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1.
Metabolism ; 152: 155765, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38142958

RESUMO

BACKGROUND AND AIM: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions. Here, we investigated the influence of exercise on LD-mitochondria interactions and its significance in the context of NAFLD. APPROACH AND RESULTS: Mice were fed high-fat diet (HFD) or HFD-0.1 % methionine and choline-deficient diet (MCD) to emulate simple hepatic steatosis or non-alcoholic steatohepatitis, respectively. In both models, aerobic exercise decreased the size of LDs bound to mitochondria and the number of LD-mitochondria contacts. Analysis showed that the effects of exercise on HOMA-IR and liver triglyceride levels were independent of changes in body weight, and a positive correlation was observed between the number of LD-mitochondria contacts and NAFLD severity and with the lipid droplet size bound to mitochondria. Cellular fractionation studies revealed that ATP-coupled respiration and fatty acid oxidation (FAO) were greater in hepatic peridroplet mitochondria (PDM) from HFD-fed exercised mice than from equivalent sedentary mice. Finally, exercise increased FAO and mitofusin-2 abundance exclusively in PDM through a mechanism involving the curvature of mitochondrial membranes and the abundance of saturated lipids. Accordingly, hepatic mitofusin-2 ablation prevented exercise-induced FAO in PDM. CONCLUSIONS: This study demonstrates that aerobic exercise has beneficial effects in murine NAFLD models by lessening the interactions between hepatic LDs and mitochondria, and by decreasing LD size, correlating with a reduced severity of NAFLD. Additionally, aerobic exercise increases FAO in PDM and this process is reliant on Mfn-2 enrichment, which modifies LD-mitochondria communication.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Masculino , Camundongos , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo
2.
Methods Cell Biol ; 176: 85-101, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37164544

RESUMO

Cardiovascular diseases are the leading cause of death and disability worldwide. After heart injury triggered by myocardial ischemia or myocardial infarction, extensive zones of tissue are damaged and some of the tissue dies by necrosis and/or apoptosis. The loss of contractile mass activates a series of biochemical mechanisms that allow, through cardiac remodeling, the replacement of the dysfunctional heart tissue by fibrotic material. Our previous studies have shown that primary cilia, non-motile antenna-like structures at the cell surface required for the activation of specific signaling pathways, are present in cardiac fibroblasts and required for cardiac fibrosis induced by ischemia/reperfusion (I/R) in mice. I/R-induced myocardial fibrosis promotes the enrichment of ciliated cardiac fibroblasts where the myocardial injury occurs. Given discussions about the existence of cilia in specific cardiac cell types, as well as the functional relevance of studying cilia-dependent signaling in cardiac fibrosis after I/R, here we describe our methods to evaluate the presence and roles of primary cilia in cardiac fibrosis after I/R in mice.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Camundongos , Animais , Cílios/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Coração , Fibrose , Miócitos Cardíacos/metabolismo , Miocárdio
3.
Front Nutr ; 9: 979624, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225871

RESUMO

Sucralose is one of the most widely used artificial sweeteners used by the food industry to reduce the calorie density of their products. Although broadly regarded as innocuous, studies show contrasting results depending on whether the research subjects are lean or overweight. In this study, we studied the effect of sucralose consumption on glucose homeostasis in a model of obesity. Male C57BL/6J mice were fed ad libitum with control or a high-fat diet (HFD) and drank either water or sucralose (0.1 mg/mL) for 8 weeks. To characterize the ensuing metabolic changes, we evaluated weight gain, glucose and pyruvate tolerance, and physical performance. Also, we assessed markers of steatosis and mitochondrial mass and function in the liver. Our results show that sucralose reduced weight gain, glucose, and pyruvate intolerance, and prevented the decrease in physical performance of HFD-fed mice. In the liver, sucralose also had a positive effect, preventing the decrease in mitochondrial mass exerted by HFD. Altogether, our results indicate that in the context of an obesogenic diet, sucralose has a beneficial effect at the organismal and hepatic levels.

4.
Cell Death Dis ; 13(7): 659, 2022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35902579

RESUMO

Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Animais , Autofagia , Cílios/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipotálamo/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Camundongos , Neurônios/metabolismo , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/farmacologia
5.
Int J Mol Sci ; 23(10)2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35628392

RESUMO

Glucocorticoids (GC) are steroids hormones that drive circulating glucose availability through gluconeogenesis in the liver. However, alternative splicing of the GR mRNA produces two isoforms, termed GRα and GRß. GRα is the classic receptor that binds to GCs and mediates the most described actions of GCs. GRß does not bind GCs and acts as a dominant-negative inhibitor of GRα. Moreover, GRß has intrinsic and GRα-independent transcriptional activity. To date, it remains unknown if GRß modulates glucose handling in hepatocytes. Therefore, the study aims to characterize the impact of GRß overexpression on glucose uptake and storage using an in vitro hepatocyte model. Here we show that GRß overexpression inhibits the induction of gluconeogenic genes by dexamethasone. Moreover, GRß activates the Akt pathway, increases glucose transports mRNA, increasing glucose uptake and glycogen storage as an insulin-mimetic. Our results suggest that GRß has agonist-independent insulin-mimetic actions in HepG2 cells.


Assuntos
Glucocorticoides , Insulina , Glucocorticoides/farmacologia , Glucose , Insulina Regular Humana , RNA Mensageiro/genética , Receptores de Glucocorticoides
6.
Food Chem Toxicol ; 165: 113083, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35577173

RESUMO

Hydrogen sulfide (H2S) has been known for its toxicity. However, recent studies have focused on the mechanisms involved in endogenous production and function. To date, the H2S role in insulin signaling and glucose homeostasis is unclear. This uncertainty is even more evident in skeletal muscle, a physiological niche highly relevant for regulating glycemia in response to insulin. This study aimed to investigate the role of H2S on insulin signaling and glucose uptake in the L6 skeletal muscle cell line. We evaluated the endogenous synthesis with the fluorescent dye, 7-azido-4-methyl coumarin (7-AzMC). Glucose restriction-induced an increase in the endogenous levels of H2S, likely through stimulation of cystathionine γ-lyase activity, as its specific inhibitor, PAG (5 mM) prevented this increase, and mRNA levels of CSE decreased with glucose and amino acid restriction. Exogenous H2S reduced insulin-induced glucose uptake at 0.5 up to 24 h, an effect dissociated from the level of Akt phosphorylation. Our results show that glucose restriction induces endogenous production of H2S via CSE. In addition, H2S disrupts insulin-induced glucose uptake independent of the Akt pathway. These results suggest that H2S antagonism over insulin-induced glucose uptake could help maintain the plasmatic glucose levels in conditions that provoke hypoglycemia, which could serve as an H2S-regulated mechanism for maintaining glucose plasmatic levels through the inhibition of the skeletal muscle insulin-depended glucose uptake.


Assuntos
Sulfeto de Hidrogênio , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Glucose/metabolismo , Sulfeto de Hidrogênio/metabolismo , Insulina/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética
7.
Life Sci ; 298: 120522, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367244

RESUMO

Lipid droplets (LD) are not just lipid stores. They are now recognized as highly dynamic organelles, having a life cycle that includes biogenesis, growth, steady-state, transport, and catabolism. Importantly, LD exhibit different features in terms of size, number, lipid composition, proteins, and interaction with other organelles, and all these features exert an impact on cellular homeostasis. The imbalance of LD function causes non-alcoholic fatty liver disease (NAFLD). Studies show that exercise attenuates NAFLD by decreasing LD content; however, reports show metabolic benefits without changes in LD amount (intrahepatic triglyceride levels) in NAFLD. Due to the multiple effects of exercise in LD features, we think that these metabolic benefits occur through changes in LD features in NAFLD, rather than only the reduction in content. Exercise increases energy mobilization and utilization from storages such as LD, and is one of the non-pharmacological treatments against NAFLD. Therefore, exercise modification of LD could be a target for NAFLD treatment. Here, we review the most up-to-date literature on this topic, and focus on recent findings showing that LD features could play an important role in the severity of NAFLD.


Assuntos
Gotículas Lipídicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia
8.
Front Nutr ; 8: 775382, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869541

RESUMO

Fatty acid overload, either of the saturated palmitic acid (PA) or the unsaturated oleic acid (OA), causes triglyceride accumulation into specialized organelles termed lipid droplets (LD). However, only PA overload leads to liver damage mediated by mitochondrial dysfunction. Whether these divergent outcomes stem from differential effects of PA and OA on LD and mitochondria joint dynamics remains to be uncovered. Here, we contrast how both fatty acids impact the morphology and interaction between both organelles and mitochondrial bioenergetics in HepG2 cells. Using confocal microscopy, we showed that short-term (2-24 h) OA overload promotes more and bigger LD accumulation than PA. Oxygen polarography indicated that both treatments stimulated mitochondrial respiration; however, OA favored an overall build-up of the mitochondrial potential, and PA evoked mitochondrial fragmentation, concomitant with an ATP-oriented metabolism. Even though PA-induced a lesser increase in LD-mitochondria proximity than OA, those LD associated with highly active mitochondria suggest that they interact mainly to fuel fatty acid oxidation and ATP synthesis (that is, metabolically "active" LD). On the contrary, OA overload seemingly stimulated LD-mitochondria interaction mainly for LD growth (thus metabolically "passive" LDs). In sum, these differences point out that OA readily accumulates in LD, likely reducing their toxicity, while PA preferably stimulates mitochondrial oxidative metabolism, which may contribute to liver damage progression.

9.
Front Nutr ; 8: 744187, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34926544

RESUMO

Adipose tissue total amount, distribution, and phenotype influence metabolic health. This may be partially mediated by the metabolic effects that these adipose tissue characteristics exert on the nearby and distant tissues. Thus, adipose tissue may influence the capacity of cells, tissues, and the organism to adapt fuel oxidation to fuel availability, i.e., their metabolic flexibility (MetF). Our aim was to systematically review the evidence for an association between adipose tissue characteristics and MetF in response to metabolic challenges in human adults. We searched in PubMed (last search on September 4, 2021) for reports that measured adipose tissue characteristics (total amount, distribution, and phenotype) and MetF in response to metabolic challenges (as a change in respiratory quotient) in humans aged 18 to <65 years. Any study design was considered, and the risk of bias was assessed with a checklist for randomized and non-randomized studies. From 880 records identified, 22 remained for the analysis, 10 of them measured MetF in response to glucose plus insulin stimulation, nine in response to dietary challenges, and four in response to other challenges. Our main findings were that: (a) MetF to glucose plus insulin stimulation seems inversely associated with adipose tissue total amount, waist circumference, and visceral adipose tissue; and (b) MetF to dietary challenges does not seem associated with adipose tissue total amount or distribution. In conclusion, evidence suggests that adipose tissue may directly or indirectly influence MetF to glucose plus insulin stimulation, an effect probably explained by skeletal muscle insulin sensitivity. Systematic Review Registration: PROSPERO [CRD42020167810].

10.
Molecules ; 26(20)2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34684731

RESUMO

Type 2 diabetes and obesity are major problems worldwide and dietary polyphenols have shown efficacy to ameliorate signs of these diseases. Anthocyanins from berries display potent antioxidants and protect against weight gain and insulin resistance in different models of diet-induced metabolic syndrome. Olanzapine is known to induce an accelerated form of metabolic syndrome. Due to the aforementioned, we evaluated whether delphinidin-3,5-O-diglucoside (DG) and delphinidin-3-O-sambubioside-5-O-glucoside (DS), two potent antidiabetic anthocyanins isolated from Aristotelia chilensis fruit, could prevent olanzapine-induced steatosis and insulin resistance in liver and skeletal muscle cells, respectively. HepG2 liver cells and L6 skeletal muscle cells were co-incubated with DG 50 µg/mL or DS 50 µg/mL plus olanzapine 50 µg/mL. Lipid accumulation was determined in HepG2 cells while the expression of p-Akt as a key regulator of the insulin-activated signaling pathways, mitochondrial function, and glucose uptake was assessed in L6 cells. DS and DG prevented olanzapine-induced lipid accumulation in liver cells. However, insulin signaling impairment induced by olanzapine in L6 cells was not rescued by DS and DG. Thus, anthocyanins modulate lipid metabolism, which is a relevant factor in hepatic tissue, but do not significantly influence skeletal muscle, where a potent antioxidant effect of olanzapine was found.


Assuntos
Antocianinas/farmacologia , Elaeocarpaceae/metabolismo , Glucosídeos/farmacologia , Antocianinas/química , Antocianinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/metabolismo , Glucosídeos/química , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos , Lipídeos/farmacologia , Fígado/efeitos dos fármacos , Fígado/patologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Olanzapina , Extratos Vegetais/farmacologia , Polifenóis/farmacologia
11.
FASEB J ; 35(10): e21891, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34569666

RESUMO

In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial dynamics response in the metabolic transition from fasting to feeding in human peripheral blood mononuclear cells (PBMCs). Six male subjects fasted for 16 h (fasting), immediately after which they consumed a 75-g oral glucose load (glucose). In both fasting and glucose conditions, blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images. We exposed in vitro acetoacetate-treated PBMCs to the specific IP3R inhibitor Xestospongin B (XeB) to reduce IP3R-mediated mitochondrial Ca2+ accumulation. This allowed us to evaluate the role of ER-mitochondria Ca2+ exchange in the mitochondrial dynamic response to substrate availability. To determine whether PBMCs could be used in obesity context (low MetFlex), we measured mitochondrial dynamics in mouse spleen-derived lymphocytes from WT and ob/ob mice. We demonstrated that the transition from fasting to feeding reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs. In addition, we demonstrated that IP3R activity is key in the mitochondrial dynamics response when PBMCs are treated with a fasting-substrate in vitro. In murine mononuclear-cells, we confirmed that mitochondria-ER interactions are regulated in the fasted-fed transition and we further highlight mitochondria-ER miscommunication in PBMCs of diabetic mice. In conclusion, our results demonstrate that the fasting/feeding transition reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs, and that IP3R activity may potentially play a central role.


Assuntos
Sinalização do Cálcio , Ingestão de Alimentos , Jejum/metabolismo , Leucócitos Mononucleares/metabolismo , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Adulto , Animais , Glucose/administração & dosagem , Humanos , Masculino , Camundongos
12.
Int J Mol Sci ; 21(20)2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066464

RESUMO

Glucocorticoids (GCs) are critical regulators of energy balance. Their deregulation is associated with the development of obesity and metabolic syndrome. However, it is not understood if obesity alters the tissue glucocorticoid receptor (GR) response, and moreover whether a moderate aerobic exercise prevents the alteration in GR response induced by obesity. METHODS: To evaluate the GR response in obese mice, we fed C57BL6J mice with a high-fat diet (HFD) for 12 weeks. Before mice were sacrificed, we injected them with dexamethasone. To assess the exercise role in GR response, we fed mice an HFD and subjected them to moderate aerobic exercise three times a week. RESULTS: We found that mice fed a high-fat diet for 12 weeks developed hepatic GC hypersensitivity without changes in the gastrocnemius or epididymal fat GR response. Therefore, moderate aerobic exercise improved glucose tolerance, increased the corticosterone plasma levels, and prevented hepatic GR hypersensitivity with an increase in epididymal fat GR response. CONCLUSION: Collectively, our results suggest that mice with HFD-induced obesity develop hepatic GR sensitivity, which could enhance the metabolic effects of HFD in the liver. Moreover, exercise was found to be a feasible non-pharmacological strategy to prevent the deregulation of GR response in obesity.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Fígado/efeitos dos fármacos , Obesidade/metabolismo , Condicionamento Físico Animal/métodos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético , Glucose/metabolismo , Fígado/metabolismo , Fígado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Obesidade/etiologia , Obesidade/prevenção & controle
13.
Front Pharmacol ; 11: 429, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32390830

RESUMO

A growing body of research indicates that cortisol, the glucocorticoid product of the activation of the hypothalamic-pituitary-adrenal axis, plays a role in the pathophysiology of metabolic syndrome. In this regard, chronic exposure to cortisol is associated with risk factors related to metabolic syndrome like weight gain, type 2 diabetes, hypertension, among others. Mifepristone is the only FDA-approved drug with antiglucocorticoids properties for improved the glycemic control in patients with type 2 patients secondary to endogenous Cushing's syndrome. Mifepristone also have been shown positive effects in rodents models of diabetes and patients with obesity due to antipsychotic treatment. However, the underlying molecular mechanisms are not fully understood. In this perspective, we summarized the literature regarding the beneficial effects of mifepristone in metabolic syndrome from animal studies to clinical research. Also, we propose a potential mechanism for the beneficial effects in insulin sensitivity which involved the regulation of mitochondrial function in muscle cells.

14.
Nutrients ; 11(6)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141968

RESUMO

Dehydration in rodents induces anorexia. In humans however, the role of dehydration in energy intake is controversial. This study investigated the effect of extreme fluid restriction on acute energy intake during and after exercise-induced dehydration. Eight physically active participants performed two exercise sessions to induce dehydration. After the exercise, the men were allowed to either rehydrate for 2 h or were maintained in a hypohydrated state, in a randomized manner. After 2 h, they were given cereal bars ad libitum for 1 h. Blood and saliva samples of the participants were collected before the exercise session, after the exercise session, after rehydration, and after the meal. Post-exercise energy intake differed between hypohydrated (1430 ± 210 kcal) and rehydrated (2190 ± 780 kcal) trials (p = 0.01). For the concentrations of ghrelin and leptin, there were no significant effects of time (p = 0.94, p = 0.21), between trials (p = 0.09, p = 0.99), or due to a trial-time interaction (p = 0.64, p = 0.68), respectively. The concentrations of peptide YY (PYY) were not different between trials (p = 0.94) but there was a significant effect of time (p = 0.0001) and a trial-time interaction (p = 0.01), with higher levels in the rehydration trial after eating in response to a higher energy intake. For saliva production, there was a significant effect of time (p = 0.02) and a trial-time interaction (p = 0.04), but no between-trial effect (p = 0.08). In conclusion, extreme fluid restriction decreased acute food intake after exercise, which may be explained by a lower flow of saliva.


Assuntos
Desidratação/fisiopatologia , Ingestão de Líquidos , Ingestão de Alimentos , Ingestão de Energia , Exercício Físico , Estado de Hidratação do Organismo , Adulto , Biomarcadores/sangue , Estudos Cross-Over , Desidratação/etiologia , Grelina/sangue , Humanos , Leptina/sangue , Masculino , Peptídeo YY/sangue , Salivação , Fatores de Tempo , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-30972025

RESUMO

Chronic consumption of high fat diets (HFDs), rich in saturated fatty acids (SatFAs) like palmitic acid (PA), is associated with the development of obesity and obesity-related metabolic diseases such as type II diabetes mellitus (T2DM). Previous studies indicate that PA accumulates in the hypothalamus following consumption of HFDs; in addition, HFDs consumption inhibits autophagy and reduces insulin sensitivity. Whether malfunction of autophagy specifically in hypothalamic neurons decreases insulin sensitivity remains unknown. PA does activate the Free Fatty Acid Receptor 1 (FFAR1), also known as G protein-coupled receptor 40 (GPR40); however, whether FFAR1 mediates the effects of PA on hypothalamic autophagy and insulin sensitivity has not been shown. Here, we demonstrate that exposure to PA inhibits the autophagic flux and reduces insulin sensitivity in a cellular model of hypothalamic neurons (N43/5 cells). Furthermore, we show that inhibition of autophagy and the autophagic flux reduces insulin sensitivity in hypothalamic neuronal cells. Interestingly, the inhibition of the autophagic flux, and the reduction in insulin sensitivity are prevented by pharmacological inhibition of FFAR1. Our findings show that dysregulation of autophagy reduces insulin sensitivity in hypothalamic neuronal cells. In addition, our data suggest FFAR1 mediates the ability of PA to inhibit autophagic flux and reduce insulin sensitivity in hypothalamic neuronal cells. These results reveal a novel cellular mechanism linking PA-rich diets to decreased insulin sensitivity in the hypothalamus and suggest that hypothalamic autophagy might represent a target for future T2DM therapies.

16.
Mol Cell Endocrinol ; 461: 277-283, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-28943275

RESUMO

Mifepristone is the only FDA-approved drug for glycaemia control in patients with Cushing's syndrome and type 2 diabetes. Mifepristone also has beneficial effects in animal models of diabetes and patients with antipsychotic treatment-induced obesity. However, the mechanisms through which Mifepristone produces its beneficial effects are not completely elucidated. PURPOSE: To determine the effects of mifepristone on insulin-stimulated glucose uptake on a model of L6 rat-derived skeletal muscle cells. RESULTS: Mifepristone enhanced insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane and Akt Ser473 phosphorylation in L6 myotubes. In addition, mifepristone reduced oxygen consumption and ATP levels and increased AMPK Thr172 phosphorylation. The knockdown of AMPK prevented the effects of mifepristone on insulin response. CONCLUSIONS: Mifepristone enhanced insulin-stimulated glucose uptake through a mechanism that involves a decrease in mitochondrial function and AMPK activation in skeletal muscle cells.


Assuntos
Glucose/metabolismo , Insulina/farmacologia , Mifepristona/farmacologia , Células Musculares/metabolismo , Músculo Esquelético/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Adenilato Quinase/metabolismo , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Células Musculares/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos
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