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1.
J Hepatol ; 2021 Sep 20.
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 nonalcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing a liver proteomic analysis 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 of patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the liver of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and NASH) 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 palmitoiltransferase I (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 NAFLD in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD, by stimulating SIRT1, CPT1a and 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.
J Clin Invest ; 131(18)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34324439

RESUMO

Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the arcuate nucleus of the hypothalamus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive connexin-43 gap junction-mediated metabolic networks by arcuate tanycytes. Selective suppression of either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.

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.

5.
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.

6.
Molecules ; 23(9)2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135414

RESUMO

No scientific report proves the action of the phytochemicals from the mangrove tree Rhizophora mangle in the treatment of diabetes. The aim of this work is to evaluate the effects of the acetonic extract of R. mangle barks (AERM) on type 2 diabetes. The main chemical constituents of the extract were analyzed by high-performance liquid chromatography (HPLC) and flow injection analysis electrospray-iontrap mass spectrometry (FIA-ESI-IT-MS/MS). High-fat diet (HFD)-fed mice were used as model of type 2 diabetes associated with obesity. After 4 weeks of AERM 5 or 50 mg/kg/day orally, glucose homeostasis was evaluated by insulin tolerance test (kiTT). Hepatic steatosis, triglycerides and gene expression were also evaluated. AERM consists of catechin, quercetin and chlorogenic acids derivatives. These metabolites have nutritional importance, obese mice treated with AERM (50 mg/kg) presented improvements in insulin resistance resulting in hepatic steatosis reductions associated with a strong inhibition of hepatic mRNA levels of CD36. The beneficial effects of AERM in an obesity model could be associated with its inhibitory α-amylase activity detected in vitro. Rhizophora mangle partially reverses insulin resistance and hepatic steatosis associated with obesity, supporting previous claims in traditional knowledge.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica/metabolismo , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Rhizophoraceae/química , Animais , Biomarcadores , Glicemia , Cromatografia Líquida de Alta Pressão , Dieta Hiperlipídica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Redes e Vias Metabólicas , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Polifenóis/química , Polifenóis/farmacocinética , Substâncias Protetoras/química , Substâncias Protetoras/farmacocinética , Substâncias Protetoras/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
7.
Nutrition ; 32(7-8): 740-7, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27036610

RESUMO

OBJECTIVE: The aim of this study was to investigate whether serum concentrations of total saturated fatty acids (SFAs), polyunsaturated fatty acids (PUFAs), and their fractions are associated with plasma adiponectin and leptin concentrations throughout pregnancy. METHODS: A prospective cohort of 201 pregnant women was followed from gestational weeks 5 to 13, 20 to 26, and 30 to 36. Blood samples were collected at the three visits after 12 h of fasting. Fatty acid concentrations were determined using fast gas-liquid chromatography. Plasma adiponectin (µg/mL) and leptin (ng/dL) concentrations were evaluated using enzyme-linked immunosorbent assay kits. Statistical analyses included median adipokine concentrations according to the tertiles of fatty acid distribution and multiple linear mixed-effect models adjusted for body mass index, gestational age, total energy intake, alcohol consumption, and smoking. RESULTS: Women classified in the third SFA concentration tertile had lower median values of adiponectin compared with those in the first tertile ([first trimester: first tertile = 5.36; third tertile = 5.00]; [second trimester: first tertile = 6.39; third tertile = 4.47]; [third trimester: first tertile = 6.46; third tertile = 4.60]). Similar trends were observed for the 14:0, 16:0 and 18:0 fractions. In the multiple longitudinal models, total SFA (ß = -41.039; P = 0.008) and 16:0 were negatively associated with plasma adiponectin (16:0, ß = -0.511; P = 0.001). Total PUFA ω-6 (ß = 28.961; P = 0.002) and 18:2 ω-6 (ß = 0.259, P = 0.006) were positively associated with the adiponectin. Total SFA (ß = 0.110, P = 0.007), 14:0 (ß = 0.072, P = 0.011), and 20:3 ω-6 (ß = 0.039; P = 0.035) were positively associated with plasma leptin. CONCLUSIONS: Total serum SFA and the 16:0 fraction were negatively associated with plasma adiponectin and positively associated with leptin concentrations. Total ω-6 PUFA was positively associated only with plasma adiponectin concentrations throughout pregnancy.


Assuntos
Adiponectina/sangue , Ácidos Graxos/sangue , Leptina/sangue , Adulto , Índice de Massa Corporal , Brasil , Cromatografia Gasosa , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Ácidos Graxos Insaturados/sangue , Feminino , Humanos , Gravidez , Estudos Prospectivos , Adulto Jovem
8.
Physiol Behav ; 124: 100-6, 2014 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-24246723

RESUMO

The most frequently used animal models of early weaning (EW) in rodents, maternal deprivation and pharmacological inhibition of lactation, present confounding factors, such as high stress or drug side effects, that can mask or interact with the effects of milk deprivation per se. Given these limitations, the development of new models of EW may provide useful information regarding the impact of a shortened period of breastfeeding on the endocrine and nervous systems, both during development and at adulthood. Using a model of EW in which lactating Wistar rat dams are wrapped with a bandage to block access to milk during the last three days of lactation, we have recently shown that the adult offspring presented higher body mass, hyperphagia, hyperleptinemia, leptin as well as insulin resistance, and higher adrenal catecholamine content at adulthood. Here, we used this EW model, which involves no pharmacological treatment or maternal separation, to analyze anxiety-like, novelty-seeking and memory/learning behavioral traits in the adult male offspring. To that end, animals were tested in the elevated plus maze, in the hole board arena and in the radial arm water maze. Except for an increased number of rearing events (a measure of vertical activity), no other behavioral differences were observed between EW and control animals. The contrasting behavioral results between the three EW models may be associated with differences in HPA axis function in the offspring at weaning, since it has been observed that bandaging does not affect corticosteronemia while maternal separation and pharmacological EW increase it.


Assuntos
Ansiedade/psicologia , Comportamento Exploratório , Aprendizagem em Labirinto , Memória , Desmame , Animais , Masculino , Modelos Animais , Ratos
9.
Metabolism ; 63(3): 352-64, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24355624

RESUMO

OBJECTIVE: Obesity and osteoporosis seem to have a common pathogenesis, especially because bone and adipose tissue have common origins. Since early weaning (EW) decreases adipogenesis and osteogenesis in neonate, further programming for obesity and hyperleptinemia, we hypothesized that these changes in adipogenesis could affect bone metabolism. MATERIALS/METHODS: Lactating rats were separated into 3 groups: control - dams whose pups ate milk throughout lactation; mechanical EW (MEW) - dams were involved with a bandage interrupting suckling in the last 3days of lactation; pharmacological EW (PEW) - dams were bromocriptine-treated (0.5mg/twice a day via intraperitoneal injection) 3days before weaning. The adult offspring was subjected to dual-energy X-ray absorptiometry and bone tissue was also evaluated by computed tomography, microcomputed tomography and biomechanical tests, beyond serum analyses. RESULTS: MEW and PEW presented higher total bone mineral density (BMD), total bone mineral content, spine BMD and bone area in postnatal day 150 (PN150). In PN180, both groups also presented increase of these parameters and higher femur BMD and fourth lumbar vertebra (LV4) BMD, femoral head radiodensity and LV4 vertebral body radiodensity, trabecular number, stiffness and break load; lower trabecular separation, maximal deformation and break deformation, and also hyperleptinemia and higher visceral fat mass and 25-hydroxivitamin D, whereas parathyroid hormone was unchanged. Serum C-terminal cross-linked telopeptide of type I collagen was lower for both groups. CONCLUSIONS: Since both models program for obesity and increased bone mass, and leptin increases plasma vitamin D levels, probably leptin is the link between obesity and higher bone mass.


Assuntos
Densidade Óssea/fisiologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Obesidade/metabolismo , Adipogenia/fisiologia , Animais , Colágeno Tipo I/metabolismo , Ingestão de Alimentos/fisiologia , Feminino , Lactação/metabolismo , Lactação/fisiologia , Masculino , Obesidade/sangue , Obesidade/fisiopatologia , Osteogênese/fisiologia , Hormônio Paratireóideo/metabolismo , Ratos , Ratos Wistar , Vitamina D/metabolismo , Desmame
10.
Br J Nutr ; 108(12): 2286-95, 2012 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-22874082

RESUMO

The interruption of lactation for a short period, without the use of pharmacological substances or maternal separation, causes offspring malnutrition and hypoleptinaemia and programmes for metabolic disorders such as higher body weight and adiposity, hyperphagia, hyperleptinaemia and central leptin resistance in adulthood. Here, in order to clarify the mechanisms underlying the phenotype observed in adult early-weaned (EW) rats, we studied the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) in different hypothalamic nuclei by immunohistochemistry and Western blot. In the EW group, the teats of lactating rats were blocked with a bandage to interrupt lactation during the last 3 d, while control pups had free access to milk throughout the entire lactation period. At age 180 d, EW offspring showed higher NPY staining in the paraventricular nucleus (PVN), as well as NPY protein content (+68 %) in total hypothalamus than control ones. AgRP showed no changes in staining or Western blot. POMC content was not affected; however, its distribution pattern was altered. CART-positive cells of EW offspring had lower immunoreactivity associated with reduced cell number in the PVN and lower protein content ( - 38 %) in total hypothalamus. The present data indicate that precocious weaning can imprint the neuronal circuitry, especially in the PVN, and cause a long-term effect on the expression of specific orexigenic and anorexigenic neuropeptides, such as NPY and CART, that can be caused by leptin resistance and are coherent with the hyperphagia observed in these animals.


Assuntos
Proteína Relacionada com Agouti/análise , Expressão Gênica , Proteínas do Tecido Nervoso/análise , Neuropeptídeo Y/análise , Núcleo Hipotalâmico Paraventricular/química , Desmame , Fatores Etários , Animais , Western Blotting , Feminino , Hipotálamo/química , Imuno-Histoquímica , Lactação , Masculino , Pró-Opiomelanocortina/análise , Ratos , Ratos Wistar
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