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1.
Nat Commun ; 12(1): 5068, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417460

RESUMO

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.


Assuntos
Acetilglucosamina/metabolismo , Glucose/metabolismo , Fígado/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Restrição Calórica , Linhagem Celular , Colforsina/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Epinefrina/metabolismo , Glucagon/metabolismo , Glucocorticoides/metabolismo , Gluconeogênese/efeitos dos fármacos , Glicosilação , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Hidrocortisona/metabolismo , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Ácido Pirúvico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética
2.
Front Endocrinol (Lausanne) ; 12: 669980, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149618

RESUMO

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN in human patients. Here, we investigate the effect of ABA on whole body energy homeostasis at different housing temperatures. Our data show that ABA rats develop hyperactivity and hypophagia, which account for a massive body weight loss and muscle cachexia, as well as reduced uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but increased browning of white adipose tissue (WAT). Increased housing temperature reverses not only the hyperactivity and weight loss of animals exposed to the ABA model, but also hypothermia and loss of body and muscle mass. Notably, despite the major metabolic impact of ABA, none of the changes observed are associated to changes in key hypothalamic pathways modulating energy metabolism, such as AMP-activated protein kinase (AMPK) or endoplasmic reticulum (ER) stress. Overall, this evidence indicates that although temperature control may account for an improvement of AN, key hypothalamic pathways regulating thermogenesis, such as AMPK and ER stress, are unlikely involved in later stages of the pathophysiology of this devastating disease.

3.
Redox Biol ; 41: 101945, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744652

RESUMO

Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuin homologs of the yeast Sir2 gene that has emerged as an important player in the regulation of energy metabolism in peripheral tissues. However, its role in the hypothalamus has not been explored. Herein, we show that the genetic inhibition of SIRT3 in the hypothalamic arcuate nucleus (ARC) induced a negative energy balance and improvement of several metabolic parameters. These effects are specific for POMC neurons, because ablation of SIRT3 in POMC, but not in AgRP neurons, decreased body weight and adiposity, increased energy expenditure and brown adipose tissue (BAT) activity, and induced browning in white adipose tissue (WAT). Notably, the depletion of SIRT3 in POMC neurons caused these effects in male mice fed a chow diet but failed to affect energy balance in males fed a high fat diet and females under both type of diets. Overall, we provide the first evidence pointing for a key role of SIRT3 in POMC neurons in the regulation of energy balance.


Assuntos
Pró-Opiomelanocortina , Sirtuína 3 , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica , Metabolismo Energético , Feminino , Masculino , Camundongos , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Sirtuína 3/metabolismo
4.
Int J Mol Sci ; 22(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572672

RESUMO

Sirtuins are NAD+ dependent deacetylases that regulate a large number of physiological processes. These enzymes are highly conserved and act as energy sensors to coordinate different metabolic responses in a controlled manner. At present, seven mammalian sirtuins (SIRT 1-7) have been identified, with SIRT1 and SIRT6 shown to exert their metabolic actions in the hypothalamus, both with crucial roles in eliciting responses to dampen metabolic complications associated with obesity. Therefore, our aim is to compile the current understanding on the role of SIRT1 and SIRT6 in the hypothalamus, especially highlighting their actions on the control of energy balance.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Obesidade/metabolismo , Sirtuínas/metabolismo , Animais , Peso Corporal , Ingestão de Alimentos , Humanos , Hipotálamo/metabolismo , Mamíferos
5.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546289

RESUMO

Several studies have reported that nicotine, the main bioactive component of tobacco, exerts a marked negative energy balance. Apart from its anorectic action, nicotine also modulates energy expenditure, by regulating brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. These effects are mainly controlled at the central level by modulation of hypothalamic neuropeptide systems and energy sensors, such as AMP-activated protein kinase (AMPK). In this study, we aimed to investigate the kappa opioid receptor (κOR)/dynorphin signaling in the modulation of nicotine's effects on energy balance. We found that body weight loss after nicotine treatment is associated with a down-regulation of the κOR endogenous ligand dynorphin precursor and with a marked reduction in κOR signaling and the p70 S6 kinase/ribosomal protein S6 (S6K/rpS6) pathway in the lateral hypothalamic area (LHA). The inhibition of these pathways by nicotine was completely blunted in κOR deficient mice, after central pharmacological blockade of κOR, and in rodents where κOR was genetically knocked down specifically in the LHA. Moreover, κOR-mediated nicotine effects on body weight do not depend on orexin. These data unravel a new central regulatory pathway modulating nicotine's effects on energy balance.


Assuntos
Região Hipotalâmica Lateral/metabolismo , Nicotina/farmacologia , Receptores Opioides kappa/metabolismo , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Peso Corporal , Dinorfinas/metabolismo , Metabolismo Energético , Região Hipotalâmica Lateral/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
6.
Diabetes ; 70(3): 680-695, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33408126

RESUMO

Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.


Assuntos
Adipócitos/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Células 3T3-L1 , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Western Blotting , Diabetes Mellitus Tipo 2/metabolismo , Genótipo , Glutationa/metabolismo , Humanos , Resistência à Insulina/fisiologia , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNA , Peixe-Zebra
7.
Neuroscience ; 447: 191-215, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33046217

RESUMO

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.

8.
Neuroscience ; 437: 215-239, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32360593

RESUMO

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.


Assuntos
Cirurgia Bariátrica , Preparações Farmacêuticas , Humanos , Obesidade/tratamento farmacológico
9.
Trends Endocrinol Metab ; 31(1): 3-12, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31597606

RESUMO

Adipose tissue macrophages (ATMs) orchestrate low-grade chronic adipose tissue inflammation, linking obesity and insulin resistance. Whereas factors contributing to macrophage accumulation in adipose tissue are established, little is known regarding signals that link adipocyte stress to proinflammatory activation of macrophages. Natural killer (NK) cells are specialized innate lymphocytes that identify and respond to stressed cells. In this Opinion, we discuss the possibility of NK cells to function as sensors recognizing adipose tissue stress. We further summarize recent literature suggesting NK cells to play an important role in development of insulin resistance via secretion of cytokines that stimulate proinflammatory polarization of ATMs. This suggests adipose tissue-resident NK cells as a pharmacological target for the treatment of obesity-induced insulin resistance.

10.
Rev Endocr Metab Disord ; 21(1): 45-56, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31758299

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are two of the most common liver diseases associated with obesity, type 2 diabetes and metabolic syndrome. The prevalence of these conditions are increasingly rising and presently there is not a pharmacological option available in the market. Elucidation of the mechanism of action and the molecular underpinnings behind liver disease could help to better understand the pathophysiology of these illnesses. In this sense, in the last years modulation of the ghrelin system in preclinical animal models emerge as a promising therapeutic tool. In this review, we compile the latest knowledge of the modulation of ghrelin system and its intracellular pathways that regulates lipid metabolism, hepatic inflammation and liver fibrosis. We also describe novel processes implicated in the regulation of liver disease by ghrelin, such as autophagy or dysregulated circadian rhythms. In conclusion, the information displayed in this review support that the ghrelin system could be an appealing strategy for the treatment of liver disease.


Assuntos
Grelina/metabolismo , Metabolismo dos Lipídeos , Cirrose Hepática/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Grelina/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Fígado/fisiopatologia , Cirrose Hepática/fisiopatologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/metabolismo , Obesidade/fisiopatologia
11.
Sci Rep ; 9(1): 14817, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616017

RESUMO

The objective of this study was to compare the biochemical changes related to glucose tolerance and lipid metabolism in non-diabetic patients shortly after vertical sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Non-diabetic women and men with morbid obesity were studied the day before and six days after SG (N = 15) or RYGB (N = 16). Patients completed an oral glucose tolerance test (OGTT; 75 g glucose) at both visits. SG and RYGB similarly improved fasting glucose homeostasis six days after surgery, with reduced glucose and insulin concentrations. The OGTT revealed differences between the two surgery groups that were not evident from the fasting serum concentrations. Postprandial (120 min) glucose and insulin concentrations were lower after RYGB but not after SG, whereas concentrations of glucagon-like peptide-1, peptide YY, glucagon and non-esterified fatty acids were elevated after both SG and RYGB. Fasting triacylglycerol concentration did not change after surgery, but concentrations of high density lipoprotein and low density lipoprotein cholesterols were reduced in both surgery groups, with no differences between the groups. To conclude, RYGB induced a more pronounced improvement in postprandial glucose homeostasis relative to SG, possibly due to improved insulin sensitivity rather than augmented insulin concentration.


Assuntos
Glicemia/metabolismo , Gastrectomia , Derivação Gástrica , Resistência à Insulina , Obesidade Mórbida/cirurgia , Adulto , Glicemia/análise , Jejum/sangue , Jejum/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Obesidade Mórbida/metabolismo , Período Pós-Operatório
12.
Int J Mol Sci ; 20(16)2019 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-31405212

RESUMO

Glucagon exerts pleiotropic actions on energy balance and has emerged as an attractive target for the treatment of diabetes and obesity in the last few years. Glucagon reduces body weight and adiposity by suppression of appetite and by modulation of lipid metabolism. Moreover, this hormone promotes weight loss by activation of energy expenditure and thermogenesis. In this review, we cover these metabolic actions elicited by glucagon beyond its canonical regulation of glucose metabolism. In addition, we discuss recent developments of therapeutic approaches in the treatment of obesity and diabetes by dual- and tri-agonist molecules based on combinations of glucagon with other peptides. New strategies using these unimolecular polyagonists targeting the glucagon receptor (GCGR), have become successful approaches to evaluate the multifaceted nature of glucagon signaling in energy balance and metabolic syndrome.


Assuntos
Regulação do Apetite , Diabetes Mellitus/metabolismo , Metabolismo Energético , Glucagon/metabolismo , Obesidade/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Regulação do Apetite/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus/tratamento farmacológico , Metabolismo Energético/efeitos dos fármacos , Glucagon/agonistas , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Terapia de Alvo Molecular , Obesidade/tratamento farmacológico , Peptídeos/farmacologia , Receptores de Glucagon/metabolismo , Termogênese/efeitos dos fármacos
13.
Front Immunol ; 10: 1255, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214196

RESUMO

Non-alcoholic fatty liver disease (NAFLD), and the progressive stage non-alcoholic steatohepatitis (NASH), is the predominant cause of chronic liver disease globally. As part of the complex pathogenesis, natural killer (NK) cells have been implicated in the development of liver inflammation in experimental murine models of NASH. However, there is a lack of knowledge on how NK cells are affected in humans with this disease. Here, we explored the presence of disease-specific changes within circulating and tissue-resident NK cell populations, as well as within other major immune cell subsets, in patients with liver biopsy-confirmed NAFLD. Using 18-color-flow cytometry, substantial changes were observed in certain myeloid populations in patients as compared to controls. NK cell numbers, on the other hand, were not altered. Furthermore, only minor differences in expression of activating and inhibitory NK cell receptors were noted, with the exception of an increased expression of NKG2D on NK cells from patients with NASH. NK cell differentiation remained constant, and NK cells from these patients retain their ability to respond adequately upon stimulation. Instead, considerable alterations were observed between liver, adipose tissue, and peripheral blood NK cells, independently of disease status. Taken together, these results increase our understanding of the importance of the local microenvironment in shaping the NK cell compartment and stress the need for further studies exploring how NASH affects intrahepatic NK cells in humans.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Biomarcadores , Suscetibilidade a Doenças , Feminino , Humanos , Imunofenotipagem , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/complicações , Obesidade/metabolismo , Especificidade de Órgãos/imunologia
14.
Expert Opin Drug Discov ; 14(5): 421-431, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30821530

RESUMO

INTRODUCTION: Current pharmacological therapies that target single receptors have limited efficacy for the treatment of diabetes and obesity. Novel approaches with hybrid peptides that activate more than one receptor at once to generate beneficial effects through synergistic effects have shown promising results. Several unimolecular dual and tri-agonists, mainly associated with GPCR like GLP-1/GCG/GIP receptors, have shown exceptional efficacy in preclinical models, and are currently being evaluated in clinical trials to investigate their safety and beneficial effects in humans. Areas covered: Herein, the authors review the development of drugs used in the treatment of metabolic disease, from single agonists to the new generation of tri-agonist peptides and compile the latest knowledge available on GPCR-based drug discovery. The authors also provide the reader with their expert perspectives on this exciting area of drug development. Expert opinion: The co-agonists that have been clinically tested so far have been well tolerated and reduce body weight as well as fasting glucose levels in patients with Type 2 Diabetes Mellitus to a higher degree than single agonists alone. The promising data collected so far now warrant large scale randomized clinical trials to assess whether a unimolecular polypharmacy-based approach could translate into safe and efficacious treatments for obesity and its comorbidities.


Assuntos
Descoberta de Drogas/métodos , Doenças Metabólicas/tratamento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos/métodos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Doenças Metabólicas/fisiopatologia , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Receptores Acoplados a Proteínas G/metabolismo
15.
Sci Rep ; 9(1): 4614, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30874564

RESUMO

Studies have implicated the extracellular matrix (ECM) of adipose tissue in insulin resistance. The proteoglycan decorin, a component of ECM, has been associated with glucose tolerance, but possible causal effects on metabolism remain to be explored. We here sought to determine metabolic consequences of loss of decorin in mice (DcnKO). DcnKO mice were fed a low-fat (LF) or high-fat (HF) diet for 10 weeks and body weight and food intake was recorded. An intraperitoneal glucose tolerance test was performed after eight weeks. Blood samples and adipose, liver and muscle tissues were collected at sacrifice. Global gene expression was measured in adipose tissue, and expression of decorin was also analyzed in human adipose samples. DcnKO mice showed increased feed efficiency during overfeeding and impaired glucose tolerance. Adipose leptin mRNA and circulating leptin levels were elevated in DcnKO mice, along with a downregulation of genes involved in ECM organization and triglyceride biosynthesis, and an upregulation of adipose genes involved in complement and coagulation cascades. Consistent with a protective metabolic role for decorin, in obese patients we found increased adipose decorin expression after profound fat loss, particularly in the stromal vascular fraction. Loss of decorin in mice caused impaired glucose tolerance in association with increased feed efficiency and altered gene expression in adipose tissue. Our data provide evidence that decorin is an important factor for maintaining glucose tolerance.


Assuntos
Decorina/metabolismo , Intolerância à Glucose/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Adiposidade , Animais , Peso Corporal , Decorina/fisiologia , Dieta Hiperlipídica , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Resistência à Insulina/fisiologia , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipernutrição , Proteoglicanas/metabolismo
16.
Cell Rep ; 25(2): 413-423.e5, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304681

RESUMO

Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in females.


Assuntos
Tecido Adiposo Marrom/fisiologia , Ceramidas/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Estradiol/farmacologia , Hipotálamo/fisiologia , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Animais , Estrogênios/farmacologia , Feminino , Homeostase , Hipotálamo/efeitos dos fármacos , Ratos
17.
Nat Commun ; 9(1): 3432, 2018 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-30143607

RESUMO

p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.


Assuntos
Dieta/efeitos adversos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Tecido Adiposo Marrom/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 8 Ativada por Mitógeno/genética , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Ratos Sprague-Dawley , Fator Esteroidogênico 1/metabolismo , Proteína Supressora de Tumor p53/genética
18.
J Endocrinol ; 238(3): 177-186, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29914932

RESUMO

Current evidence suggests that estradiol (E2), the main ovarian steroid, modulates energy balance by regulating both feeding and energy expenditure at the central level, through the energy sensor AMP-activated protein kinase (AMPK). We hypothesized that the hypothalamic mechanistic target of rapamycin (mTOR) pathway, a well-established nutrient sensor and modulator of appetite and puberty, could also mediate the anorectic effect of E2. Our data showed that ovariectomy (OVX) elicited a marked downregulation of the mTOR signaling in the arcuate nucleus of the hypothalamus (ARC), an effect that was reversed by either E2 replacement or central estrogen receptor alpha (ERα) agonism. The significance of this molecular signaling was given by the genetic inactivation of S6 kinase B1 (S6K1, a key downstream mTOR effector) in the ARC, which prevented the E2-induced hypophagia and weight loss. Overall, these data indicate that E2 induces hypophagia through modulation of mTOR pathway in the ARC.


Assuntos
Anorexia/induzido quimicamente , Anorexia/metabolismo , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Estradiol/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Depressores do Apetite/farmacologia , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Feminino , Ovariectomia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologia
19.
Mol Nutr Food Res ; 62(10): e1800060, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29536615

RESUMO

SCOPE: Angiopoietin-like protein 4 (ANGPTL-4) regulates plasma lipoprotein levels, but its relevance in human obesity and type 2 diabetes (T2D) is largely unknown. We aim to investigate the regulation of circulating ANGPTL-4 levels in obesity, T2D, and after changes in body weight. METHODS AND RESULTS: Circulating ANGPTL-4 levels were measured in two different cohorts. First, in a cross-sectional study, we evaluated ANGPTL-4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (AGT; n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow-up 2 years later. ANGPTL-4 levels were significantly increased in obese patients with AGT compared to lean participants. Moreover, ANGPTL-4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA-IR, fasting triglycerides, and with inflammatory markers. Participants gaining weight after the follow-up showed increased ANGPTL-4 levels in parallel to increased BMI, fat mass, and fasting glucose, while ANGPTL-4 levels were reduced in participants losing weight. CONCLUSION: Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes.


Assuntos
Proteína 4 Semelhante a Angiopoietina/sangue , Diabetes Mellitus Tipo 2/sangue , Obesidade/sangue , Adulto , Peso Corporal , Estudos Transversais , Feminino , Intolerância à Glucose , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Circunferência da Cintura , Perda de Peso
20.
Mol Metab ; 8: 132-143, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29290620

RESUMO

OBJECTIVE: Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). METHODS: We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat) and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet). We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2). RESULTS: The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. CONCLUSION: These data provide new evidence for targeting p53 as a strategy to treat liver disease.


Assuntos
Doxorrubicina/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Inibidores da Topoisomerase II/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Inibidores da Topoisomerase II/administração & dosagem , Inibidores da Topoisomerase II/farmacologia , Proteína Supressora de Tumor p53/genética
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