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1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361032

RESUMO

17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Benzoatos/uso terapêutico , Obesidade/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adipogenia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/farmacologia , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Graxos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia
2.
Ann Intern Med ; 174(8): JC88, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34339232

RESUMO

SOURCE CITATION: Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325:1414-25. 33755728.


Assuntos
Sobrepeso , Perda de Peso , Adulto , Método Duplo-Cego , Peptídeos Semelhantes ao Glucagon , Humanos , Injeções Subcutâneas , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico
3.
Plant Foods Hum Nutr ; 76(3): 363-370, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34378171

RESUMO

Elicitation is a biotechnological approach to improve phenolic compounds content and antioxidant properties of ready-to-eat functional foods. This study aimed to evaluate the chemical elicitation effects using salicylic acid (SA) and hydrogen peroxide (H2O2) in optimized-germination conditions on seedling vigor, phenolic content, and their antioxidant capacities in vitro and serum and urine of Wistar obese rats. Optimized-germination conditions of 26.5 °C and 178 h produced a 64% of germination and a sprout length of 56 mm. Only, the elicitation with H2O2 (20 mM) enhanced the germination (75%) and H2O2 (10 and 20 mM) the sprout length (69 and 59 mm, respectively). In contrast, both elicitors enhanced phenolic contents, being more significant total phenolic compounds content for SA (1 and 2 mM), up to 65.5-73.5%. SA and H2O2 improved total flavonoids content (36.5-64.1%), ABTS (19.3-61.1%), and DPPH capacities (51-86%), depending on SA and H2O2 concentration, compared with non-elicited chia sprouts. The QUENCHER antioxidant capacities of elicited chia sprouts increased up to three times more than extracts capacities, principally Q-ABTS, which could be attributed to phenolic bounds to dietary fiber. Rats fed with a high-fat and fructose diet (HFFD) and supplemented with chia sprouts, especially 1-mM SA, improve the obesity-related oxidative stress through an increase of antioxidant capacities, using DPPH and ABTS test, on serum (70-118%) and urine samples (80-116%). These results suggest that chia sprouts elicited with 1-mM SA are a source of antioxidant compounds that can be used to decrease obesity related oxidative stress.


Assuntos
Antioxidantes , Peróxido de Hidrogênio , Animais , Antioxidantes/farmacologia , Obesidade/tratamento farmacológico , Ratos , Ratos Wistar , Ácido Salicílico/farmacologia , Sementes
4.
Plant Foods Hum Nutr ; 76(3): 377-384, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34462872

RESUMO

The two main components from a Nelumbo nucifera leaf extract (NnEx) were investigated for their ability to prevent triglyceride accumulation and promoting lipolysis. Sun-dried Nelumbo nucifera leaves were immersed in hot water to extract the soluble components, and the resulting solution was analyzed by LC-MS and nuclear magnetic resonance. The results showed that quercetin-3-O-ß-glucuronide (Q3GA) and quercetin were the key components of the NnEx. In vitro experiments confirmed that quercetin and Q3GA functioned in lipid metabolism by promoting triglyceride degradation through inhibition of the cAMP pathway. In vivo experiments showed that NnEx ingestion inhibited the accumulation of neutral fats in ICR mice and transitioned the hepatocytes of type II diabetic KK-Ay mice out of glycogenosis. These results highlight the ability of NnEx to control metabolism by modulating fat and sugar absorption and may provide an interesting novel treatment for obesity and related lifestyle diseases such as type II diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Nelumbo , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Obesidade/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta
5.
Adipocyte ; 10(1): 408-411, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34402717

RESUMO

Angiotensin converting enzyme-2 (ACE2) is the cell-surface receptor enabling cellular entry of SARS-CoV-2. ACE2 is highly expressed in adipose tissue (AT), rendering AT a potential SARS-CoV-2 reservoir contributing to massive viral spread in COVID-19 patients with obesity. Although rodent and cell studies suggest that the polyphenol resveratrol alters ACE2, human studies are lacking. Here, we investigated the effects of 30-days resveratrol supplementation on RAS components in AT and skeletal muscle in men with obesity in a placebo-controlled cross-over study. Resveratrol markedly decreased ACE2 (~40%) and leptin (~30%), but did neither alter angiotensinogen, ACE and AT1R expression in AT nor skeletal muscle RAS components. These findings demonstrate that resveratrol supplementation reduces ACE2 in AT, which might dampen SARS-CoV-2 spread in COVID-19.


Assuntos
Tecido Adiposo/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Resveratrol/administração & dosagem , Tecido Adiposo/citologia , Enzima de Conversão de Angiotensina 2/genética , COVID-19/patologia , COVID-19/virologia , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Regulação para Baixo/efeitos dos fármacos , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/patologia , Efeito Placebo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Resveratrol/farmacologia , SARS-CoV-2/isolamento & purificação
7.
J Agric Food Chem ; 69(32): 9299-9312, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34342980

RESUMO

Ginsenoside F2 (GF2) is a protopanaxdiol saponin from Panax ginseng leaves and possesses many potential pharmacological properties. GF2 may prevent obesity by directly binding to the peroxisome proliferator-activated receptor-γ (PPARγ) and inhibiting adipocyte differentiation. However, the mechanism by which GF2 alleviates obesity is unknown. We therefore explored the anti-adipogenesis and anti-obesity effects of GF2 in vitro and in vivo. GF2 inhibited differentiation and reduced the triglyceride (TG) content of 3T3-L1 preadipocytes in the early stage of adipogenesis. Administration of GF2 (50 and 100 mg/kg) to obese mice for 4 weeks reduced the body weight gain, weight of adipose tissues, adipocyte size, and total cholesterol, TG, and AST levels in serum. RNA sequencing and real-time quantitative PCR indicated that GF2 decreased the expression levels of adipokines, including PPARγ, fatty acid synthase, and adiponectin. KEGG enrichment and western blot analyses demonstrated that GF2 accelerated the phosphorylation of AMPK and ACC in vitro and in vivo. Moreover, GF2 promoted the biosynthesis of mitochondria in 3T3-L1 adipocytes and increased the expression of antioxidant enzymes such as SOD and GSH-Px in the liver of obese mice. Therefore, GF2 suppressed adipogenesis and obesity by regulating the expression of adipokines and activating the AMPK pathway. Hence, the findings suggest that GF2 may have potential therapeutic implications to treat obesity.


Assuntos
Adipogenia , Fármacos Antiobesidade , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipogenia/genética , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Ginsenosídeos , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/genética , PPAR gama/genética
8.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445208

RESUMO

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.


Assuntos
Temperatura Baixa , Canais de Cátion TRPM , Sensação Térmica , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/metabolismo , Humanos , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/genética , Doenças Respiratórias/metabolismo , Canais de Cátion TRPM/química , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Doenças Urológicas/tratamento farmacológico , Doenças Urológicas/genética , Doenças Urológicas/metabolismo
9.
Medicina (Kaunas) ; 57(8)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34441028

RESUMO

Non-alcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is a metabolic condition distinguished by fat deposition in the hepatocytes. It has a prevalence of about 25% worldwide and is associated with other conditions such as diabetes mellitus, obesity, hypertension, etc. Background and Objectives: There is currently no approved drug therapy for NAFLD. Current measures in the management of NAFLD include lifestyle modification such as an increase in physical activity or weight loss. Development of NAFLD involves a number of parallel hits: including genetic predisposition, insulin resistance, disordered lipid metabolism, mitochondrial dysfunction, lipotoxicity, oxidative stress, etc. Herbal therapy may have a role to play in the treatment of NAFLD, due to their numerous bioactive constituents and the multiple pharmacological actions they exhibit. Therefore, this systematic review aims to investigate the potential multi-targeting effects of plant-derived extracts in experimental models of NAFLD. Materials and Methods: We performed a systematic search on databases and web search engines from the earliest available date to 30 April 2021, using relevant keywords. The study included articles published in English, assessing the effects of plant-derived extracts, fractions, or polyherbal mixtures in the treatment of NAFLD in animal models. These include their effects on at least disordered lipid metabolism, insulin resistance/type 2 diabetes mellitus (T2DM), and histologically confirmed steatosis with one or more of the following: oxidative stress, inflammation, hepatocyte injury, obesity, fibrosis, and cardiometabolic risks factors. Results: Nine articles fulfilled our inclusion criteria and the results demonstrated the ability of phytomedicines to simultaneously exert therapeutic actions on multiple targets related to NAFLD. Conclusions: These findings suggest that herbal extracts have the potential for effective treatment or management of NAFLD.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Animais , Fígado , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/complicações , Obesidade/tratamento farmacológico , Fitoterapia
10.
Biomed Res Int ; 2021: 9924314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368359

RESUMO

Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N-methyltransferase (NNMT) has been emerging as a new mechanism-of-action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small-molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.


Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Nicotinamida N-Metiltransferase/metabolismo , Obesidade/enzimologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metabolismo Energético , Humanos , Redes e Vias Metabólicas , Terapia de Alvo Molecular , Obesidade/tratamento farmacológico
11.
Nutrients ; 13(6)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34205871

RESUMO

Background: Increasing evidence supports the role of the gut microbiota in the control of body weight and feeding behavior. Moreover, recent studies have reported that the probiotic strain Hafnia alvei HA4597® (HA), which produces the satietogenic peptide ClpB mimicking the effect of alpha-MSH, reduced weight gain and adiposity in rodent models of obesity. Methods: To investigate the clinical efficacy of HA, 236 overweight subjects were included, after written informed consent, in a 12-week prospective, double-blind, randomized study. All subjects received standardized counselling for a -20% hypocaloric diet and were asked to maintain their usual physical activity. Subjects of the HA group received two capsules per day providing 100 billion bacteria per day and subjects in the Placebo (P) group received two placebo capsules. The primary endpoint was the percentage of subjects achieving a weight loss of at least 3% after 12 weeks. Intention-to-treat statistical analysis was performed using exact-Fischer, Mann-Whitney and paired-Wilcoxon tests as appropriate. Results: In the HA group, significantly more subjects (+33%) met the primary endpoint than in the P group (54.9 vs. 41.4%, p = 0.048). In the HA group, an increased feeling of fullness (p = 0.009) and a greater loss of hip circumference (p < 0.001) at 12 weeks were also observed. Fasting glycemia at 12 weeks was significantly lower (p < 0.05) in the HA compared to P group. Clinical and biological tolerance was good in both groups. Conclusions: A 12-week treatment with the probiotic strain H. alvei HA4597® significantly improves weight loss, feeling of fullness and reduction of hip circumference in overweight subjects following moderate hypocaloric diet. These data support the use of H. alvei HA4597® in the global management of excess weight.


Assuntos
Dieta Redutora , Hafnia alvei/fisiologia , Sobrepeso/tratamento farmacológico , Probióticos/uso terapêutico , Perda de Peso/efeitos dos fármacos , Adolescente , Adulto , Idoso , Fármacos Antiobesidade/uso terapêutico , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Exercício Físico , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Estudos Prospectivos , Estatísticas não Paramétricas , Adulto Jovem
12.
FASEB J ; 35(8): e21794, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34314059

RESUMO

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high-fat diet (HFD)-induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD-induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway-driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Biglicano/administração & dosagem , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Obesidade/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular , Comportamento Alimentar , Camundongos , Camundongos Endogâmicos ICR , Ratos
13.
Trials ; 22(1): 464, 2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281590

RESUMO

BACKGROUND: Preclinical studies demonstrated that glucagon-like peptide 1 (GLP-1) is locally synthesized in taste bud cells and that GLP-1 receptor exists on the gustatory nerves in close proximity to GLP-1-containing taste bud cells. This local paracrine GLP-1 signalling seems to be specifically involved in the perception of sweets. However, the role of GLP-1 in taste perception remains largely unaddressed in clinical studies. Whether any weight-reducing effects of GLP-1 receptor agonists are mediated through the modulation of taste perception is currently unknown. METHODS AND ANALYSIS: This is an investigator-initiated, randomized single-blind, placebo-controlled clinical trial. We will enrol 30 women with obesity and polycystic ovary syndrome (PCOS). Participants will be randomized in a 1:1 ratio to either semaglutide 1.0 mg or placebo for 16 weeks. The primary endpoints are alteration of transcriptomic profile of tongue tissue as changes in expression level from baseline to follow-up after 16 weeks of treatment, measured by RNA sequencing, and change in taste sensitivity as detected by chemical gustometry. Secondary endpoints include change in neural response to visual food cues and to sweet-tasting substances as assessed by functional MRI, change in body weight, change in fat mass and change in eating behaviour and food intake. DISCUSSION: This is the first study to investigate the role of semaglutide on taste perception, along with a neural response to visual food cues in reward processing regions. The study may identify the tongue and the taste perception as a novel target for GLP-1 receptor agonists. ETHICS AND DISSEMINATIONS: The study has been approved by the Slovene National Medical Ethics Committee and will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Results will be submitted for publication in an international peer-reviewed scientific journal. TRIAL REGISTRATION: ClinicalTrials.gov NCT04263415 . Retrospectively registered on 10 February 2020.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Método Duplo-Cego , Feminino , Peptídeos Semelhantes ao Glucagon , Humanos , Hipoglicemiantes/efeitos adversos , Obesidade/diagnóstico , Obesidade/tratamento farmacológico , Percepção , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Paladar
14.
Int J Clin Pharmacol Ther ; 59(8): 539-548, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34236303

RESUMO

OBJECTIVE: Mexico has the second largest prevalence of obesity among adults worldwide, a condition especially affecting the low-income population. There is a pressing need to improve therapeutic options for weight loss. Phentermine is an old and low-cost agent given as an adjuvant therapy for obesity for a 12-week period, at an initial dose of 15 mg or 30 mg. However, there are no precise guidelines on the suitability of both the starting dose and the continuation of treatment for 6 months. The aim of this study was to evaluate the 3- and 6-month efficacy and safety of phentermine in obese Mexican patients to elucidate the aforementioned. MATERIALS AND METHODS: In this prospective, multi-center, open-label study, 932 obese adults received 15 mg or 30 mg phentermine once daily for 6 months. RESULTS: 30 mg phentermine was more effective than 15 mg phentermine in improving anthropometric variables in the 3-month follow-up, but not after completing the 6-month treatment period. Nearly 40% of 3-month non-responders reached a body weight reduction of at least 5% at 6 months. Conversely, ~ 65% and 25% of 3-month responders maintained or improved, respectively, their body weight reduction with long-term phentermine. Potential tolerance as weight regain was ~ 10% from 3 to 6 months. None of the doses increased cardiovascular risk, although mild-to-moderate adverse events were more frequent with 30 mg phentermine. CONCLUSION: 30 mg phentermine was more effective than 15 mg phentermine after 3 months, but not at 6 months of treatment. An important number of subjects could benefit following the therapy from 3 to 6 months.


Assuntos
Fármacos Antiobesidade , Depressores do Apetite , Adulto , Fármacos Antiobesidade/efeitos adversos , Humanos , México , Obesidade/tratamento farmacológico , Fentermina/efeitos adversos , Estudos Prospectivos
15.
Molecules ; 26(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299638

RESUMO

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Transdução de Sinais , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologia
16.
BMJ Open ; 11(7): e045663, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285005

RESUMO

INTRODUCTION: The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity. METHODS AND ANALYSIS: 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA1c ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1) energy balance (energy intake and energy expenditure measured by indirect calorimetry); (2) appetite (between and within meals) and satiety quotient; (3) body composition including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include metabolic changes in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), central nervous system responses to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and changes in cardiovascular function (using transthoracic echocardiography, cardiac MR and duplex ultrasonography). ETHICS AND DISSEMINATION: This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and/or presented at scientific conferences and summarised for distribution to the participants. TRIAL SPONSOR: University of Liverpool. TRIAL REGISTRATION NUMBER: ISRCTN 52028580; EUDRACT number 2015-005242-60.


Assuntos
Diabetes Mellitus Tipo 2 , Compostos Benzidrílicos , Glicemia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Exenatida , Glucosídeos , Hemoglobina A Glicada/análise , Humanos , Hipoglicemiantes/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
J Thromb Haemost ; 19(8): 1874-1882, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34259389

RESUMO

Although direct-acting oral anticoagulants (DOACs) have widespread first-line use for treatment and prevention of venous thromboembolism (VTE), uncertainty remains regarding their efficacy and safety in patients with obesity. We reviewed available data for use of DOACs for VTE treatment and prevention in patients with obesity, including phase 3, phase 4, meta-analyses, and pharmacokinetic and pharmacodynamics studies. In addition, we reviewed available data regarding DOACs in bariatric surgery. We provide updated guidance recommendations on using DOACs in patients with obesity for treatment and prevention of VTE, as well as following bariatric surgery.


Assuntos
Tromboembolia Venosa , Administração Oral , Anticoagulantes/efeitos adversos , Comunicação , Humanos , Obesidade/complicações , Obesidade/tratamento farmacológico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle
18.
Adv Exp Med Biol ; 1291: 121-137, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34331687

RESUMO

BACKGROUND: Curcumin is an active molecule present in turmeric and is the main therapeutic compound. There is growing evidence that curcumin could affect various anthropometric indices. We performed a systematic review to evaluate the efficacy of curcumin supplementation on anthropometric indices in obese and overweight individuals. METHODS: A comprehensive search was conducted in PubMed, Scopus, Web of Science, and Google Scholar from inception up to February 2020 to identify randomized controlled trials investigating the effect of curcumin supplementation on anthropometric indices including body weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), arm circumference (AC), waist-hip ratio (WHR), total body fat (TBF), and visceral fat (VF) in obese and overweight individuals. The Jadad scale was used to assess the quality of the included studies. RESULT: Twenty-eight randomized controlled trials, comprising 2168 participants, were included in the systematic review. The results of 16 papers indicated that curcumin reduced at least one of the anthropometric indices among individuals with a BMI ≥ 25 kg/m2. Nevertheless, 12 articles showed that curcumin supplementation was not effective in any of the measured anthropometric factors. The included trials exhibited substantial heterogeneity in terms of the treatment protocol, follow-up duration, curcumin dosage, and background diseases of the participants. CONCLUSION: Clinical trials that have independently examined the effects of curcumin in obese or overweight individuals are limited. However, available studies indicate that curcumin has beneficial impacts on various anthropometric indices. Further trials with longer duration of interventions are needed to confirm these findings.


Assuntos
Curcumina , Índice de Massa Corporal , Peso Corporal , Curcumina/uso terapêutico , Suplementos Nutricionais , Humanos , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209270

RESUMO

Resveratrol butyrate esters (RBE) are derivatives of resveratrol (RSV) and butyric acid and exhibit biological activity similar to that of RSV but with higher bioavailability. The aim of this study was designed as an animal experiment to explore the effects of RBE on the serum biochemistry, and fat deposits in the offspring rats exposed to bisphenol A (BPA), along with the growth and decline of gut microbiota. We constructed an animal model of perinatal Bisphenol A (BPA) exposure to observe the effects of RBE supplementation on obesity, blood lipids, and intestinal microbiota in female offspring rats. Perinatal exposure to BPA led to weight gain, lipid accumulation, high levels of blood lipids, and deterioration of intestinal microbiota in female offspring rats. RBE supplementation reduced the weight gain and lipid accumulation caused by BPA, optimised the levels of blood lipids, significantly reduced the Firmicutes/Bacteroidetes (F/B) ratio, and increased and decreased the abundance of S24-7 and Lactobacillus, respectively. The analysis of faecal short-chain fatty acid (SCFA) levels revealed that BPA exposure increased the faecal concentration of acetate, which could be reduced via RBE supplementation. However, the faecal concentrations of propionate and butyrate were not only significantly lower than that of acetate, but also did not significantly change in response to BPA exposure or RBE supplementation. Hence, RBE can suppress BPA-induced obesity in female offspring rats, and it demonstrates excellent modulatory activity on intestinal microbiota, with potential applications in perinatological research.


Assuntos
Compostos Benzidrílicos/toxicidade , Ácido Butírico/farmacologia , Obesidade , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Resveratrol/farmacologia , Animais , Ácidos Graxos Voláteis/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley
20.
Molecules ; 26(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34210097

RESUMO

Obesity and hyperlipidemia are metabolic dysregulations that arise from poor lifestyle and unhealthy dietary intakes. These co-morbidity conditions are risk factors for vascular diseases. Piper sarmentosum (PS) is a nutritious plant that has been shown to pose various phytochemicals and pharmacological actions. This study aimed to investigate the effect of PS on obesity and hyperlipidemia in an animal model. Forty male Wistar rats were randomly divided into five experimental groups. The groups were as follows: UG-Untreated group; CTRL-control; FDW-olive oil + 20% fructose; FDW-PS-PS (125 mg/kg) + 20% fructose; FDW-NGN-naringin (100 mg/kg) + 20% fructose. Fructose drinking water was administered daily for 12 weeks ad libitum to induce metabolic abnormality. Treatment was administered at week 8 for four weeks via oral gavage. The rats were sacrificed with anesthesia at the end of the experimental period. Blood, liver, and visceral fat were collected for further analysis. The consumption of 20% fructose water by Wistar rats for eight weeks displayed a tremendous increment in body weight, fat mass, percentage fat, LDL, TG, TC, HMG-CoA reductase, leptin, and reduced the levels of HDL and adiponectin as well as adipocyte hypertrophy. Following the treatment period, FDW-PS and FDW-NGN showed a significant reduction in body weight, fat mass, percentage fat, LDL, TG, TC, HMG-CoA reductase, and leptin with an increment in the levels of HDL and adiponectin compared to the FDW group. FDW-PS and FDW-NGN also showed adipocyte hypotrophy compared to the FDW group. In conclusion, oral administration of 125 mg/kg PS methanolic extract to fructose-induced obese rats led to significant amelioration of obesity and hyperlipidemia through suppressing the adipocytes and inhibiting HMG-CoA reductase. PS has the potential to be used as an alternative or adjunct therapy for obesity and hyperlipidemia.


Assuntos
Frutose/efeitos adversos , Hiperlipidemias , Síndrome Metabólica , Metanol/química , Obesidade , Piper/química , Extratos Vegetais , Animais , Frutose/farmacologia , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar
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