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1.
J Hepatol ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34555423

RESUMO

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. LAY SUMMARY: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis.

2.
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
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.
Hepatology ; 73(2): 606-624, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32329085

RESUMO

BACKGROUND AND AIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing ß-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.

6.
Biomaterials ; 247: 120016, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32272302

RESUMO

Gene-activated matrices (GAMs) encoding pivotal transcription factors (TFs) represent a powerful tool to direct stem cell specification for tissue engineering applications. However, current TF-based GAMs activated with pDNA, are challenged by their low transfection efficiency and delayed transgene expression. Here, we report a GAM technology activated with mRNAs encoding TFs SOX9 (cartilage) and MYOD (muscle). We find that these mRNA-GAMs induce a higher and faster TF expression compared to pDNA-GAMs, especially in the case of RNase resistant mRNA sequences. This potent TF expression was translated into a high synthesis of cartilage- and muscle-specific markers, and ultimately, into successful tissue specification in vitro. Additionally, we show that the expression of tissue-specific markers can be further modulated by altering the properties of the mRNA-GAM environment. These results highlight the value of this GAM technology for priming cell lineage specification, a key centerpiece for future tissue engineering devices.


Assuntos
Engenharia Tecidual , Fatores de Transcrição , Diferenciação Celular , RNA Mensageiro/genética , Transfecção
7.
Neuroendocrinology ; 110(11-12): 1042-1054, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31945763

RESUMO

Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin (UGN) is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and proximal small intestine. UGN is the endogenous ligand of Gucy2c and decreases body weight in diet-induced obese (DIO) mice via the activation of the thermogenic program in brown adipose tissue. Therefore, we wanted to evaluate whether oral linaclotide could also improve DIO mice metabolic phenotype. In this study, we have demonstrated that DIO mice orally treated with linaclotide exhibited a significant reduction of body weight without modifying food intake. Linaclotide exerts its actions through the central nervous system, and more specifically, via Gucy2c receptors located in the mediobasal hypothalamus, leading to the activation of the sympathetic nervous system to trigger the thermogenic activity of brown fat stimulating energy expenditure. These findings indicate for first time that, in addition to its effects at intestinal level to treat irritable bowel syndrome with constipation and chronic constipation, linaclotide also exerts a beneficial effect in whole body metabolism.

8.
Nat Metab ; 1(8): 811-829, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31579887

RESUMO

Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.


Assuntos
Tecido Adiposo Marrom/metabolismo , Dopamina/metabolismo , Hipotálamo/metabolismo , Transdução de Sinais , Termogênese/fisiologia , Animais , Bromocriptina/administração & dosagem , Bromocriptina/farmacologia , Feminino , Humanos , Hipotálamo/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Ratos
9.
Nat Commun ; 10(1): 4037, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492869

RESUMO

Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Nicotina/farmacologia , Receptores Opioides kappa/metabolismo , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adulto , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/farmacologia , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Ratos Sprague-Dawley , Receptores Opioides kappa/genética , Proteína Desacopladora 1/metabolismo
10.
Diabetes ; 68(12): 2210-2222, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31530579

RESUMO

Melanin-concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism, and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological and genetic approaches to show that the sirtuin 1 (SIRT1)/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, and glucose intolerance. MCH reduces proopiomelanocortin (POMC) neuronal activity, and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of agouti-related peptide (AgRP) neurons because inhibition of γ-aminobutyric acid receptor in the ARC did not prevent the orexigenic action of MCH, and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild-type mice; however, these effects were abolished in mice overexpressing SIRT1 fed a high-fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight, and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity.


Assuntos
Adiposidade/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Intolerância à Glucose/metabolismo , Hiperfagia/metabolismo , Hormônios Hipotalâmicos/farmacologia , Melaninas/farmacologia , Neurônios/efeitos dos fármacos , Hormônios Hipofisários/farmacologia , Pró-Opiomelanocortina/metabolismo , Sirtuína 1/metabolismo , Adiposidade/fisiologia , Animais , Proteína Forkhead Box O1/genética , Intolerância à Glucose/genética , Hiperfagia/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Sirtuína 1/genética
11.
Neuroscience ; 396: 119-137, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30447390

RESUMO

Seipin is a widely expressed protein but with highest levels found in the brain and testes. Seipin function is not yet completely understood, therefore the aim of this study was to evaluate the expression of BSCL2 transcripts in the central nervous system (CNS) of humans and investigate the effect of their overexpression on a neuron model and their relationship with oxidative stress protection, as well as shed light on the pathogenic mechanisms of Celia's Encephalopathy. We analyzed the expression of BSCL2 transcripts using real-time RT-PCR in samples across the brain regions of subjects who underwent necropsy and from a case with Celia's Encephalopathy. The transcript encoding the long seipin isoform (BSCL2-203, 462 aa) is expressed primarily in the brain and its expression is inversely correlated with age in the temporal lobe, amygdala, and hypothalamus. Strong positive correlations were found between BSCL2 expression and some genes encoding protective enzymes against oxidative stress including SOD1 and SOD2, as well as peroxisome proliferator-activated receptor gamma (PPARG) in the amygdala. These results were experimentally corroborated by overexpressing BSCL2 transcripts in SH-SY5Y cells with lentiviral transduction and assessing their effects on neuron differentiated cells. Confocal microscopy studies showed that both seipin and PEX16 are closely expressed in the hypothalami of healthy human brains, and PEX16 was absent in the same region of the PELD case. We hypothesize that seipin has specific CNS functions and may play a role in peroxisome biogenesis.


Assuntos
Encefalopatias/metabolismo , Encéfalo/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/fisiologia , Estresse Oxidativo , Peroxissomos/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Autopsia , Linhagem Celular Tumoral , Feminino , Subunidades gama da Proteína de Ligação ao GTP/biossíntese , Humanos , Masculino , Proteínas de Membrana/biossíntese , Pessoa de Meia-Idade , PPAR gama/biossíntese , Isoformas de Proteínas/biossíntese , Fatores Sexuais , Superóxido Dismutase/biossíntese , Superóxido Dismutase-1/biossíntese , Regulação para Cima , Adulto Jovem
12.
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
13.
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
14.
Neuropharmacology ; 130: 62-70, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29191753

RESUMO

Melanin-Concentrating Hormone (MCH) is one of the most relevant orexigenic factors specifically located in the lateral hypothalamic area (LHA), with its physiological relevance demonstrated in studies using several genetically manipulated mice models. However, the central mechanisms controlling MCH-induced hyperphagia remain largely uncharacterized. Here, we show that central injection of MCH in mice deficient for kappa opoid receptor (k-OR) failed to stimulate feeding. To determine the hypothalamic area responsible for this MCH/k-OR interaction, we performed virogenetic studies and found that downregulation of k-OR by adeno-associated viruses (shOprk1-AAV) in LHA, but not in other hypothalamic nuclei, was sufficient to block MCH-induced food intake. Next, we sought to investigate the molecular signaling pathway within the LHA that mediates acute central MCH stimulation of food intake. We found that MCH activates k-OR and that increased levels of phosphorylated extracellular signal regulated kinase (ERK) are associated with downregulation of phospho-S6 Ribosomal Protein. This effect was prevented when a pharmacological inhibitor of k-OR was co-administered with MCH. Finally, the specific activation of the direct upstream regulator of S6 (p70S6K) in the LHA attenuated MCH-stimulated food consumption. Our results reveal that lateral hypothalamic k-OR system modulates the orexigenic action of MCH via the p70S6K/S6 pathway.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Hormônios Hipotalâmicos/administração & dosagem , Melaninas/administração & dosagem , Hormônios Hipofisários/administração & dosagem , Receptores Opioides kappa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Animais , Depressores do Apetite/administração & dosagem , Depressores do Apetite/metabolismo , Dependovirus , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hormônios Hipotalâmicos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Melaninas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hormônios Hipofisários/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Proteínas Quinases S6 Ribossômicas/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas/metabolismo
15.
Hepatology ; 64(4): 1086-104, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27387967

RESUMO

UNLABELLED: The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose-regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH-R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone-induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline-deficient, diet-induced and choline-deficient, high-fat diet-induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose-regulated protein 78 kDa in the liver abolished hypothalamic κOR-induced steatosis by reducing hepatic ER stress. CONCLUSIONS: This study reveals a novel hypothalamic-parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086-1104).


Assuntos
Dieta , Estresse do Retículo Endoplasmático , Hormônios Hipotalâmicos/fisiologia , Hipotálamo/fisiologia , Hepatopatias/etiologia , Melaninas/fisiologia , Hormônios Hipofisários/fisiologia , Receptores Opioides kappa/fisiologia , Animais , Inflamação/complicações , Inflamação/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley
16.
Endocrinology ; 157(7): 2735-49, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27183316

RESUMO

p53 is a well-known tumor suppressor that plays multiple biological roles, including the capacity to modulate metabolism at different levels. However, its metabolic role in brown adipose tissue (BAT) remains largely unknown. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance. To this end, we generated and characterized global p53-null mice and mice lacking p53 specifically in BAT. Additionally we performed gain-and-loss-of-function experiments in the BAT of adult mice using virogenetic and pharmacological approaches. BAT was collected and analyzed by immunohistochemistry, thermography, real-time PCR, and Western blot. p53-deficient mice were resistant to diet-induced obesity due to increased energy expenditure and BAT activity. However, the deletion of p53 in BAT using a Myf5-Cre driven p53 knockout did not show any changes in body weight or the expression of thermogenic markers. The acute inhibition of p53 in the BAT of adult mice slightly increased body weight and inhibited BAT thermogenesis, whereas its overexpression in the BAT of diet-induced obese mice reduced body weight and increased thermogenesis. On the other hand, pharmacological activation of p53 improves body weight gain due to increased BAT thermogenesis by sympathetic nervous system in obese adult wild-type mice but not in p53(-/-) animals. These results reveal that p53 regulates BAT metabolism by coordinating body weight and thermogenesis, but these metabolic actions are tissue specific and also dependent on the developmental stage.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Obesidade/genética , Termogênese/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Tecido Adiposo Marrom/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Composição Corporal/genética , Peso Corporal/genética , Linhagem Celular , Doxorrubicina/farmacologia , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Ratos , Somatotrofos/citologia , Somatotrofos/efeitos dos fármacos , Somatotrofos/metabolismo , Termogênese/genética , Proteína Supressora de Tumor p53/agonistas , Proteína Supressora de Tumor p53/metabolismo
17.
Diabetes ; 65(2): 421-32, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26566631

RESUMO

The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.


Assuntos
Encéfalo/metabolismo , Mucosa Intestinal/metabolismo , Peptídeos Natriuréticos/farmacologia , Obesidade/fisiopatologia , Ganho de Peso/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Vias Autônomas , Defecação/efeitos dos fármacos , Ingestão de Alimentos , Vias Eferentes , Metabolismo Energético , Homeostase , Masculino , Camundongos , Camundongos Knockout , Peptídeos Natriuréticos/administração & dosagem , Peptídeos Natriuréticos/metabolismo , Sistema Nervoso Simpático/metabolismo , Termogênese , Nervo Vago/metabolismo
18.
Neurobiol Dis ; 83: 44-53, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26282322

RESUMO

Celia's Encephalopathy (MIM #615924) is a recently discovered fatal neurodegenerative syndrome associated with a new BSCL2 mutation (c.985C>T) that results in an aberrant isoform of seipin (Celia seipin). This mutation is lethal in both homozygosity and compounded heterozygosity with a lipodystrophic BSCL2 mutation, resulting in a progressive encephalopathy with fatal outcomes at ages 6-8. Strikingly, heterozygous carriers are asymptomatic, conflicting with the gain of toxic function attributed to this mutation. Here we report new key insights about the molecular pathogenic mechanism of this new syndrome. Intranuclear inclusions containing mutant seipin were found in brain tissue from a homozygous patient suggesting a pathogenic mechanism similar to other neurodegenerative diseases featuring brain accumulation of aggregated, misfolded proteins. Sucrose gradient distribution showed that mutant seipin forms much larger aggregates as compared with wild type (wt) seipin, indicating an impaired oligomerization. On the other hand, the interaction between wt and Celia seipin confirmed by coimmunoprecipitation (CoIP) assays, together with the identification of mixed oligomers in sucrose gradient fractionation experiments can explain the lack of symptoms in heterozygous carriers. We propose that the increased aggregation and subsequent impaired oligomerization of Celia seipin leads to cell death. In heterozygous carriers, wt seipin might prevent the damage caused by mutant seipin through its sequestration into harmless mixed oligomers.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , Encéfalo/metabolismo , Subunidades gama da Proteína de Ligação ao GTP/genética , Mutação , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Adipócitos/metabolismo , Adulto , Idoso , Encéfalo/patologia , Encefalopatias/patologia , Criança , Retículo Endoplasmático/metabolismo , Feminino , Heterozigoto , Humanos , Masculino , Agregados Proteicos , Proteômica , Deficiências na Proteostase/patologia
19.
Diabetes ; 63(10): 3346-58, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24917578

RESUMO

GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hipoglicemiantes/farmacologia , Hipotálamo/efeitos dos fármacos , Proteínas Quinases/metabolismo , Termogênese/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Quimioterapia Combinada , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Exenatida , Feminino , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Hipotálamo/metabolismo , Liraglutida , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Ratos , Peçonhas/farmacologia , Peçonhas/uso terapêutico , Adulto Jovem
20.
Endocrinology ; 154(10): 3671-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23832961

RESUMO

Ghrelin, a stomach-derived peptide, stimulates feeding behavior and adiposity. For its orexigenic action, ghrelin triggers a central SIRT1/p53/AMPK pathway. The tumor suppressor p53 also plays an important role in white adipose tissue (WAT), where it is up-regulated in the adipocytes of obese mice. It is not known, however, whether p53 has any role in mediating the peripheral action of ghrelin. In the present study, chronic peripheral ghrelin treatment resulted in increased body weight and fat-mass gain in wild-type mice. Correspondingly, mRNA levels of several adipogenic and fat-storage-promoting enzymes were up-regulated in WAT, whereas hepatic triglyceride content and lipogenic enzymes were also increased in wild-type mice following ghrelin treatment. In contrast, mice lacking p53 failed to respond to ghrelin treatment, with their body weight, fat mass, and adipocyte and hepatic metabolism remaining unchanged. Thus, our results show that p53 is necessary for the actions of ghrelin on WAT and liver, leading to changes in expression levels of lipogenic and adipogenic genes, and modifying body weight.


Assuntos
Adipogenia , Tecido Adiposo Branco/metabolismo , Indução Enzimática , Grelina/metabolismo , Lipogênese , Fígado/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Cruzamentos Genéticos , Feminino , Perfilação da Expressão Gênica , Grelina/administração & dosagem , Injeções Intraperitoneais , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Técnicas de Cultura de Tecidos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Proteína Supressora de Tumor p53/genética , Ganho de Peso
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