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1.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445679

RESUMO

It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their ability to improve metabolic syndromes, and they have also been proposed as classical drug targets for the treatment of hyperlipidemia and type 2 diabetes (T2D) mellitus. In parallel, adipose tissue is known to play a unique role in the pathogenesis of insulin resistance and metabolic syndromes due to its ability to "safely" store lipids and secrete cytokines that regulate whole-body metabolism. Adipose tissue relies on a complex and subtle network of transcription factors to maintain its normal physiological function, by coordinating various molecular events, among which PPARs play distinctive and indispensable roles in adipocyte differentiation, lipid metabolism, adipokine secretion, and insulin sensitivity. In this review, we discuss the characteristics of PPARs with special emphasis on the roles of the different isotypes in adipocyte biology.


Assuntos
Tecido Adiposo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Adipócitos/fisiologia , Homeostase , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia
2.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445677

RESUMO

Adiponectin is an adipokine associated with the healthy obese phenotype. Adiponectin increases insulin sensitivity and has cardio and vascular protection actions. Studies related to adiponectin, a modulator of the innate and acquired immunity response, have suggested a role of this molecule in asthma. Studies based on various asthma animal models and on the key cells involved in the allergic response have provided important insights about this relation. Some of them indicated protection and others reversed the balance towards negative effects. Many of them described the cellular pathways activated by adiponectin, which are potentially beneficial for asthma prevention or for reduction in the risk of exacerbations. However, conclusive proofs about their efficiency still need to be provided. In this article, we will, briefly, present the general actions of adiponectin and the epidemiological studies supporting the relation with asthma. The main focus of the current review is on the mechanisms of adiponectin and the impact on the pathobiology of asthma. From this perspective, we will provide arguments for and against the positive influence of this molecule in asthma, also indicating the controversies and sketching out the potential directions of research to complete the picture.


Assuntos
Adiponectina/metabolismo , Asma/metabolismo , Asma/fisiopatologia , Adipocinas/metabolismo , Adiponectina/fisiologia , Humanos , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445300

RESUMO

Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic ß-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to ß-cell decline through the IAPP-RAGE induced ß-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.


Assuntos
Resistência à Insulina/fisiologia , Insulina/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia
4.
Nutrients ; 13(7)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209599

RESUMO

Amino acids are needed for general bodily function and well-being. Despite their importance, augmentation in their serum concentration is closely related to metabolic disorder, insulin resistance (IR), or worse, diabetes mellitus. Essential amino acids such as the branched-chain amino acids (BCAAs) have been heavily studied as a plausible biomarker or even a cause of IR. Although there is a long list of benefits, in subjects with abnormal amino acids profiles, some amino acids are correlated with a higher risk of IR. Metabolic dysfunction, upregulation of the mammalian target of the rapamycin (mTOR) pathway, the gut microbiome, 3-hydroxyisobutyrate, inflammation, and the collusion of G-protein coupled receptors (GPCRs) are among the indicators and causes of metabolic disorders generating from amino acids that contribute to IR and the onset of type 2 diabetes mellitus (T2DM). This review summarizes the current understanding of the true involvement of amino acids with IR. Additionally, the involvement of GPCRs in IR will be further discussed in this review.


Assuntos
Aminoácidos/metabolismo , Resistência à Insulina/fisiologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Diabetes Mellitus Tipo 2/sangue , Microbioma Gastrointestinal , Humanos , Doenças Metabólicas/sangue , Regulação para Cima
5.
Int J Mol Sci ; 22(13)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34281257

RESUMO

The modern lifestyle brings both excessive fructose consumption and daily exposure to stress which could lead to metabolic disturbances and type 2 diabetes. Muscles are important points of glucose and lipid metabolism, with a crucial role in the maintenance of systemic energy homeostasis. We investigated whether 9-week fructose-enriched diet, with and without exposure to 4-week unpredictable stress, disturbs insulin signaling in the skeletal muscle of male rats and evaluated potential contributory roles of muscle lipid metabolism, glucocorticoid signaling and inflammation. The combination of fructose-enriched diet and stress increased peroxisome proliferator-activated receptors-α and -δ and stimulated lipid uptake, lipolysis and ß-oxidation in the muscle of fructose-fed stressed rats. Combination of treatment also decreased systemic insulin sensitivity judged by lower R-QUICKI, and lowered muscle protein content and stimulatory phosphorylations of insulin receptor supstrate-1 and Akt, as well as the level of 11ß-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor. At the same time, increased levels of protein tyrosine phosphatase-1B, nuclear factor-κB, tumor necrosis factor-α, were observed in the muscle of fructose-fed stressed rats. Based on these results, we propose that decreased glucocorticoid signaling in the skeletal muscle can make a setting for lipid-induced inflammation and the development of insulin resistance in fructose-fed stressed rats.


Assuntos
Frutose/administração & dosagem , Glucocorticoides/metabolismo , Inflamação/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Estresse Fisiológico/fisiologia , Animais , Frutose/efeitos adversos , Humanos , Inflamação/etiologia , Resistência à Insulina/fisiologia , Masculino , Modelos Biológicos , Ratos , Ratos Wistar , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais
6.
Int J Mol Sci ; 22(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203166

RESUMO

Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain (p = 0.02) and an improved insulin tolerance (p = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment (p = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.


Assuntos
Acetilglucosamina/metabolismo , Peso Corporal/fisiologia , Resistência à Insulina/fisiologia , Insulina/farmacologia , N-Acetilglucosaminiltransferases/metabolismo , Placenta/efeitos dos fármacos , Placenta/metabolismo , Animais , Peso Corporal/genética , Feminino , Resistência à Insulina/genética , Masculino , Camundongos , N-Acetilglucosaminiltransferases/genética , Gravidez
7.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299261

RESUMO

Many approaches have been used in the effective management of type 2 diabetes mellitus. A recent paradigm shift has focused on the role of adipose tissues in the development and treatment of the disease. Brown adipose tissues (BAT) and white adipose tissues (WAT) are the two main types of adipose tissues with beige subsets more recently identified. They play key roles in communication and insulin sensitivity. However, WAT has been shown to contribute significantly to endocrine function. WAT produces hormones and cytokines, collectively called adipocytokines, such as leptin and adiponectin. These adipocytokines have been proven to vary in conditions, such as metabolic dysfunction, type 2 diabetes, or inflammation. The regulation of fat storage, energy metabolism, satiety, and insulin release are all features of adipose tissues. As such, they are indicators that may provide insights on the development of metabolic dysfunction or type 2 diabetes and can be considered routes for therapeutic considerations. The essential roles of adipocytokines vis-a-vis satiety, appetite, regulation of fat storage and energy, glucose tolerance, and insulin release, solidifies adipose tissue role in the development and pathogenesis of diabetes mellitus and the complications associated with the disease.


Assuntos
Tecido Adiposo/metabolismo , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Adipocinas/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Metabolismo Energético/fisiologia , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Leptina/metabolismo , Obesidade/metabolismo
8.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299508

RESUMO

Although the hypoglycemic potential of brewer's yeast extract has been reported, there is limited information pertaining to the hypoglycemic ingredients of Saccharomyces pastorianus extract and their mechanisms of action available. This study aimed to investigate the in vivo and in vitro hypoglycemic effect of S. pastorianus extract and to elucidate its molecular mechanisms. S. pastorianus extract was mainly composed of proteins followed by carbohydrates. In diabetic rats, oral administration of S. pastorianus extract significantly reduced the levels of plasma glucose and enhanced the activity of hepatic glucose-6-phosphatase dehydrogenase. Treatment with S. pastorianus extract increased the localization of type 4 glucose transporter (GLUT4), PTP, and insulin receptor at 3T3-L1 cell membranes and raised the levels of P38 MAPK, PI3K, and AKT in the cytosol. In agreement with these results, pretreatment of 3T3-L1 cells with inhibitors of PTP, PI3K, Akt/PKB, and p38 MAPK inhibited glucose uptake induced by application of S. pastorianus extract. Most importantly, a 54 kDa protein with hypoglycemic activity was identified and suggested as the major ingredient contributing to the hypoglycemic activity of S. pastorianus extract. In summary, these results clearly confirm the hypoglycemic activity of S. pastorianus extract and provide critical insights into the underlying molecular mechanisms.


Assuntos
Hipoglicemiantes/farmacologia , Saccharomyces/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Metabolismo dos Carboidratos/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Proteínas de Transporte de Monossacarídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Molecules ; 26(14)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34299620

RESUMO

Type 2 diabetes mellitus (T2DM) is linked to insulin resistance and a loss of insulin sensitivity, leading to millions of deaths worldwide each year. T2DM is caused by reduced uptake of glucose facilitated by glucose transporter 4 (GLUT4) in muscle and adipose tissue due to decreased intracellular translocation of GLUT4-containing vesicles to the plasma membrane. To treat T2DM, novel medications are required. Through a fluorescence microscopy-based high-content screen, we tested more than 600 plant extracts for their potential to induce GLUT4 translocation in the absence of insulin. The primary screen in CHO-K1 cells resulted in 30 positive hits, which were further investigated in HeLa and 3T3-L1 cells. In addition, full plasma membrane insertion was examined by immunostaining of the first extracellular loop of GLUT4. The application of appropriate inhibitors identified PI3 kinase as the most important signal transduction target relevant for GLUT4 translocation. Finally, from the most effective hits in vitro, four extracts effectively reduced blood glucose levels in chicken embryos (in ovo), indicating their applicability as antidiabetic pharmaceuticals or nutraceuticals.


Assuntos
Glicemia/efeitos dos fármacos , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Extratos Vegetais/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cricetulus , Diabetes Mellitus Tipo 2 , Transportador de Glucose Tipo 4/metabolismo , Células HeLa , Humanos , Resistência à Insulina/fisiologia , Camundongos , Transporte Proteico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
10.
Biomolecules ; 11(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208360

RESUMO

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.


Assuntos
Proteína Forkhead Box O1/metabolismo , Glucose/metabolismo , Metformina/farmacologia , Animais , Aspirina/metabolismo , Aspirina/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Proteína Forkhead Box O1/farmacologia , Gluconeogênese/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Resistência à Insulina/fisiologia , Fígado/metabolismo , Masculino , Metformina/metabolismo , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fosforilação , Transdução de Sinais , Estreptozocina/farmacologia
11.
Nutrients ; 13(7)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202724

RESUMO

BACKGROUND: A low-sodium (LS) diet reduces blood pressure, contributing to the prevention of cardiovascular diseases. However, intense dietary sodium restriction impairs insulin sensitivity and worsens lipid profile. Considering the benefits of aerobic exercise training (AET), the effect of LS diet and AET in hepatic lipid content and gene expression was investigated in LDL receptor knockout (LDLr-KO) mice. METHODS: Twelve-week-old male LDLr-KO mice fed a normal sodium (NS) or LS diet were kept sedentary (S) or trained (T) for 90 days. Body mass, plasma lipids, insulin tolerance testing, hepatic triglyceride (TG) content, gene expression, and citrate synthase (CS) activity were determined. Results were compared by 2-way ANOVA and Tukey's post-test. RESULTS: Compared to NS, LS increased body mass and plasma TG, and impaired insulin sensitivity, which was prevented by AET. The LS-S group, but not the LS-T group, presented greater hepatic TG than the NS-S group. The LS diet increased the expression of genes related to insulin resistance (ApocIII, G6pc, Pck1) and reduced those involved in oxidative capacity (Prkaa1, Prkaa2, Ppara, Lipe) and lipoprotein assembly (Mttp). CONCLUSION: AET prevented the LS-diet-induced TG accumulation in the liver by improving insulin sensitivity and the expression of insulin-regulated genes and oxidative capacity.


Assuntos
Dieta Hipossódica/efeitos adversos , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Condicionamento Físico Animal/fisiologia , Receptores de LDL/deficiência , Animais , Peso Corporal , Citrato (si)-Sintase/metabolismo , Expressão Gênica , Lipídeos/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Sódio na Dieta/metabolismo , Triglicerídeos/metabolismo
12.
Biomed Pharmacother ; 139: 111662, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243629

RESUMO

Metformin is one of the most prescribed drugs in type II diabetes (T2DM) which has recently found new applications in the prevention and treatment of various illnesses, from metabolic disorders to cardiovascular and age-related diseases. Metformin improves insulin resistance (IR) by modulating metabolic mechanisms and mitochondrial biogenesis. Alternation of microRNAs (miRs) in the treatment of IR-related illnesses has been observed by metformin therapy. MiRs are small non-coding RNAs that play important roles in RNA silencing, targeting the 3'untranslated region (3'UTR) of most mRNAs and inhibiting the translation of related proteins. As a result, their dysregulation is associated with many diseases. Metformin may alter miRs levels in the treatment of various diseases by AMPK-dependent or AMPK-independent mechanisms. Here, we summarized the therapeutic role of metformin by modifying the aberrant expression of miRs as potential biomarkers or therapeutic targets in diseases in which IR plays a key role.


Assuntos
Hipoglicemiantes/uso terapêutico , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Metformina/farmacologia , Metformina/uso terapêutico , MicroRNAs/genética , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Humanos , Hipoglicemiantes/farmacologia , Insulina/genética
13.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
14.
Nat Commun ; 12(1): 3350, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099721

RESUMO

Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.


Assuntos
Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Endoteliais/metabolismo , Resistência à Insulina/fisiologia , Obesidade Abdominal/metabolismo , Animais , Antígenos CD , Caderinas , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Inflamação , Vasos Linfáticos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Transcriptoma , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
15.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065474

RESUMO

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217+/-) mice were constructed. Zfp217+/- mice and Zfp217+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217+/- mice had less weight gain than Zfp217+/+ mice. Histological observations revealed that Zfp217+/- mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217+/- mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217+/+ mice compared to Zfp217+/- mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.


Assuntos
Metabolismo Energético/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Transativadores/metabolismo , Adipócitos Brancos/metabolismo , Adipócitos Brancos/fisiologia , Adipogenia/fisiologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Animais , Dieta Hiperlipídica , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Termogênese/fisiologia , Ganho de Peso/fisiologia
16.
FASEB J ; 35(7): e21712, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34110637

RESUMO

Palmitic acid (PA) is a saturated fatty acid whose high consumption has been largely associated with the development of different metabolic alterations, such as insulin resistance, metabolic syndrome, and type 2 diabetes. Particularly in the brain, insulin signaling disruption has been linked to cognitive decline and is considered a risk factor for Alzheimer's disease. Cumulative evidence has demonstrated the participation of PA in the molecular cascade underlying cellular insulin resistance in peripheral tissues, but its role in the development of neuronal insulin resistance and the mechanisms involved are not fully understood. It has generally been accepted that the brain does not utilize fatty acids as a primary energy source, but recent evidence shows that neurons possess the machinery for fatty acid ß-oxidation. However, it is still unclear under what conditions neurons use fatty acids as energy substrates and the implications of their oxidative metabolism in modifying insulin-stimulated effects. In the present work, we have found that neurons differentiated from human neuroblastoma MSN exposed to high but nontoxic concentrations of PA generate ATP through mitochondrial metabolism, which is associated with an increase in the cytosolic Ca2+ and diminished insulin signaling in neurons. These findings reveal a novel mechanism by which saturated fatty acids produce Ca2+ entry and insulin resistance that may play a causal role in increasing neuronal vulnerability associated with metabolic diseases.


Assuntos
Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Resistência à Insulina/fisiologia , Neurônios/efeitos dos fármacos , Ácido Palmítico/farmacologia , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Citosol/efeitos dos fármacos , Citosol/metabolismo , Ácidos Graxos/farmacologia , Humanos , Insulina/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neuroblastoma/metabolismo , Neurônios/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Nutrients ; 13(5)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063252

RESUMO

Innate immunity plays a determinant role in high fat diet (HFD)-induced insulin resistance. This study compares the effects of immunonutritional bioactives from Chenopodium quinoa (WQ) or Salvia hispanica L. (Ch) when used to partially replace wheat flour (WB) into bread formulations. These flours were chosen to condition starch and lipid content in the products as well as because their immunonutritional activity. To be administered with different bread formulations, HFD-fed C57BL/6J mice were distributed in different groups: (i) wild type, (ii) displaying inherited disturbances in glucose homeostasis, and (iii) displaying dietary iron-mediated impairment of the innate immune TLR4/TRAM/TRIF pathway. We analyze the effects of the products on glycaemia and insulin resistance (HOMA-IR), plasmatic triglycerides, intestinal and hepatic gene expression and variations of myeloid (MY), and lymphoid (LY) cells population in peripheral blood. Our results show that feeding animals with WQ and Ch formulations influenced the expression of lipogenic and coronary risk markers, thus attaining a better control of hepatic lipid accumulation. WQ and Ch products also improved glucose homeostasis compared to WB, normalizing the HOMA-IR in animals with an altered glucose and lipid metabolism. These positive effects were associated with positive variations in the peripheral myeloid cells population.


Assuntos
Chenopodium quinoa , Farinha , Resistência à Insulina/fisiologia , Células Mieloides/efeitos dos fármacos , Compostos Fitoquímicos/administração & dosagem , Salvia , Animais , Glicemia/imunologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Imunidade Inata/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fenômenos Fisiológicos da Nutrição/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição/imunologia , Triglicerídeos/sangue
18.
Nutrients ; 13(5)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069950

RESUMO

Insulin resistance is a key etiological factor in promoting not only type 2 diabetes mellitus but also cardiovascular disease (CVD). Exercise is a first-line therapy for combating chronic disease by improving insulin action through, in part, reducing hepatic glucose production and lipolysis as well as increasing skeletal muscle glucose uptake and vasodilation. Just like a pharmaceutical agent, exercise can be viewed as a "drug" such that identifying an optimal prescription requires a determination of mode, intensity, and timing as well as consideration of how much exercise is done relative to sitting for prolonged periods (e.g., desk job at work). Furthermore, proximal nutrition (nutrient timing, carbohydrate intake, etc.), sleep (or lack thereof), as well as alcohol consumption are likely important considerations for enhancing adaptations to exercise. Thus, identifying the maximal exercise "drug" for reducing insulin resistance will require a multi-health behavior approach to optimize type 2 diabetes and CVD care.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Ingestão de Energia/fisiologia , Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Sono/fisiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Metabolismo dos Carboidratos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Metabolismo Energético , Glucose/biossíntese , Humanos , Lipólise , Fígado/metabolismo , Músculo Esquelético/metabolismo , Vasodilatação/fisiologia
19.
Nutrients ; 13(6)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071972

RESUMO

The biomedical potential of the edible red seaweed Agarophyton chilense (formerly Gracilaria chilensis) has not been explored. Red seaweeds are enriched in polyunsaturated fatty acids and eicosanoids, which are known natural ligands of the PPARγ nuclear receptor. PPARγ is the molecular target of thiazolidinediones (TZDs), drugs used as insulin sensitizers to treat type 2 diabetes mellitus. Medical use of TZDs is limited due to undesired side effects, a problem that has triggered the search for selective PPARγ modulators (SPPARMs) without the TZD side effects. We produced Agarophyton chilense oleoresin (Gracilex®), which induces PPARγ activation without inducing adipocyte differentiation, similar to SPPARMs. In a diet-induced obesity model of male mice, we showed that treatment with Gracilex® improves insulin sensitivity by normalizing altered glucose and insulin parameters. Gracilex® is enriched in palmitic acid, arachidonic acid, oleic acid, and lipophilic antioxidants such as tocopherols and ß-carotene. Accordingly, Gracilex® possesses antioxidant activity in vitro and increased antioxidant capacity in vivo in Caenorhabditis elegans. These findings support the idea that Gracilex® represents a good source of natural PPARγ ligands and antioxidants with the potential to mitigate metabolic disorders. Thus, its nutraceutical value in humans warrants further investigation.


Assuntos
Gracilaria/química , Resistência à Insulina/fisiologia , Obesidade/metabolismo , PPAR gama/metabolismo , Extratos Vegetais , Animais , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/farmacologia , Caenorhabditis elegans , Modelos Animais de Doenças , Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia
20.
Nutrients ; 13(6)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063822

RESUMO

Vitamin D has been implicated in the regulation of glucose metabolism and insulin resistance. We designed this study to provide evidence that insulin resistance is dependent on the concentration of vitamin D in the body. Forty observational studies of both type 2 diabetes mellitus patients and healthy subjects were included in this meta-analysis. Related articles were searched from Embase, PubMed, and Medline through January 2021. Filters for search were used to obtain more focused results. We used Comprehensive Meta-Analysis Version 3 for the construction of forest plots. RevMan software version 5.3 was used to build the risk of bias tables and summary plots. The observational studies included in this systematic review and meta-analysis showed an inverse relationship of insulin resistance with the status of vitamin D both in non-diabetic (r = -0.188; 95% CI = -0.141 to -0.234; p = 0.000) and diabetic (r = -0.255; 95% CI = -0.392 to -0.107, p = 0.001) populations. From the meta-analysis we concluded that hypovitaminosis D is related to increased levels of insulin resistance in both type 2 diabetes patients and the healthy population all over the world.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Resistência à Insulina/fisiologia , Estado Nutricional , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Humanos , Insulina/sangue , Estudos Observacionais como Assunto , Vitamina D/sangue , Deficiência de Vitamina D/complicações
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