) and type 2 diabetes. METHODS: The study used quantitative adipose and muscle tissue measures derived from magnetic resonance imaging data from UK Biobank (N = 40,174). Fat distribution and muscle composition of selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) users were compared with sex-, age-, and BMI-matched control individuals. Cox regression models were used to test for increased risk of developing CVD and type 2 diabetes. RESULTS: SSRI users had more visceral fat, smaller muscle volume, and higher muscle fat infiltration compared with matched control individuals. Female users showed a larger increase in BMI over time compared with male users. However, male users displayed an unhealthier body composition profile. Male SSRI users also had an increased risk of developing CVD. Both male and female TCA users showed lower muscle volume and an increased risk of developing type 2 diabetes. CONCLUSIONS: Adverse changes in body composition of antidepressant users are not captured by tracking the body weight or the BMI of the patients. These changes may lead to a worsened cardiometabolic risk profile.
Assuntos
Antidepressivos , Composição Corporal , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Composição Corporal/efeitos dos fármacos , Antidepressivos/efeitos adversos , Adulto , Índice de Massa Corporal , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/diagnóstico por imagem , Idoso , Fatores de Risco , Fatores de Risco Cardiometabólico , Imageamento por Ressonância Magnética , Gordura Intra-Abdominal/efeitos dos fármacos , Reino Unido/epidemiologia , Antidepressivos Tricíclicos/efeitos adversos , Estudos de Casos e ControlesRESUMO
Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.
Assuntos
Adipocinas , Citocinas , Ácidos Graxos Ômega-3 , Oxilipinas , Animais , Oxilipinas/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Camundongos , Citocinas/metabolismo , Adipocinas/metabolismo , Masculino , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/induzido quimicamente , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacosRESUMO
Inadequate blood supply to the expanding adipose tissue (AT) is involved in the unhealthy AT remodeling and cardiometabolic consequences of obesity. Because of the pathophysiological role of upregulated mineralocorticoid receptor (MR) signaling in the complications of obesity, this study tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries of human AT. Arteries isolated from the visceral AT of obese subjects were studied in a wire myograph. Finerenone resulted in a concentration-dependent relaxation of arteries precontracted with either the thromboxane-A2 analog U46619, ET-1, or high-K+ solution; the steroidal MR antagonist potassium canrenoate, by contrast, did not relax arteries contracted with either U46619 or high-K+ solution. Finerenone-induced relaxation after precontraction with U46619 was greater in the arteries of obese versus nonobese subjects. Mechanistically, the vasorelaxing response to finerenone was not influenced by preincubation with the nitric oxide synthase inhibitor L-NAME or by endothelium removal. Interestingly, finerenone, like the dihydropyridine Ca2+-channel blocker nifedipine, relaxed arteries contracted with the L-type Ca2+-channel agonist Bay K8644. In conclusion, finerenone relaxes arteries of human visceral AT, likely through antagonism of L-type Ca2+ channels. This finding identifies a novel mechanism by which finerenone may improve AT perfusion, hence protecting against the cardiometabolic complications of obesity.
Assuntos
Canais de Cálcio Tipo L , Gordura Intra-Abdominal , Antagonistas de Receptores de Mineralocorticoides , Naftiridinas , Vasodilatação , Humanos , Canais de Cálcio Tipo L/metabolismo , Masculino , Naftiridinas/farmacologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/irrigação sanguínea , Gordura Intra-Abdominal/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Vasodilatação/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Obesidade/metabolismo , Artérias/metabolismo , Artérias/efeitos dos fármacos , Adulto , Bloqueadores dos Canais de Cálcio/farmacologiaRESUMO
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
BACKGROUND: HIV-associated lipohypertrophy, which is characterised by an abnormal accumulation of abdominal visceral adipose tissue, remains problematic in people with HIV. Effective interventions are lacking, despite HIV-associated lipohypertrophy carrying a substantial risk of cardiometabolic comorbidity. The primary aim of this trial was to investigate effects of the GLP-1 receptor agonist, semaglutide, on adipose tissue in HIV-associated lipohypertrophy. METHODS: This randomised, double-blind, placebo-controlled phase 2b clinical trial was conducted at a single US site. Key inclusion criteria included people with HIV aged 18 years or older with controlled HIV-1, a BMI of 25 kg/m2 or more, and lipohypertrophy but without type 1 or type 2 diabetes. Participants were randomly assigned 1:1 to receive 32 weeks of once-weekly subcutaneous semaglutide (8-week dose titration and 24 weeks at 1·0 mg) or placebo; all research personnel and participants remained masked to treatment assignment. Primary outcomes were changes at 32 weeks in adipose tissue quantity by body compartment. Analyses, including safety, were performed using intention-to-treat principles. This trial was registered ClinicalTrials.gov (NCT04019197) and is complete. FINDINGS: Between June 10, 2019, and July 28, 2022, 108 participants were randomly assigned to receive semaglutide (n=54) or placebo (n=54). Eight (15%) in each group withdrew prematurely. Significant effects of semaglutide were seen over the 32-week study period in sex-adjusted multiplicative regression analyses for the primary outcome, abdominal visceral adipose tissue (ß -30·82 cm2, 95% CI -50·13 to -11·51; % change -30·6%). Decreases were also seen in other key measures, including abdominal subcutaneous adipose tissue (ß -42·01 cm2, 95% CI -75·49 to -8·52; % change -11·2%) and total body fat (natural logarithmic -0·21 kg, 95% CI -0·33 to -0·08; % change -18·9%). There were no statistically significant differences in possibly related or related adverse events (absolute risk difference 0·1111, 95% CI -0·0727 to 0·2869); however, one semaglutide-related grade 4 elevated lipase and two possibly related cases of cholelithiasis (grades 1 and 2) were observed. INTERPRETATION: Semaglutide holds promise as an effective treatment for HIV-associated lipohypertrophy. The potential risk of serious adverse events deserves further scrutiny in large trials in people with HIV. FUNDING: National Institutes of Health.
Assuntos
Peptídeos Semelhantes ao Glucagon , Humanos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Feminino , Masculino , Método Duplo-Cego , Pessoa de Meia-Idade , Adulto , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Síndrome de Lipodistrofia Associada ao HIV/tratamento farmacológico , Resultado do Tratamento , Gordura Intra-Abdominal/efeitos dos fármacosRESUMO
Development of type 2 diabetes mellitus (T2DM) is associated with low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via the production of type 2 cytokines. Here, we demonstrate that CB2, a G-protein-coupled receptor (GPCR) and member of the endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB2 engagement on VAT ILC2s in a T2DM model. Our results show that CB2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin resistance. Our mechanistic studies reveal that the therapeutic effects of CB2 are mediated through activation of the AKT, ERK1/2, and CREB pathways on ILC2s. The results reveal that the CB2 agonist can serve as a candidate for the prevention and treatment of T2DM.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Linfócitos , Receptor CB2 de Canabinoide , Animais , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/agonistas , Linfócitos/metabolismo , Linfócitos/imunologia , Linfócitos/efeitos dos fármacos , Humanos , Camundongos , Masculino , Camundongos Endogâmicos C57BL , Imunidade Inata/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Obesity is characterized by excessive accumulation of adipose tissue (mainly visceral). The morphology and function of mitochondria are crucial for regulating adipose browning and weight loss. Research suggests that the SGLT2 inhibitor canagliflozin may induce weight loss through an unknown mechanism, particularly targeting visceral adipose tissue. While Krueppel-Like Factor 4 (KLF4) is known to be essential for energy metabolism and mitochondrial function, its specific impact on visceral adipose tissue remains unclear. We administered canagliflozin to db/db mice for 8 weeks, or exposed adipocytes to canagliflozin for 24 h. The expression levels of browning markers, mitochondrial dynamics, and KLF4 were assessed. Then we validated the function of KLF4 through overexpression in vivo and in vitro. Adenosine monophosphate-activated protein kinase (AMPK) agonists, inhibitors, and KLF4 si-RNA were employed to elucidate the relationship between AMPK and KLF4. The findings demonstrated that canagliflozin significantly decreased body weight in db/db mice and augmented cold-induced thermogenesis. Additionally, canagliflozin increased the expression of mitochondrial fusion-related factors while reducing the levels of fission markers in epididymal white adipose tissue. These consistent findings were mirrored in canagliflozin-treated adipocytes. Similarly, overexpression of KLF4 in both adipocytes and db/db mice yielded comparable results. In all, canagliflozin mitigates obesity in db/db mice by promoting the brown visceral adipocyte phenotype through enhanced mitochondrial fusion via AMPK/KLF4 signaling.
Assuntos
Proteínas Quinases Ativadas por AMP , Tecido Adiposo Marrom , Canagliflozina , Gordura Intra-Abdominal , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like , Dinâmica Mitocondrial , Transdução de Sinais , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Dinâmica Mitocondrial/efeitos dos fármacos , Canagliflozina/farmacologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , Masculino , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Termogênese/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Peso Corporal/efeitos dos fármacosRESUMO
BACKGROUND: The introduction of tyrosine kinase inhibitors (TKI) has greatly improved the management of metastatic melanoma. Recent studies have uncovered a relationship between the body mass index (BMI) and outcome of patients with metastatic melanoma. However, conflicting results have challenged the relevance of this finding. In the current work, we aim to dissect body composition features of melanoma patients treated with TKI to evaluate their value as biomarkers. PATIENTS AND METHODS: We analyze body composition features via CT scans in a retrospective cohort of 57 patients with non-resectable stage III/IV melanoma receiving first-line treatment with TKI in our department, focusing on the impact of body composition on treatment efficacy and occurrence of adverse events. RESULTS: In uni- and multivariate analyses, we identify an association between the visceral adipose tissue gauge index (VATGI) and survival. We furthermore profile additional body composition features including sarcopenia, which was also associated with a shorter overall survival. Finally, we detected an enrichment of cases with fatigue in patients with low VATGI. CONCLUSIONS: Our study represents the first exploratory study evaluating the suitability of body composition measurements as biomarkers for melanoma patients treated with TKI. Our data suggest a putative use of VATGI as a biomarker predicting patient outcome.
Assuntos
Composição Corporal , Melanoma , Inibidores de Proteínas Quinases , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Composição Corporal/efeitos dos fármacos , Masculino , Feminino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Idoso , Índice de Massa Corporal , Adulto , Resultado do Tratamento , Tomografia Computadorizada por Raios X , Estadiamento de Neoplasias , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/efeitos dos fármacosRESUMO
INTRODUCTION: Anti-interleukin 12/23 agents have shown greater durability in response compared with anti-tumor necrosis factor α agents. Data on the association between body composition (BC) or body mass index (BMI) and ustekinumab's therapeutic response is limited. We aimed to evaluate the impact of BC on time to failing standard doses of ustekinumab in patients with Crohn's disease (CD). METHOD: Patients with CD aged 16 years and older from 2 tertiary centers were studied retrospectively. Included patients had abdominal imaging within 6 months of ustekinumab induction and were followed until April 30, 2022. An experienced abdominal radiologist blinded to the clinical information measured the area of visceral fat area and skeletal muscle area at the mid L3 vertebral level, with values corrected for height 2 to derive respective indices (visceral fat index [VFI], skeletal muscle index [SMI]) and the VFI:SMI ratio. RESULTS: Ninety-nine patients met inclusion criteria. The mean age at ustekinumab induction was 46.6 (±1.6) years. The median BMI (interquartile range) was 26.5 (22.6-30.8). Twenty-four patients (24.2%) did not respond or lost response to standard doses of ustekinumab over the follow-up duration. A younger age (hazard ratio 0.96, 95% confidence interval 0.94-0.99, P = 0.01) and a VFI:SMI ratio >1.6 (hazard ratio 4.65, 95% confidence interval 1.73-12.45, P = 0.002) were both associated with a shorter time to failing ustekinumab at standard doses on multivariate analysis. BMI, notably, had no association with the primary outcome. DISCUSSION: A high VFI:SMI ratio is associated with an increased risk of failing standard doses of ustekinumab. BC measurements derived from cross-sectional imaging at the start of ustekinumab therapy is a useful indicator for therapeutic durability.
Assuntos
Índice de Massa Corporal , Doença de Crohn , Gordura Intra-Abdominal , Músculo Esquelético , Falha de Tratamento , Ustekinumab , Humanos , Ustekinumab/administração & dosagem , Ustekinumab/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/efeitos dos fármacos , Doença de Crohn/tratamento farmacológico , Doença de Crohn/diagnóstico por imagem , Composição Corporal/efeitos dos fármacos , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: There is insufficient research on how gender-affirming hormone therapy (GAHT) affects body fat modifications in transwomen from China. It is unclear whether hormone therapy affects the prevalence of obesity and blood lipid levels within this population. The current research aimed to assess how GAHT and treatment duration had an impact on the change in and redistribution of body fat in Chinese transwomen. METHODS: This study included 40 transwomen who had not received GAHT and 59 who had. Body fat, blood lipid, and blood glucose levels were measured. GAHT is mainly a pharmacologic (estrogen and anti-androgen) treatment. The study also stratified participants based on the duration of GAHT to assess its impact on body fat distribution. The duration of GAHT was within one year, one to two years, two to three years, or more than three years. RESULTS: After receiving GAHT, total body fat increased by 19.65%, and the percentage of body fat increased by 17.63%. The arm, corrected leg, and leg regions showed significant increases in fat content (+ 24.02%, + 50.69%, and + 41.47%, respectively) and percentage (+ 25.19%, + 34.90%, and + 30.39%, respectively). The total visceral fat content decreased (-37.49%). Based on the diagnostic standards for a body mass index ≥ 28 or total body fat percentage ≥ 25% or 30%, the chance of developing obesity did not change significantly. Blood glucose levels significantly increased (+ 12.31%). Total cholesterol levels (-10.45%) decreased significantly. Fat changes in those who received GAHT for one to two years were significantly different from those who did not receive GAHT. CONCLUSION: After receiving GAHT, total body fat and regional fat increased in Chinese transwomen, and the body fat distribution changed from masculine to feminine, especially during the first two years. However, neither the increase in total body fat percentage nor the decrease in visceral fat content didn't bring about significant changes in the incidence of obesity, nor did triglycerides or low-density lipoprotein-cholesterol.
Assuntos
Pessoas Transgênero , Adulto , Feminino , Humanos , Masculino , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Povo Asiático , Glicemia/metabolismo , Distribuição da Gordura Corporal , Índice de Massa Corporal , Estudos de Casos e Controles , China/epidemiologia , População do Leste Asiático , Estrogênios/sangue , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Obesidade/sangue , Estudos Retrospectivos , Procedimentos de Readequação Sexual , Transexualidade/tratamento farmacológico , Transexualidade/sangueRESUMO
Accumulation of visceral adipose tissue is associated with metabolic syndrome (MS), insulin resistance, and dyslipidemia. Here we examined several morphometric and biochemical parameters linked to MS in a rodent litter size reduction model, and how a 30-day fish oil (FO) supplementation affected these parameters. On day 3 post-birth, pups were divided into groups of ten or three. On day 22, rats were split into control (C) and small litter (SL) until 60 days old. Then, after metabolic disturbance and obesity were confirmed, FO supplementation started for 30 days and the new groups were named control (C), FO supplemented (FO), obese (Ob), and obese FO supplemented (ObFO). Comparison was performed by Student t-test or 2-way ANOVA followed by Tukey post hoc test. At the end of the 60-day period, SL rats were hyperphagic, obese, hypoinsulinemic, normoglycemic, and had high visceral fat depot and high interleukin (IL)-6 plasma concentration. Obese rats at 90 days of age were fatter, hyperphagic, hyperglycemic, hypertriacylgliceromic, hipoinsulinemic, with low innate immune response. IL-6 production ex vivo was higher, but in plasma it was not different from the control group. FO supplementation brought all biochemical changes to normal values, normalized food intake, and reduced body weight and fat mass in obese rats. The innate immune response was improved but still not as efficient as in lean animals. Our results suggested that as soon MS appears, FO supplementation must be used to ameliorate the morpho- and biochemical effects caused by MS and improve the innate immune response.
Assuntos
Suplementos Nutricionais , Óleos de Peixe , Síndrome Metabólica , Obesidade , Ratos Wistar , Animais , Síndrome Metabólica/dietoterapia , Óleos de Peixe/administração & dosagem , Obesidade/dietoterapia , Obesidade/metabolismo , Masculino , Ratos , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Interleucina-6/sangue , Modelos Animais de Doenças , FemininoRESUMO
OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.
Assuntos
Ácidos e Sais Biliares , Iridoides , Fígado , Obesidade , Ratos Sprague-Dawley , Animais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Iridoides/farmacologia , Ácidos e Sais Biliares/metabolismo , Masculino , Ratos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Bile/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismoRESUMO
INTRODUCTION: Excessive visceral adiposity is known to drive the onset of metabolic derangements, mostly involving oxidative stress, prolonged inflammation, and cellular senescence. N-acetylcysteine (NAC) is a synthetic form of
Assuntos
Acetilcisteína , Senescência Celular , Inibidor de Quinase Dependente de Ciclina p21 , Interleucina-6 , Gordura Intra-Abdominal , Obesidade , Fator de Necrose Tumoral alfa , beta-Galactosidase , Humanos , Acetilcisteína/farmacologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Adulto , Masculino , beta-Galactosidase/metabolismo , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Feminino , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Inflamação/metabolismoRESUMO
This randomised, placebo-controlled, double-blind, parallel-group study aimed to determine whether encapsulated Ashitaba chalcone (16 mg comprising 10.1 mg 4-hydroxyderricin and 5.9 mg xanthoangelol) could reduce obesity in 17 men and 25 women with a body mass index (BMI) of 25 to < 30. Participants ingested capsules containing either the chalcone or a placebo daily for 12 weeks. The primary endpoint was changes in visceral fat areas determined by computed tomography (CT) at baseline, and at 8 and 12 weeks later. The primary endpoint, abdominal visceral fat area, was significantly reduced in the chalcone, compared with a placebo group 12 weeks after screening (p < 0.05). The secondary endpoint, waist circumference, was significantly decreased in the chalcone, compared with the placebo group at weeks 8 and 12 (p < 0.05 at week 8; p < 0.01 at week 12). Therefore, Ashitaba chalcone has anti-obesity benefits for overweight men and women.
Assuntos
Chalcona , Gordura Intra-Abdominal , Sobrepeso , Circunferência da Cintura , Humanos , Masculino , Feminino , Método Duplo-Cego , Adulto , Pessoa de Meia-Idade , Gordura Intra-Abdominal/efeitos dos fármacos , Chalcona/análogos & derivados , Chalcona/farmacologia , Índice de Massa Corporal , Obesidade , Fármacos Antiobesidade/farmacologiaRESUMO
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.
Assuntos
Diabetes Mellitus Tipo 2 , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon , Hepatopatia Gordurosa não Alcoólica , Obesidade , Humanos , Adiposidade/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
PURPOSE: We aimed to investigate whether visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle area (SMA) index are predictive for efficacy and hematological toxicity in ER + HER2-metastatic breast cancer (BC) patients who received CDK 4/6 inhibitors. METHODS: This retrospective cohort study analyzed 52 patients who were treated with CDK 4/6 inhibitors between January 2018 and February 2021. The values of VAT, SAT, SMA indices and hematological parameters were noted before the start, at the third and sixth months of this treatment. The skeletal muscle area (SMA) and adipose tissue measurements were calculated at the level of the third lumbar vertebra. A SMA-index value of <40 cm2/m2 was accepted as the threshold value for sarcopenia. RESULTS: Patients with sarcopenia had a worse progression-free survival (PFS) compared to patients without sarcopenia (19.6 vs. 9.0 months, p = 0.005). Patients with a high-VAT-index had a better PFS (20.4 vs. 9.3 months, p = 0.033). Only the baseline low-SMA- index (HR: 3.89; 95% CI: 1.35-11.25, p = 0.012) and baseline low-VAT-index (HR: 2.15; 95% CI: 1.02-4.53, p = 0.042) had significantly related to poor PFS in univariate analyses. The low-SMA-index was the only independent factor associated with poor PFS (HR: 3.99; 95% CI: 1.38-11.54, p = 0.011). No relationship was observed between body composition parameters and grade 3-4 hematological toxicity. CONCLUSION: The present study supported the significance of sarcopenia and low visceral adipose tissue as potential early indicators of poor PFS in patients treated with CDK 4/6 inhibitors.
Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Obesidade Abdominal , Inibidores de Proteínas Quinases , Sarcopenia , Humanos , Sarcopenia/induzido quimicamente , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Obesidade Abdominal/induzido quimicamente , Adulto , Intervalo Livre de Progressão , Gordura Intra-Abdominal/efeitos dos fármacos , Metástase Neoplásica , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Gordura Subcutânea/efeitos dos fármacosRESUMO
AIMS: To describe the overall fat distribution patterns independent of body mass index (BMI) in participants with type 2 diabetes (T2D) in the SURPASS-3 MRI substudy by comparison with sex- and BMI-matched virtual control groups (VCGs) derived from the UK Biobank imaging study at baseline and Week 52. METHODS: For each study participant at baseline and Week 52 (N = 296), a VCG of ≥150 participants with the same sex and similar BMI was identified from the UK Biobank imaging study (N = 40 172). Average visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT) and liver fat (LF) levels and the observed standard deviations (SDs; standardized normal z-scores: z-VAT, z-aSAT and z-LF) were calculated based on the matched VCGs. Differences in z-scores between baseline and Week 52 were calculated to describe potential shifts in fat distribution pattern independent of weight change. RESULTS: Baseline fat distribution patterns were similar across pooled tirzepatide (5, 10 and 15 mg) and insulin degludec (IDeg) arms. Compared with matched VCGs, SURPASS-3 participants had higher baseline VAT (mean [SD] z-VAT +0.42 [1.23]; p < 0.001) and LF (z-LF +1.24 [0.92]; p < 0.001) but similar aSAT (z-aSAT -0.13 [1.11]; p = 0.083). Tirzepatide-treated participants had significant decreases in z-VAT (-0.18 [0.58]; p < 0.001) and z-LF (-0.54 [0.84]; p < 0.001) but increased z-aSAT (+0.11 [0.50]; p = 0.012). Participants treated with IDeg had a significant change in z-LF only (-0.46 [0.90]; p = 0.001), while no significant changes were observed for z-VAT (+0.13 [0.52]; p = 0.096) and z-aSAT (+0.09 [0.61]; p = 0.303). CONCLUSION: In this exploratory analysis, treatment with tirzepatide in people with T2D resulted in a significant reduction of z-VAT and z-LF, while z-aSAT was increased from an initially negative value, suggesting a possible treatment-related shift towards a more balanced fat distribution pattern with prominent VAT and LF loss.
Assuntos
Distribuição da Gordura Corporal , Diabetes Mellitus Tipo 2 , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico , Receptor do Peptídeo Semelhante ao Glucagon 2 , Hipoglicemiantes/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
Obesity is a pressing problem worldwide for which standard therapeutic strategies have limited effectiveness. The use of natural products seems to be a promising approach to alleviate obesity and its associated complications. The tepals of Crocus sativus (Cr) plant, usually wasted in saffron production, are an unexplored source of bioactive compounds. Our aim was to elucidate the mechanisms of Cr tepals extract in obesity by investigating its effects on adipocyte differentiation, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) hypertrophy, and lipid metabolism in an animal model of diet-induced obesity. To this end, mouse 3T3-F442A preadipocytes were treated with Cr tepals extract and the expression of adipocyte differentiation genes was determined. Caloric intake, body mass, triglycerides, systemic insulin sensitivity, histology, insulin signaling, and lipid metabolism in VAT and SAT were analyzed in mice fed a 60% fat diet for 14 weeks and treated orally with Cr tepals extract during the last 5 weeks of the diet. We demonstrated for the first time that Cr tepals extract inhibits adipocyte differentiation in vitro. The animal model confirmed that oral treatment with Cr tepals extract results in weight loss, improved systemic insulin sensitivity, lower triglycerides, and improved lipid peroxidation. The suppressive effect of Cr tepals extract on adipocyte hypertrophy and inflammation was observed only in SAT, which, together with preserved SAT insulin signaling, most likely contributed to improved systemic insulin sensitivity. Our results suggest the functionality of SAT as a possible target for the treatment of obesity and its complications.
Assuntos
Adipócitos , Crocus , Dieta Hiperlipídica , Resistência à Insulina , Obesidade , Extratos Vegetais , Animais , Camundongos , Dieta Hiperlipídica/efeitos adversos , Extratos Vegetais/farmacologia , Crocus/química , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Masculino , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Gordura Subcutânea/metabolismo , Gordura Subcutânea/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Hipertrofia/tratamento farmacológico , Camundongos Endogâmicos C57BL , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Adipogenia/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacosRESUMO
The purpose of this study was to investigate the effect of an egg white hydrolysate (EWH) to protect white adipose tissue damage from cardiometabolic changes induced by severe hypertension. Male Wistar rats were uninephrectomised and divided: SHAM (weekly subcutaneous vehicle (mineral oil + propylene glycol, 1:1)), SHAM + EWH (subcutaneous vehicle plus EWH via gavage, 1 g/kg per day), DOCA (deoxycorticosterone acetate diluted in vehicle subcutaneously weekly in subsequent doses of 20 mg/kg -1st week, 12 mg/kg - 23th week, and 6 mg/kg -48th week, respectively, plus 1 % NaCl and 0·2 % KCl in drinking water), and DOCA + EWH. Body weight gain, food and water intake, glucose and lipid metabolism were evaluated. Oxidative stress was assessed by biochemical assay and immunofluorescence for NOX-1, nuclear factor kappa B (NFκB), and caspase-3 in retroperitoneal white adipose tissue (rtWAT). Proinflammatory cytokines (IL-6 and 1ß), CD163+ macrophage infiltration, and immunohistochemistry for TNFα and uncoupling protein-1 were evaluated, as well as histological analysis on rtWAT. Glutathione peroxidase and reductase were also determined in plasma. EWH showed hypocholesterolemic, antioxidant, anti-inflammatory, and anti-apoptotic properties in the arterial hypertension DOCA-salt model. The results demonstrated the presence of functional changes in adipose tissue function by a decrease in macrophage infiltration and in the fluorescence intensity of NFκB, NOX-1, and caspase-3. A reduction of proinflammatory cytokines and restoration of antioxidant enzymatic activity and mitochondrial oxidative damage by reducing uncoupling protein-1 fluorescence intensity were also observed. EWH could be used as a potential alternative therapeutic strategy in the treatment of cardiometabolic complications associated with malignant secondary arterial hypertension.
Assuntos
Tecido Adiposo Branco , Acetato de Desoxicorticosterona , Clara de Ovo , Estresse Oxidativo , Ratos Wistar , Animais , Masculino , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Clara de Ovo/química , Ratos , Hipertensão/metabolismo , Hipertensão/induzido quimicamente , Hidrolisados de Proteína/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/efeitos dos fármacosRESUMO
OBJECTIVE: Obesity is characterized by excessive accumulation of white adipose tissue (WAT). Conversely, brown adipose tissue is protective against obesity. We recently reported liraglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), could inhibit high-fat-diet-induced obesity by browning of WAT. However, the molecular mechanism involved is not well defined. Hence, we aimed to explore whether GLP-1RA could promote brown remodeling in WAT by regulating miRNAs. METHODS: After the obesity model was successfully constructed, C57BL/6J mice were treated with liraglutide (200 µg/kg/d) or equivoluminal saline subcutaneously for 12 weeks. Then, the deposition of abdominal fat was measured by CT scanning. At the end of the treatments, glucose and insulin tolerance in mice were assessed. Serum lipid levels were monitored and epididymal WAT (eWAT) were collected for analysis. Quantitative real-time PCR and western blot analyses were conducted to evaluate the expression of genes and miRNAs associated with white fat browning. RESULTS: Liraglutide significantly reduced body weight and visceral fat mass. Levels of lipid profile were also improved. Liraglutide upregulated the expression of browning-related genes in eWAT. Meanwhile, the expression level of miRNAs (miR-196a and miR-378a) positively associated with the browning of WAT were increased, while the expression of miR-155, miR-199a, and miR-382 negatively related with browning of WAT were decreased. CONCLUSION: Our findings suggest that liraglutide could promote brown remodeling of visceral WAT by bi-regulating miRNAs; this might be one of the mechanisms underlying its effect on weight loss.