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1.
Nat Commun ; 11(1): 4981, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020469

RESUMO

Antagonism or agonism of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) prevents weight gain and leads to dramatic weight loss in combination with glucagon-like peptide-1 receptor agonists in preclinical models. Based on the genetic evidence supporting GIPR antagonism, we previously developed a mouse anti-murine GIPR antibody (muGIPR-Ab) that protected diet-induced obese (DIO) mice against body weight gain and improved multiple metabolic parameters. This work reconciles the similar preclinical body weight effects of GIPR antagonists and agonists in vivo, and here we show that chronic GIPR agonism desensitizes GIPR activity in primary adipocytes, both differentiated in vitro and adipose tissue in vivo, and functions like a GIPR antagonist. Additionally, GIPR activity in adipocytes is partially responsible for muGIPR-Ab to prevent weight gain in DIO mice, demonstrating a role of adipocyte GIPR in the regulation of adiposity in vivo.


Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Membrana Celular/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia , Receptores dos Hormônios Gastrointestinais/deficiência , Receptores dos Hormônios Gastrointestinais/metabolismo
2.
Anticancer Res ; 40(10): 5445-5456, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988866

RESUMO

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.


Assuntos
Jejum , Neoplasias Renais/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Humanos , Imunoterapia/efeitos adversos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Neoplasias Renais/patologia , Camundongos , Obesidade/complicações , Obesidade/genética
3.
Nat Commun ; 11(1): 4765, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958780

RESUMO

Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.


Assuntos
Antígenos CD36/metabolismo , Endocitose/fisiologia , Ácidos Graxos/metabolismo , Lipoilação , Células 3T3-L1 , Aciltransferases/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/deficiência , Antígenos CD36/genética , Cavéolas/metabolismo , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Humanos , Gotículas Lipídicas/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Obesidade/tratamento farmacológico , Fosforilação , Transdução de Sinais , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Ganho de Peso/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
4.
Life Sci ; 258: 118153, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738361

RESUMO

AIMS: Obesity-related glomerulopathy (ORG) is characterized by glomerulomegaly with or without focal and segmental glomerulosclerosis lesions. Isothiocyanate sulforaphane (SFN) can protect kidneys from ORG-related damages. In this study, we investigated the effects of SFN as a preventive therapy or intervention for ORG to reveal its mechanism of action. MAIN METHODS: We established a mouse obesity model with preventive SFN or N-acetylcysteine treatment for 2 months. Thereafter, we used nuclear factor erythroid 2-related factor 2-deficient (Nrf2-/-) and wild type mice in our ORG model with SFN treatment. Finally, we generated a corresponding mouse podocyte model in vitro. The body weight, wet weight of perirenal-and peritesticular fat, and urinary albumin/creatinine ratio were assessed. We used periodic acid-Schiff staining and electron microscopy to assess the function of the kidneys and podocytes. In addition, we evaluated the expression of Nrf2 and podocyte-specific proteins by western blotting. KEY FINDINGS: Treatment with SFN reduced body weight, organ-associated fat weight, and urinary albumin/creatinine ratio in both the preventive treatment and disease intervention regimens. SFN treated mice exhibited higher expression levels of podocyte-specific proteins and better podocyte function. However, treatment with SFN did not affect these parameters in obese Nrf2-/- mice. Light chain 3 of microtubule-associated protein 1-II and metallothionein had higher expression in the wild type than in the Nrf2-/- mice. SIGNIFICANCE: Treatment with SFN limited ORG-induced damage by enhancing podocyte autophagy via Nrf2.


Assuntos
Isotiocianatos/uso terapêutico , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/complicações , Substâncias Protetoras/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Células Cultivadas , Nefropatias/metabolismo , Glomérulos Renais/citologia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Podócitos/citologia , Podócitos/efeitos dos fármacos , Podócitos/metabolismo
5.
Life Sci ; 258: 118222, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768577

RESUMO

AIMS: We previously reported that fenugreek-derived 4-hydroxyisoleucine ameliorates insulin resistance via regulation of TNF-α converting enzyme (TACE) expression. In the present study, we further investigate the effects and mechanisms of fenugreek on obesity-induced inflammation and insulin signaling in the high-fat diet (HFD)-challenged obese mice. MAIN METHODS: After 12 weeks of HFD intervention, mice were treated with the low or high dosages of fenugreek. Serum levels of glucose, insulin, lipid profile, inflammation cytokines, and adipokines were detected. Macrophage infiltration and adipose tissue morphology were observed. Western blot was conducted to investigate the expressions of inactive rhomboid 2 (iRhom2) and TACE as well as other signaling pathways in subcutaneous adipose tissue. KEY FINDINGS: We showed that fenugreek significantly suppressed body weight gain and fat accumulation in HFD-challenged obese mice. Meanwhile, fasting glucose, insulin, and HOMA-IR in fenugreek-treated mice were remarkably decreased, which were properly explained by fenugreek-induced activation of the insulin receptor signaling pathway. Moreover, the anti-inflammatory properties of fenugreek were shown by the decrease of systemic and local expressions of pro-inflammatory cytokines as well as reduced macrophage infiltration into adipose tissue. Additionally, fenugreek markedly deactivated NF-κB and JNK pathways. Finally, we demonstrated that fenugreek strikingly repressed the transcriptions and expressions of iRhom2 and TACE. SIGNIFICANCE: Fenugreek shows an encouraging and promising property in ameliorating insulin resistance and suppressing inflammation in obesity, which might be realized by fenugreek-mediated inhibition of iRhom2/TACE axis-facilitated TNF-α release from adipocytes.


Assuntos
Proteína ADAM17/antagonistas & inibidores , Proteínas de Transporte/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Resistência à Insulina/fisiologia , Obesidade/tratamento farmacológico , Trigonella , Proteína ADAM17/sangue , Animais , Proteínas de Transporte/sangue , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Inflamação/sangue , Inflamação/tratamento farmacológico , Mediadores da Inflamação/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Sementes
6.
Am J Chin Med ; 48(5): 1073-1090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32668968

RESUMO

Pro-inflammatory cytokines interfere with blood glucose homeostasis, which leads to hyperglycemia. Andrographis paniculata (AP) has been shown to possess anti-inflammatory activity and to reduce blood glucose levels in diabetes. The two major bioactive diterpenoids in AP, andrographolide (AND) and 14-deoxy-11,12-didehydroandrographolide (deAND), have potent anti-inflammatory activity. We studied whether APE (an ethanolic extract of AP), AND, and deAND could improve a high-fat diet (HFD)-induced hyperglycemia in vivo and TNF[Formula: see text]-induced impairment of insulin signaling in vitro. Male C57BL/6JNarl mice were fed a normal diet (ND) or the HFD, and the fatty mice were treated with APE, deAND, or AND for 16 weeks. 3T3-L1 cells were used to study the underlying mechanisms by which APE, deAND, or AND attenuated TNF[Formula: see text]-induced insulin resistance. The HFD significantly induced obesity, hyperglycemia, insulin resistance, and inflammation, whereas APE and deAND significantly ameliorated HFD-induced obesity, hyperglycemia, insulin resistance, and TNF[Formula: see text] production. The HFD significantly impaired insulin signaling by decreasing the protein expression of p-IRS1 tyr632 and p-AKT ser473, as well as the membrane translocation of GLUT4 in response to insulin stimulation in epididymal adipose tissue. HFD-impaired the membrane translocation of GLUT4 was significantly reversed by deAND and APE. In addition, deAND and APE markedly reversed the detrimental effect of TNF[Formula: see text] on the insulin signaling pathway and glucose uptake in 3T3-L1 cells. Despite no significant positive effect on p-AS160, a trend for recovery by deAND and APE was observed. These results suggest that deAND and APE protect against HFD-induced insulin resistance by ameliorating inflammation-driven impairment of insulin sensitivity.


Assuntos
Andrographis/química , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Obesidade/metabolismo , Extratos Vegetais/farmacologia , Células 3T3 , Animais , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Fitoterapia , Extratos Vegetais/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
7.
Arch Biochem Biophys ; 690: 108505, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32679195

RESUMO

Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (-)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity.


Assuntos
Catequina/farmacologia , Obesidade/tratamento farmacológico , Animais , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Comorbidade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Disbiose/metabolismo , Dislipidemias/metabolismo , Retículo Endoplasmático/metabolismo , Endotoxinas/metabolismo , Flavonoides/farmacologia , Humanos , Inflamação/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estresse Oxidativo
8.
Eur J Endocrinol ; 183(4): 439-452, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698159

RESUMO

Objective: Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Design: Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). Results: CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). Conclusions: A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.


Assuntos
Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Estrogênios Conjugados (USP)/farmacologia , Glucose/metabolismo , Indóis/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Estudos Cross-Over , Método Duplo-Cego , Estrogênios Conjugados (USP)/uso terapêutico , Feminino , Humanos , Indóis/uso terapêutico , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Projetos Piloto , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/metabolismo
9.
J Mol Cell Cardiol ; 146: 41-42, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32687852
11.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 6-11, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476366

RESUMO

OBJECTIVE: To observe the effects of dihydromyricetin (DHM) on obesity induced by high-fat diet in mice, and to explore whether its mechanism of action is related to the promotion of WAT browning. METHODS: Sixty c57bl/6j mice were randomly divided into 6 groups (n=10): ①normal control group (ND group): normal feed feeding; ②Normal control + low dose DHM group (ND+L-DHM group): normal feed feeding was treated with low dose DHM (125 mg/(kg·d)); ③Normal control + high dose DHM group (ND+H-DHM group): normal feed feeding was treated with high dose DHM (250 mg/(kg·d)); ④High-fat diet group (HFD): high-fat diet; ⑤high-fat diet + low-dose DHM group (HFD+L-DHM group): high-fat diet feeding with low-dose DHM; ⑥High-fat diet + high-dose DHM group (HFD+H-DHM group): High-fat diet was treated with high-dose DHM. After 16 weeks, the mice were fasted overnight, blood samples were collected for fasting blood glucose and blood lipids, then the animals were sacrificed, body length was measured, and Lee's index was calculated. After weighing the adipose tissue in the scapula, groin and epididymis, formaldehyde fixation and HE staining were used to observe the fat cells size, immunohistochemistry was used to detect the expression of uncoupling protein 1 (UCP1). The body weight was measured every 4 weeks during the experiment. RESULTS: Compared with the ND group, the body weight of the mice in the HFD group was increased significantly, suggesting that the obese mouse model replicated successfully. In addition, the body fat weight, fat cell diameter, Lee's index and blood glucose of the HFD group were increased significantly, and the expression of UCP1 in the adipocytes was increased. Body weight, fat cell diameter, Lee's index and blood glucose of HFD mice treated with L-DHM and H-DHM were reversed significantly, while the expression of UCP1 in adipocytes was more significantly increased; however, L-DHM and H-DHM had no significant effects on the above indicators in normal mice. CONCLUSION: Dihydromyricetin inhibited high fat diet induced mouse obesity; the mechanism might be associated with promoting WAT browning.


Assuntos
Tecido Adiposo Marrom/fisiologia , Dieta Hiperlipídica , Flavonóis/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Peso Corporal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
12.
Cent Eur J Public Health ; 28(2): 114-119, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32592555

RESUMO

OBJECTIVE: The aim of this analysis was to analyze the presence of the most important cardiovascular (CV) risk factors and to discuss patterns of LDL cholesterol management in the population studied. METHODS: We enrolled 961 males, average age of 42.9 ± 4.7, and 851 females, average age of 51.2 ± 3.6. Data on personal, pharmacological and family history, and laboratory examinations were collected. Cardiovascular (CV) risk was calculated using the Systematic Coronary Risk Evaluation (SCORE) algorithm with modifications according to the guidelines. RESULTS: The distribution of CV risk in the observed cohort was as follows: 24% of the subjects had low, 51% moderate, 17% high and 8% very high risk. The percentage of patients who reached target values of LDL cholesterol was dramatically lower in the groups with very high (1%) and high (3%) risk than in the groups with moderate (14%) or low risk (59%). Dyslipidemia was newly identified in 20% of both sexes. Arterial hypertension was newly diagnosed in 8% of males and 5% of females, and type 2 diabetes mellitus was newly diagnosed in 3% of both the males and females. Dyslipidemia was present in 39% of males and 41% of females; arterial hypertension in 43% of males and 45% of females, and type 2 diabetes mellitus was diagnosed in 11% of the subjects of both sexes. 49% of males and 31% of females were overweight and 32% of both genders were obese. There were 36% of male smokers and 22% of female smokers. 48% of the participants were pharmacologically treated. Non-pharmacological treatment was recommended to 62% of male and to 65% of female participants. Pharmacological intervention was started in 53% of males and 51% of females. In both gender antihypertensive treatment with angiotensin-converting enzyme (ACE) inhibitors (29% of males and 27% of females) and lipid lowering therapy with a statin (28% of males, 27% of females) were the most commonly initiated treatments. In the subgroup of the 101 patients with LDL cholesterol levels > 5 mmol/L 56% were not treated with a statin. The analysis of relationship between the positive family history of any of the followed CV risks showed significant increases of the risk for arterial hypertension, type 2 diabetes mellitus and dyslipidemia. CONCLUSION: European guidelines suggest general screening for risk factors, including analysis of lipid profiles in the population of 40-year-old males and 50-year-old or postmenopausal women. Our study documents high prevalence and incidence of CV risk factors together with insufficient control of the risk factors in Czech patients of this age range. This finding suggests that preventive examinations should be undertaken earlier (e.g., in 30-year-old males and 40-year-old women). Exact timing of the preventive check-ups to yield the best cost-benefit ratio needs to be verified.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/epidemiologia , Hipertensão/epidemiologia , Obesidade/epidemiologia , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , República Tcheca/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/tratamento farmacológico , Incidência , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Prevalência , Fatores de Risco , Inquéritos e Questionários
13.
Nutr. hosp ; 37(3): 483-489, mayo-jun. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-193855

RESUMO

INTRODUCCIÓN: el efecto del entrenamiento intervalado de alta intensidad (HIIT) sobre la utilización de grasas durante el ejercicio necesita ser estudiado en mayor profundidad. OBJETIVO: determinar el efecto de un programa de entrenamiento HIIT en sujetos con sobrepeso u obesidad sobre la utilización de grasas, la composición corporal y variables cardiovasculares. El segundo objetivo fue comparar las variables de estudio según el tiempo de duración del programa (es decir, 12,16 y 20 semanas). MATERIAL Y MÉTODOS: se estudiaron 30 sujetos (edad, 44,8 ± 11,6 años). Se formaron 3 grupos de forma aleatoria: el G1 realizó 12 semanas (G1, n = 12, 48,08 ± 8,20 años); el G2 realizó 16 semanas (G2, n = 10, 42,10 ± 11,60 años) y el G3 realizó 20 semanas (G3, n = 8, 43,38 ± 15,76 años). Todos los grupos realizaron el mismo protocolo de HIIT 3 veces por semana. RESULTADOS: los tres grupos presentaron una disminución de la grasa corporal de forma significativa (p < 0,05), sin diferencias entre grupos. Las variables cardiovasculares no reportaron diferencias entre grupos (p interacción > 0,05). Sin embargo, los grupos disminuyeron la presión arterial sistólica (p < 0,05). En el análisis pre vs. post, los tres grupos presentaron mejoras en el VO2max, sin diferencias entre grupos (p interacción, > 0,05). Por último, los tres grupos aumentaron la utilización de grasas durante el ejercicio (p < 0,05). CONCLUSIÓN: el programa incrementó la utilización de grasas durante el ejercicio, disminuyó el tanto por ciento de grasa corporal y se mejoraron parámetros cardiovasculares; sin embargo, después de las 12 semanas es recomendable aplicar variaciones al entrenamiento para maximizar los resultados


INTRODUCTION: the effect of high intensity interval training (HIIT) on fat utilization during exercise needs to be studied in depth. OBJECTIVE: to determine the effect of HIIT training program in subjects with overweight or obesity on the use of fat during exercise, body composition and cardiovascular variables. The second objective was to compare the variables according to the duration of the program (i.e., 12, 16 and 20 weeks). MATERIAL AND METHODS: 30 subjects were studied (age 44.8 ± 11.6 years). Three groups were formed at random, the G1 (12 weeks, n = 12, 48.08 ± 8.20 years), G2 (16 weeks, n = 10, 42.10 ± 11.60 years) and G3 (20 weeks, n = 8, 43.38 ± 15.76 years). All groups performed HIIT 3 times per week. RESULTS: the three groups showed a significant decrease in body fat percentage (p < 0.05), without differences between groups. Similarly, cardiovascular variables did not report differences between groups (p-interaction > 0.05) after the intervention; however, the groups reported a significant decrease systolic blood pressure (p < 0, 05). In the pre vs. post analysis by groups, the three groups showed improvements in VO2max without differences between groups (p-interaction > 0.05). Finally, the three groups increased the fats utilization during exercise (p < 0.05). CONCLUSION: the program increased fat utilization during exercise, decreased body fat % and improved cardiovascular parameters, however after 12 training weeks it is advisable to apply variations to training to maximize results


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Ácidos Graxos/administração & dosagem , Sobrepeso/tratamento farmacológico , Obesidade/tratamento farmacológico , Exercício Físico , Pressão Arterial/fisiologia , Composição Corporal , Ingestão de Alimentos , Gorduras na Dieta , Análise de Variância , Antropometria
14.
Obesity (Silver Spring) ; 28(7): 1254-1262, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32568464

RESUMO

OBJECTIVE: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 (13 C)-labeled glycerol. METHODS: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U-13 C3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models. RESULTS: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss. CONCLUSIONS: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gluconeogênese/efeitos dos fármacos , Glucosídeos/uso terapêutico , Glicerol/metabolismo , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adulto , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Feminino , Humanos , Gordura Intra-Abdominal , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Placebos , Perda de Peso/efeitos dos fármacos
15.
Arch Biochem Biophys ; 689: 108470, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32592802

RESUMO

The accumulation of lipid as a result of long-term consumption of a high-fat diet (HFD) may lead to metabolic and brain dysfunction. Atorvastatin, a recommended first-line lipid-lowering agent, has shown beneficial effects on metabolic and brain functions in several models. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was approved as an effective therapeutic drug for dyslipidemia patients. However, few studies have reported on the effect of this PCSK9 inhibitor on brain function. In addition, the comparative efficacy on the improvement of metabolic and brain functions between PCSK9 inhibitor and atorvastatin in obese models have not been elucidated. We hypothesized that PCSK9 inhibitor improves metabolic and brain functions in an obese model to a greater extent than atorvastatin. Thirty-two female rats were fed with either a normal diet (ND) or HFD for 15 weeks. At week 13, ND rats were given normal saline and HFD rats were given either normal saline, atorvastatin (40 mg/kg/day) or PCSK9 inhibitor (4 mg/kg/day) for 3 weeks. Oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity, apoptosis, amyloid proteins production in the hippocampus and cognitive decline were found in HFD-fed rats. Atorvastatin and PCSK9 inhibitor therapies equally attenuated hippocampal apoptosis and amyloid protein production in HFD-fed rats. Interestingly, PCSK9 inhibitor had the greater efficacy than atorvastatin on the amelioration of hippocampal oxidative stress, blood brain barrier breakdown, microglial hyperactivity, synaptic dysplasticity in the hippocampus and cognitive decline. These findings suggest that PCSK9 inhibitor may be another drug of choice for improving brain function in the obese condition with discontinued statin therapy.


Assuntos
Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Obesidade/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Feminino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Pró-Proteína Convertase 9/metabolismo , Ratos
16.
Clin Drug Investig ; 40(8): 695-713, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32583294

RESUMO

Polycystic ovary syndrome is a complex and heterogenous disorder involving multiple organ systems and different molecular pathways. It is tightly associated with obesity and especially abdominal obesity. As body weight reduction is the main modifiable risk factor for polycystic ovary syndrome, therapeutic approaches in overweight or obese women with polycystic ovary syndrome have been developed. Liraglutide is a glucagon-like peptide-1 receptor agonist that promotes sustained weight loss, as well as abdominal fat reduction, in individuals with obesity, prediabetes, and type 2 diabetes mellitus. The majority of current clinical studies have demonstrated that liraglutide therapy achieved significant reductions in body weight, body mass index, and abdominal circumference in overweight and obese women with polycystic ovary syndrome. Liraglutide therapy promoted significant improvements in free testosterone and sex hormone-binding globulin levels in some studies. Important metabolic and hormonal improvements were also reported after the combination of liraglutide with metformin. Increased menstrual frequency, as well as potential positive effects in reproduction, were described. However, the small number of participants, short duration, and low daily liraglutide dose are some of the main limitations of these studies. Larger and longer, multi-centred, double-blind, placebo-controlled trials of liraglutide monotherapy or combination therapy, with prolonged post-interventional monitoring, are crucially anticipated. Metabolic, hormonal, and reproductive primary outcomes should be uniformly addressed, to tailor future targeted treatment approaches, according to the patient phenotype and needs. This will improve long-term therapeutic outcomes in this population.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Liraglutida/uso terapêutico , Síndrome do Ovário Policístico/complicações , Adulto , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Metformina/administração & dosagem , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Sobrepeso/complicações , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/fisiopatologia , Perda de Peso/efeitos dos fármacos
17.
Arch Endocrinol Metab ; 64(3): 290-297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555996

RESUMO

OBJECTIVE: To evaluate the use of metformin for preventing cesarean deliveries and large-for-gestational-age (LGA) newborn (NB) outcomes in non-diabetic obese pregnant women. SUBJECTS AND METHODS: This is a randomized clinical trial with obese pregnant women, divided into 2 groups: metformin group and control group, with followed-up prenatal routine. The gestational age of participants was less than or equal to 20 weeks and were monitored throughout entire prenatal period. For outcomes of delivery and LGA newborns, absolute risk reduction (ARR) and the number needed to treat (NNT) were calculated with a 95% confidence interval (CI). RESULTS: 357 pregnant women were evaluated. From the metformin group (n = 171), 68 (39.8%) subjects underwent cesarean delivery, and 117 (62.9%) subjects from the control group (n = 186) had intercurrence (p < 0.01). As for the mothers' general characteristics, there was significance for marital status (p < 0.01). Maternal-fetal results presented reduced preeclampsia (p < 0,01). Primary prophylactic results presented an ARR of 23.1 times (95% CI: 13.0-33.4) with NNT of 4 (95% CI: 3.0-7.7) and no significant values for LGA NB (p > 0.01). Secondary prophylactic outcomes presented decreased odds ratio for preeclampsia (OR = 0.17, 95% CI: 0.10-0.41). CONCLUSION: The use of metformin reduced cesarean section rates, resulted in a small number of patients to be treated, but it did not reduce LGA NB. Administering a lower dosage of metformin from the early stages to the end of treatment may yield significant results with fewer side effects. Arch Endocrinol Metab. 2020;64(3):290-7.


Assuntos
Cesárea/estatística & dados numéricos , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Obesidade/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Fatores Socioeconômicos
18.
PLoS One ; 15(6): e0229806, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555600

RESUMO

The A2 adenosine receptors play an important role, among others, in the regulation of inflammatory process and glucose homeostasis in diabetes and obesity. Thus, the presented project evaluated of influence of the selective antagonist of A2A adenosine receptor-KD-64 as compared to the known non-selective antagonist-caffeine on these two particular processes. Two different inflammation models were induced namely local and systemic inflammation. Obesity was induced in mice by high-fat diet and the tested compounds (KD-64 and caffeine) were administrated for 21 days. KD-64 showed anti-inflammatory effect in both tested inflammation models and administered at the same dose as ketoprofen exerted stronger effect than this reference compound. Elevated levels of IL-6 and TNF-α observed in obese control mice were significantly lowered by the administration of KD-64 and were similar to the values observed in control non-obese mice. Interestingly, caffeine increased the levels of these parameters. In contrast to caffeine which had no influence on AlaT activity, KD-64 administration significantly lowered AlaT activity in the obese mice. Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance. Thus, the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Anti-Inflamatórios/farmacologia , Dieta/efeitos adversos , Antagonistas do Receptor A2 de Adenosina/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Peso Corporal/efeitos dos fármacos , Cafeína/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Resistência à Insulina , Interleucina-6/sangue , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Peritônio/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangue
19.
FP Essent ; 492: 25-29, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32383845

RESUMO

Pharmacotherapy, adjunctively with lifestyle interventions, is an option for any patient diagnosed with obesity (ie, body mass index [BMI] of 30 kg/m2 or greater) or with a BMI of 27 kg/m2 or greater and at least one coexisting condition, including type 2 diabetes, hypertension, hyperlipidemia, and sleep apnea. If the appropriate criteria are met, pharmacotherapy should be initiated for patients with overweight or obesity if lifestyle modification does not produce adequate weight loss. Lifestyle modifications should be continued and emphasized throughout treatment because it has been shown that adjunctive pharmacotherapy produces greater weight loss and weight loss maintenance than lifestyle interventions alone. Currently, five drugs are approved for weight management in adults: phentermine, orlistat, phentermine-topiramate, bupropion-naltrexone, and liraglutide. Certain drugs are approved for short-term management while others are approved for long-term management. Drug therapy should be customized to the individual patient, depending on needs, contraindications, and cost. Benefits of these drugs should be assessed regularly and a different drug should be considered if at least 5% of body weight is not lost by 3 months of therapy.


Assuntos
Fármacos Antiobesidade , Diabetes Mellitus Tipo 2 , Obesidade , Adulto , Fármacos Antiobesidade/uso terapêutico , Benzazepinas , Diabetes Mellitus Tipo 2/complicações , Humanos , Obesidade/complicações , Obesidade/tratamento farmacológico , Fentermina/uso terapêutico
20.
Obesity (Silver Spring) ; 28(6): 1068-1074, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32352644

RESUMO

OBJECTIVE: Epicardial adipose tissue (EAT) thickness is a marker of visceral fat and an emerging therapeutic target. Dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, improves glucose control and induces moderate weight loss in patients with type 2 diabetes mellitus. Dapagliflozin has recently been shown to reduce cardiovascular risk. Nevertheless, whether dapagliflozin could reduce EAT thickness is unknown. METHODS: This hypothesis was tested in a 24-week, randomized, double-blind, placebo-controlled clinical trial in 100 patients with type 2 diabetes mellitus with BMI ≥ 27 kg/m2 and a hemoglobin A1c level ≤ 8% on metformin monotherapy. Individuals were randomly assigned to 2 groups to receive additional dapagliflozin up to 10 mg once daily or to remain on metformin up to 1,000 mg twice daily. Ultrasound-measured EAT thickness was measured at baseline, 12 weeks, and 24 weeks. RESULTS: In the dapagliflozin group, EAT decreased by 20% from baseline to 24 weeks, by 15% after 12 weeks, and by 7% between 12 and 24 weeks, respectively (P < 0.01 for all), whereas in the metformin group, there was a significant but smaller EAT reduction. There was no statistically significant correlation between EAT and body weight changes. CONCLUSIONS: Dapagliflozin causes a rapid and significant EAT reduction that could be independent of weight loss.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Compostos Benzidrílicos/farmacologia , Método Duplo-Cego , Feminino , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
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