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1.
Zhen Ci Yan Jiu ; 45(1): 27-32, 2020 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-32144905

RESUMO

OBJECTIVE: To investigate the effect of electroacupuncture (EA) on silent information regulator 1 (SIRT1), forkhead transcription factor O1 (FoxO1), and proopiomelanocortin (POMC) in the hypothalamus of rats with high-fat diet-induced obesity (DIO), as well as the mechanism of EA in regulating central appetite peptides to help lose weight. METHODS: Male Wistar rats were randomly divided into normal group, model group, EA group, EA+inhibitor group, inhibitor group, and sham-operation group, with 10 rats in each group. High-fat diet was used to establish a rat model of DIO. The rats in the EA group and EA+inhibitor group were given EA at "Fenglong" (ST40), "Zhongwan "(CV12),"Guanyuan "(CV4), and"Zusanli" (ST36) with continuous wave at a frequency of 2 Hz and an intensity of 1 mA, for 10 minutes each time. The rats in the EA+inhibitor group and inhibitor group were given tube placement in the third ventricle and injection of the specific SIRT1 antagonist EX-527. The rats in the sham-operation group were given tube placement in the third ventricle and injection of artificial cerebrospinal fluid. The above treatment was given 3 times a week for 8 weeks in total. Body weight, food intake, and Lee's index were observed before and after treatment. An automatic biochemical analyzer was used to measure the serum levels of total cholesterol (TC), triglyceride (TG), and free fatty acid (FFA), and Western blot was used to measure the protein expression of SIRT1, FoxO1, acetylated FoxO1(AC-FoxO1), and POMC in the hypothalamus. RESULTS: Before treatment, the model group, the EA group, the EA+inhibitor group, the inhibitor group, and the sham-operation group had significantly higher body weight and food intake than the normal group (P<0.01), and the model group and the sham-operation group had a significantly higher Lee's index than the normal group (P<0.05). Compared with the model group after treatment, the EA group and the EA+inhibitor group had significant reductions in body weight, food intake, TC, and the protein expression of AC-FoxO1 (P<0.01, P<0.05) and significant increases in the protein expression of SIRT1, FoxO1 and POMC (P<0.01, P<0.05); the EA group had significant reductions in Lee's index and the levels of TG, FFA(P<0.05,P<0.01);the inhibitor group had significant increases in food intake, the serum levels of TC, TG, FFA(P<0.01) and significant reductions in the protein expression of SIRT1, FoxO1 and POMC (P<0.01,P<0.05). Compared with the EA group, the EA+inhibitor group and the inhibitor group had significant increases in body weight, food intake, Lee's index, the levels of TG, FFA and the protein expression of AC-FoxO1 (P<0.01, P<0.05) and significant reductions in the protein expression of SIRT1, FoxO1 and POMC (P<0.01); the inhibitor group had significant increases in the serum levels of TC (P<0.01). Compared with the EA+inhibitor group, the inhibitor group had significant increases in body weight, food intake, the serum levels of TC, TG, FFA, and the protein expression of AC-FoxO1 (P<0.01), as well as significant reductions in the protein expression of SIRT1, FoxO1 and POMC (P<0.01). CONCLUSION: In rats with DIO, EA can effectively up-regulate the expression of SIRT1 in the hypothalamus, exert a deacetylation effect on FoxO1, and promote the expression of the downstream appetite-inhibiting peptide POMC, which may be one of the mechanisms of EA to help lose weight by regulating central appetite peptides in the obesity model.


Assuntos
Eletroacupuntura , Pró-Opiomelanocortina , Pontos de Acupuntura , Animais , Dieta Hiperlipídica , Hipotálamo , Masculino , Proteínas do Tecido Nervoso , Obesidade , Ratos , Ratos Wistar
2.
Nat Commun ; 11(1): 561, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047148

RESUMO

Parabens are preservatives widely used in consumer products including cosmetics and food. Whether low-dose paraben exposure may cause adverse health effects has been discussed controversially in recent years. Here we investigate the effect of prenatal paraben exposure on childhood overweight by combining epidemiological data from a mother-child cohort with experimental approaches. Mothers reporting the use of paraben-containing cosmetic products have elevated urinary paraben concentrations. For butyl paraben (BuP) a positive association is observed to overweight within the first eight years of life with a stronger trend in girls. Consistently, maternal BuP exposure of mice induces a higher food intake and weight gain in female offspring. The effect is accompanied by an epigenetic modification in the neuronal Pro-opiomelanocortin (POMC) enhancer 1 leading to a reduced hypothalamic POMC expression. Here we report that maternal paraben exposure may contribute to childhood overweight development by altered POMC-mediated neuronal appetite regulation.


Assuntos
Exposição Materna/efeitos adversos , Sobrepeso/etiologia , Parabenos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Conservantes Farmacêuticos/efeitos adversos , Animais , Criança , Pré-Escolar , Ingestão de Alimentos , Feminino , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sobrepeso/genética , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Parabenos/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Conservantes Farmacêuticos/análise , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Urina/química , Ganho de Peso
3.
Gen Comp Endocrinol ; 285: 113266, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493394

RESUMO

In the present study, the effects of photic environments, such as background color (white and black) and chromatic lights (blue, green, and red), on body color and gene expressions of melanin-concentrating hormone (mch) in the brain and proopiomelanocortin (pomc) in the pituitary, as well as the roles of the eyes and brain as mediators of ambient light to these genes, were examined in goldfish (Carassius auratus). Body color of goldfish exposed to fluorescent light (FL) under white background (WBG) was paler than those under black background (BBG). Gene expression levels for mch and pomc were reciprocally different depending on background color; under WBG, mRNA levels of mch and pomc were high and low, respectively, while under BBG, these levels were reversed. mch and pomc mRNA expressions of the fish exposed to chromatic light from LED were primarily similar to those exposed to FL, while blue light stimulated the expressions of mch and pomc. Ophthalmectomized goldfish exposed to FL or blue light showed minimum expression levels of mch gene, suggesting that eyes are the major mediator of ambient light for mch gene expression. Contrastingly, mRNA expressions of pomc in ophthalmectomized goldfish exposed to FL were different from those of intact goldfish. These results suggest that eyes play a functional role in mediating ambient light to regulate pomc gene expression. Since ophthalmectomy caused an increase in pomc mRNA contents in the fish exposed to blue light, we suggest that the brain is an additional mediator to regulate pomc gene expression.


Assuntos
Regulação da Expressão Gênica , Carpa Dourada/genética , Hormônios Hipotalâmicos/genética , Luz , Melaninas/genética , Pigmentação/genética , Pigmentação/efeitos da radiação , Hormônios Hipofisários/genética , Pró-Opiomelanocortina/genética , Animais , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Cor , Regulação da Expressão Gênica/efeitos da radiação , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Hipófise/metabolismo , Hipófise/efeitos da radiação , Hormônios Hipofisários/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
4.
Int J Mol Sci ; 20(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795078

RESUMO

The effect of dietary nutrients on novel farm species has always garnered wide research and economic interest. Chinese perch, an economically important carnivorous fish, accepts an artificial diet after taming, so it is essential to evaluate and optimize the nutritional and metabolic demands of this species. However, little is known about the effect of an artificial diet on the growth and metabolism of Chinese perch. Therefore, the present study evaluated the growth and metabolic responses of Chinese perch to experimental diets with different dietary protein/energy (P/E) ratios. Five isoenergetic diets (18 kJ/g) with graded levels of P/E ratios of 30.58, 33.22, 35.90, 38.6, and 41.35 mg/kJ (named A, B, C, D, and E) were formulated. A total of 225 Chinese perch (64.89 ± 0.28 g) were divided into five groups (triplicate tanks for each group), distributed into 15 (350 L) fiberglass tanks, and fed twice a day at 4% of fish wet body weight with the respective P/E ratio diets for 10 weeks. Compared with the other groups, Chinese perch in Group C showed significantly improved growth performance, weight gain (WG), specific growth rate (SGR), viscerosomatic index (VSI), hepatosomatic index (HSI), intraperitoneal fat (IPF), feed utilization, feed intake (FI), feed conversion ratio (FCR), protein efficiency ratio (PER), protein retention efficiency (PRE), energy retention efficiency (ERE), and feed efficiency (FE) as well as whole-body, muscle, and liver composition. Chinese perch in Group A, on the other hand, had the lowest growth performance, feed utilization, and body composition compared with the other groups. The activities of nitrogen metabolism-related enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), and adenosine 5'-monophosphate deaminase (AMPD)) as well as the mRNA expression of the GDH and AMPD genes were significantly lower than those in the other groups. Similarly, the expression of NPY and AgRp were significantly higher in Group C compared with the other groups. However, the gene expression of CART and POMC was not affected by the dietary P/E ratios. In Group A, the expression of mTOR, S6K, and 4EBP1 was significantly lower and that of AMPK, LKB1, and eEF2 was significantly higher when compared with the other groups. Biochemical analysis of blood showed that ALT, AST, total protein (TP), alkaline phosphatase (ALP), glucose (GLU), blood urea nitrogen (BUN), and triglyceride (TG) levels were also affected by the dietary P/E ratio. From our results, we concluded that Chinese perch growth performance and nutrient metabolism were significantly affected by the P/E ratio of the artificial diet. Second-order polynomial regression analysis revealed that Chinese perch growth performance was optimal at a P/E ratio of 37.98 in the artificial diet.


Assuntos
Composição Corporal , Dieta , Proteínas na Dieta/metabolismo , Metabolismo Energético , Percas/metabolismo , AMP Desaminase/genética , AMP Desaminase/metabolismo , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Pesqueiros , Glutamato Desidrogenase/genética , Glutamato Desidrogenase/metabolismo , Percas/crescimento & desenvolvimento , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
5.
Anim Reprod Sci ; 210: 106196, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31635770

RESUMO

Pro-opiomelanocortin (POMC) is a member of prohormone family and has important functions in stress response, skin pigmentation, thermoregulation and reproduction. In this study, the single nucleotide polymorphisms (SNPs) of POMC gene exons were detected by direct sequencing in 317 Zhenning yellow chickens. The sequencing results indicated there were seven mutation sites (g.1140C > T, g.1185 T > C, g.2085 T > C, g.3566A > C, g.3572 G > A, g.3594 G > A and g.3628 G > A) and all of these were synonymous. Furthermore, seven haplotypes were formed and sixteen diplotypes were obtained. The associations between the POMC gene polymorphisms or diplotypes and reproduction traits were also analyzed. The association analysis results indicated that the SNP of g.1140C > T was associated with egg production at 300 d of age (E300), fertilization rate (FR), hatching rate of hatching eggs (HEHR) and hatching rate of fertilized eggs (FEHR; P < 0.05). The SNP of g.3566A>C was associated with FR (P < 0.05), SNP of g.3594G>A was associated with egg weight at 300d of age (EW300; P < 0.05), and SNP of g.3628G>A was associated with HEHR and FEHR (P < 0.01), respectively. Furthermore, chickens with H2H3 diplotype had greater EW300 and FR than those with H1H7 and H3H4 diplotypes (P < 0.05). These results indicate the expression of the POMC gene had significant genotype effects on the reproduction traits of Zhenning yellow chickens, and that the H2H3 diplotype could be used as a potential genetic marker to improve the reproduction traits in chicken breeding.


Assuntos
Galinhas/genética , Galinhas/fisiologia , Polimorfismo de Nucleotídeo Único , Pró-Opiomelanocortina/genética , Reprodução/genética , Animais
6.
Endocrinol Metab (Seoul) ; 34(3): 302-313, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31565883

RESUMO

BACKGROUND: Oxytocin (OXT) has been reported to act as a growth regulator in various tumor cells. However, there is a paucity of data on the influence of OXT on cell proliferation of corticotroph adenomas. This study aimed to examine whether OXT affects cell growth in pituitary tumor cell lines (AtT20 and GH3 cells) with a focus on corticotroph adenoma cells. METHODS: Reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay were conducted with AtT20 cells to confirm the effects of OXT on hormonal activity; flow cytometry was used to assess changes in the cell cycle after OXT treatment. Moreover, the impact of OXT on proliferating cell nuclear antigen (PCNA), nuclear factor κB, and mitogen-activated protein kinase signaling pathway was analyzed by Western blot. RESULTS: OXT treatment of 50 nM changed the gene expression of OXT receptor and pro-opiomelanocortin within a short time. In addition, OXT significantly reduced adrenocorticotropic hormone secretion within 1 hour. S and G2/M populations of AtT20 cells treated with OXT for 24 hours were significantly decreased compared to the control. Furthermore, OXT treatment decreased the protein levels of PCNA and phosphorylated extracellular-signal-regulated kinase (P-ERK) in AtT20 cells. CONCLUSION: Although the cytotoxic effect of OXT in AtT20 cells was not definite, OXT may blunt cell proliferation of corticotroph adenomas by altering the cell cycle or reducing PCNA and P-ERK levels. Further research is required to investigate the role of OXT as a potential therapeutic target in corticotroph adenomas.


Assuntos
Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/metabolismo , Proliferação de Células/efeitos dos fármacos , Ocitocina/farmacologia , Adenoma Hipofisário Secretor de ACT/genética , Adenoma/genética , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Pró-Opiomelanocortina/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Receptores de Ocitocina/metabolismo
7.
Cell Physiol Biochem ; 53(4): 701-712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31592599

RESUMO

BACKGROUND/AIMS: Cholinergic signalling mediated by the activation of muscarinic and nicotinic receptors has been described in the literature as a classic and important signalling pathway in the regulation of the inflammatory response. Recent research has investigated the role of acetylcholine, the physiological agonist of these receptors, in the control of energy homeostasis at the central level. Studies have shown that mice that do not express acetylcholine in brain regions regulating energy homeostasis present with excessive weight gain and hyperphagia. However, it has not yet been well-described in the literature which cholinergic receptor subunits are involved in this response; moreover, the signalling pathways responsible for the observed effects are not fully delineated. The hypothalamus is the regulating centre of energy homeostasis, and the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) is highly expressed in this region. When active, α7nAChR recruits proteins such as JAK2/STAT3 to mediate its signalling; the same intracellular components are required by leptin, an anorexigenic hormone. The aim of the present study was to evaluate the role of the hypothalamic α7nAChR in the control of energy homeostasis. METHODS: The work was performed on Swiss male mice. Initially, using immunofluorescent staining on brain sections, the presence of α7nAChR in hypothalamic cells regulating energy homeostasis was evaluated. Animals were submitted to stereotaxis in the lateral ventricle and intracerebroventricular stimulation (ICV) was used for the administration of an agonist (PNU) or antagonist (α-bungarotoxin) of α7nAChR. Metabolic parameters were evaluated and the expression of neuropeptides was evaluated in the hypothalamus by real-time PCR and western blot. The expression of hypothalamic neuropeptides was evaluated in mice treated with siRNA or inhibitors of JAK2/STAT3 (AG490 and STATTIC) proteins. We also evaluated food intake in α7nAChR knockout animals (α7KO). Additionally, in mouse hypothalamic cell culture (the mypHoA-POMC/GFP lineage), we evaluated the expression of neuropeptides and pSTAT3 after stimulation with PNU. RESULTS: Our results indicate co-localisation of α7nAChR with α-MSH, AgRP and NPY in hypothalamic cells. Pharmacological activation of α7nAChR reduced food intake and increased hypothalamic POMC expression and decreased NPY and AgRP mRNA levels and the protein content of pAMPK. Inhibition of α7nAChR with an antagonist increased the mRNA content of NPY and AgRP. Inhibition of α7nAChR with siRNA led to the suppression of POMC expression and an increase in AgRP mRNA levels. α7KO mice showed no changes in food intake. Inhibition of proteins involved in the JAK2/STAT3 signalling pathway reversed the effects observed after PNU stimulation. POMC-GFP cells, when treated with PNU, showed increased POMC expression and nuclear translocation of pSTAT3. CONCLUSION: Thus, selective activation of α7nAChR is able to modulate important markers of the response to food intake, suggesting that α7nAChR activation can suppress the expression of orexigenic markers and favour the expression of anorexics using the intracellular JAK2/STAT3 machinery.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Janus Quinase 2/metabolismo , Pró-Opiomelanocortina/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Benzamidas/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Bungarotoxinas/farmacologia , Linhagem Celular , Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Pró-Opiomelanocortina/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Receptor Nicotínico de Acetilcolina alfa7/genética
8.
Int J Mol Sci ; 20(20)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615150

RESUMO

The micronutrients vitamins B9 and B12 act as methyl donors in the one-carbon metabolism involved in transmethylation reactions which critically influence epigenetic mechanisms and gene expression. Both vitamins are essential for proper development, and their deficiency during pregnancy has been associated with a wide range of disorders, including persisting growth retardation. Energy homeostasis and feeding are centrally regulated by the hypothalamus which integrates peripheral signals and acts through several orexigenic and anorexigenic mediators. We studied this regulating system in a rat model of methyl donor deficiency during gestation and lactation. At weaning, a predominance of the anorexigenic pathway was observed in deficient pups, with increased plasma peptide YY and increased hypothalamic pro-opiomelanocortin (POMC) mRNA, in line with abnormal leptin, ghrelin, and insulin secretion and/or signaling during critical periods of fetal and/or postnatal development of the hypothalamus. These results suggest that early methyl donor deficiency can affect the development and function of energy balance circuits, resulting in growth and weight deficits. Maternal administration of folic acid (3 mg/kg/day) during the perinatal period tended to rectify peripheral metabolic signaling and central neuropeptide and receptor expression, leading to reduced growth retardation.


Assuntos
Metabolismo Energético/genética , Grelina/genética , Peptídeo YY/genética , Pró-Opiomelanocortina/genética , Animais , Depressores do Apetite/farmacologia , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Feminino , Ácido Fólico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Grelina/sangue , Hipotálamo/metabolismo , Insulina/sangue , Insulina/genética , Lactação , Leptina/sangue , Leptina/genética , Metilação/efeitos dos fármacos , Peptídeo YY/sangue , Gravidez , Pró-Opiomelanocortina/sangue , RNA Mensageiro/genética , Ratos , Vitamina B 12/genética , Vitamina B 12/farmacologia
9.
Endocrinology ; 160(11): 2630-2645, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504391

RESUMO

Common mutations in the human prohormone convertase (PC)1/3 gene (PCKSI) are linked to increased risk of obesity. Previous work has shown that the rs6232 single-nucleotide polymorphism (N221D) results in slightly decreased activity, although whether this decrease underlies obesity risk is not clear. We observed significantly decreased activity of the N221D PC1/3 enzyme at the pH of the trans-Golgi network; at this pH, the mutant enzyme was less stable than wild-type enzyme. Recombinant N221D PC1/3 also showed enhanced susceptibility to heat stress. Enhanced susceptibility to tunicamycin-induced endoplasmic reticulum stress was observed in AtT-20/PC2 cell clones in which murine PC1/3 was replaced by human N221D PC1/3, as compared with wild-type human PC1/3. However, N221D PC1/3-expressing AtT-20/PC2 clones processed proopiomelanocortin to α-MSH similarly to wild-type PC1/3. We also generated a CRISPR-edited mouse line expressing the N221D mutation in the PCKSI gene. When homozygous N221D mice were fed either a standard or a high-fat diet, we found no increase in body weight compared with their wild-type sibling controls. Sexual dimorphism was observed in pituitary ACTH for both genotypes, with females exhibiting lower levels of pituitary ACTH. In contrast, hypothalamic α-MSH content for both genotypes was higher in females compared with males. Hypothalamic corticotropin-like intermediate peptide content was higher in wild-type females compared with wild-type, but not N221D, males. Taken together, these data suggest that the increased obesity risk linked to the N221D allele in humans may be due in part to PC1/3-induced loss of resilience to stressors rather than strictly to decreased enzymatic activity on peptide precursors.


Assuntos
Obesidade/genética , Pró-Proteína Convertase 1/metabolismo , Animais , Estresse do Retículo Endoplasmático , Estabilidade Enzimática , Feminino , Intolerância à Glucose , Humanos , Concentração de Íons de Hidrogênio , Hipotálamo/metabolismo , Masculino , Camundongos , Neuropeptídeo Y/metabolismo , Hipófise/metabolismo , Polimorfismo de Nucleotídeo Único , Pró-Opiomelanocortina/metabolismo , Pró-Proteína Convertase 1/genética , Caracteres Sexuais , alfa-MSH/metabolismo
10.
Endocr Regul ; 53(1): 8-13, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31517616

RESUMO

OBJECTIVE: The hypothalamic arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) circuitries are involved in the inhibition and stimulation of the appetite, respectively. The aim of this study was to investigate the effects of one-month lasting high-intensity exercise on the POMC mRNA and NPY mRNA expression in the above-mentioned brain structure and appetite and food intake levels. METHODS: Fourteen male Wistar rats (250±50 g) were used and kept in the well-controlled conditions (22±2 °C, 50±5% humidity, and 12 h dark/light cycle) with food and water ad libitum. The rats were divided into two groups (n=7): 1) control group (C, these rats served as controls) and 2) exercised group (RIE, these rats performed a high-intensity exercise for one month (5 days per week) 40 min daily with speed 35 m/min. The total exercise time was 60 min. The body weight and food intake were recorded continuously during the experiments. RESULTS: The results showed relative mRNA expression of POMC and NPY estimated in the hypothalamic arcuate nucleus. There were no significant differences in the NPY and POMC mRNAs expression levels and food intake between C and RIE groups. CONCLUSIONS: The present data indicate that one-month regular intensive exercise did not alter the levels of NPY and POMC mRNAs expression (as two important factors in the regulation of appetite) in the hypothalamic arcuate nucleus and food intake suggesting that this type of exercise itself is not an appropriate procedure for the body weight reduction.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Ingestão de Alimentos/fisiologia , Neuropeptídeo Y/genética , Condicionamento Físico Animal/fisiologia , Pró-Opiomelanocortina/genética , Animais , Regulação da Expressão Gênica , Masculino , Neuropeptídeo Y/metabolismo , Condicionamento Físico Animal/métodos , Pró-Opiomelanocortina/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Fatores de Tempo
11.
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
12.
Neuropeptides ; 77: 101962, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31488323

RESUMO

Hindbrain energy state shapes hypothalamic control of glucostasis. Dorsal vagal complex (DVC) L-lactate deficiency is a potent glucose-stimulatory signal that triggers neuronal transcriptional activation in key hypothalamic metabolic loci. The energy gauge AMPK is activated in DVC metabolic-sensory A2 noradrenergic neurons by hypoglycemia-associated lactoprivation, but sensor reactivity is diminished by antecedent hypoglycemia (AH). Current research addressed the premise that AH alters hindbrain lactoprivic regulation of hypothalamic metabolic transmitter function. AH did not modify reductions in A2 dopamine-beta-hydroxylase and monocarboxylate-2 (MCT2) protein expression elicited by caudal fourth ventricular delivery of the MCT inhibitor alpha-cyano-4-hydroxycinnamic acid (4CIN), but attenuated 4CIN activation of A2 AMPK. 4CIN constraint of hypothalamic norepinephrine (NE) activity was averted by AH in a site-specific manner. 4CIN induction of Fos immunolabeling in hypothalamic arcuate (ARH), ventromedial (VMN), dorsomedial (DMN) and paraventricular (PVN) nuclei and lateral hypothalamic area (LHA) was avoided by AH. AH affected reactivity of select hypothalamic metabolic neurotransmitter/enzyme marker proteins, e.g. ARH neuropeptide Y, VMN glutamate decarboxylase, DMN RFamide-related peptide-1 and -3, and LHA orexin-A profiles to 4CIN, but did not alleviate drug inhibition of ARH proopiomelanocortin. AH prevented 4CIN augmentation of circulating glucagon, but did not alter hyperglycemic or hypocorticosteronemic responses to that treatment. Results identify hindbrain lactate deficiency as a stimulus for glucagon secretion, and imply that habituation of this critical counter-regulatory hormone to recurring hypoglycemia may involve one or more hypothalamic neurotransmitters characterized here by acclimation to this critical sensory stimulus.


Assuntos
Hipoglicemia/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Rombencéfalo/metabolismo , Animais , Glicemia/metabolismo , Hipoglicemia/induzido quimicamente , Insulina , Masculino , Neuropeptídeo Y/metabolismo , Norepinefrina/metabolismo , Pró-Opiomelanocortina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Ativação Transcricional
13.
Nat Commun ; 10(1): 3960, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481663

RESUMO

Translation is a basic cellular process and its capacity is adapted to cell function. In particular, secretory cells achieve high protein synthesis levels without triggering the protein stress response. It is unknown how and when translation capacity is increased during differentiation. Here, we show that the transcription factor Creb3l2 is a scaling factor for translation capacity in pituitary secretory cells and that it directly binds ~75% of regulatory and effector genes for translation. In parallel with this cell-autonomous mechanism, implementation of the physiological UPR pathway prevents triggering the protein stress response. Knockout mice for Tpit, a pituitary differentiation factor, show that Creb3l2 expression and its downstream regulatory network are dependent on Tpit. Further, Creb3l2 acts by direct targeting of translation effector genes in parallel with signaling pathways that otherwise regulate protein synthesis. Expression of Creb3l2 may be a useful means to enhance production of therapeutic proteins.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Hipófise/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular/fisiologia , Linhagem Celular , Retículo Endoplasmático/genética , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Hipófise/citologia , Pró-Opiomelanocortina/metabolismo , Transdução de Sinais , Proteínas com Domínio T/genética , Proteína 1 de Ligação a X-Box/metabolismo , Xenopus laevis
14.
Vitam Horm ; 111: 1-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31421696

RESUMO

Proopiomelanocortin (POMC) belongs to the opioid/orphanin gene family whose peptide precursors include either opioid (YGGF) or the orphanin/nociceptin core sequences (FGGF). In addition to POMC the family includes the proenkephalin (PENK), prodynorphin (PDYN), and nociceptin/proorphanin (PNOC) precursors. The opioid core sequence in POMC is incorporated by the ß-endorphin that occupies the C-terminal region but this propeptide also exhibits at least two "alien" melanocortin core sequences (HFRW). An ACTH/MSH fragment merged into the opioid fragment not earlier than the two tetraploidizations of the vertebrate genome. Therefore, POMC exhibit a complex "evolutionary life" since the gene has coevolved together with two different receptor systems, i.e., opioid and melanocortin following a horse trading system. In this article, we summarize the different evolutionary hypotheses proposed for POMC evolution.


Assuntos
Evolução Molecular , Pró-Opiomelanocortina/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Humanos , Melanocortinas/química , Melanocortinas/genética , Hormônios Estimuladores de Melanócitos , Peptídeos Opioides/genética , Filogenia , Pró-Opiomelanocortina/química
15.
Sheng Wu Gong Cheng Xue Bao ; 35(8): 1433-1440, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441614

RESUMO

The social problems and medical burdens caused by obesity have become more serious in recent years. Obesity is mainly caused by the imbalance of energy intake and consumption in the body. The central nervous system and related neurons regulate the balance of energy metabolism. The hypothalamic arcuate nucleus (ARC) contains anorexigenic proopiomelanocortin (POMC) neurons and orexigenic neuropeptid Y(NPY)/agouti-related protein (AgRP) neurons that regulate the feeding behavior of body. High-fat diet induces phosphorylation of Rb protein in POMC neurons, and inactivation of Rb phosphorylation leads to re-entry of POMC neurons from the resting-state into the cell cycle, which rapidly shifts to apoptosis. High-fat diet also causes the inhibition of neuronal regeneration, induces inflammation and neuronal damage, loss of neuronal homeostasis, leptin resistance, and ultimately leads to obesity. This review discusses the relationship between loss of neuronal homeostasis and dietary obesity, as well as the underlying mechanisms, which might provide the evidence for prevention and treatment of these diseases.


Assuntos
Núcleo Arqueado do Hipotálamo , Obesidade , Homeostase , Humanos , Leptina , Pró-Opiomelanocortina
16.
Brain Behav ; 9(9): e01340, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31392839

RESUMO

INTRODUCTION: Ginseng polysaccharide (GPS, same as Panax polysaccharide) is a kind of polysaccharide extracted from ginseng. It has been reported that GPS has the ability to activate innate immunity, regulates blood sugar balance, and improves antioxidant capacity, but the effect on feeding behavior and its mechanism remains unclear. METHOD: To investigate the possible effect of GPS on feeding behavior of animals, mice were supplied with GPS in water, and food intake, hedonic feeding behavior, anxiety-like behavior, expression of appetite-regulation peptides in the central nervous system and glucose-related hormone levels in the serum of mice were measured. RESULTS: Ginseng polysaccharide significantly increased the average daily food intake in mice and promoted hedonic eating behavior. Meanwhile, the levels of serum glucose and glucagon were significantly reduced by GPS, and GPS promoted hypothalamic neuropeptide Y expression, inhibited proopiomelanocortin (POMC) expression, and reduced dopamine D1 receptor (DRD1) levels in the midbrain. We also found that the anxiety level of mice was significantly lower after GPS intake. In conclusion, oral supplementation with GPS promoted food intake in mice, most likely through the regulation of circulating glucose levels.


Assuntos
Comportamento Alimentar/efeitos dos fármacos , Panax , Polissacarídeos/farmacologia , Animais , Ansiedade , Comportamento Animal/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Suplementos Nutricionais , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Ingestão de Alimentos/efeitos dos fármacos , Glucagon/efeitos dos fármacos , Glucagon/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Insulina/metabolismo , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Neuropeptídeo Y/efeitos dos fármacos , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/efeitos dos fármacos , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/genética
17.
Eur J Endocrinol ; 181(3): 351-361, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31319379

RESUMO

Objective: Silent corticotroph tumors are a pituitary neuroendocrine tumor subtype of corticotroph lineage that do not clinically express Cushing's disease. The silencing of this type of tumor is not fully understood. The aim of the present study was to delve into the lack of secretory activity, studying the post-transcriptional and post-translational regulation of POMC/ACTH in a series of molecularly identified functioning and silent corticotroph tumors. Design: We analyzed 24 silent corticotroph, 23 functioning corticotroph and 25 silent gonadotroph tumors. Methods: We used Sanger sequencing, quantitative real-time PCR and Western blot to analyze genetic alterations in POMC, gene expression of TBX19, NEUROD1, POMC, PCSK1, PCSK2, CPE and PAM and protein expression of POMC, PC1/3, PC2, CPE and PAM. Results: We found different polymorphisms in the POMC gene of corticotroph tumors, some of them related to deficiency of proopiomelanocortin. Silent corticotroph tumors showed lower PC1/3 gene and protein expression than functioning ones, especially compared to micro-functioning corticotroph tumors (all P < 0.05). Moreover, we found a positive correlation between PC2 and CPE gene and protein expression (rho ≥ 0.670, P < 0.009) in silent corticotroph tumors compared with functioning ones. Conclusions: By studying the post-transcriptional and post-translational processing of POMC and ACTH, respectively, in a large series of silent and functioning corticotroph tumors, we found that the lack of secretory activity of these tumors is related to an impaired processing of POMC and a high degradation of ACTH, with the macro-functioning corticotroph tumor behaving as an intermediate state between micro-functioning and silent corticotroph tumors.


Assuntos
Adenoma/genética , Hormônio Adrenocorticotrópico/genética , Corticotrofos , Hipersecreção Hipofisária de ACTH/genética , Neoplasias Hipofisárias/genética , Pró-Opiomelanocortina/genética , Adenoma/diagnóstico , Adenoma/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Corticotrofos/metabolismo , Corticotrofos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/diagnóstico , Hipersecreção Hipofisária de ACTH/metabolismo , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/metabolismo , Pró-Opiomelanocortina/metabolismo , Interferência de RNA/fisiologia
18.
Neuron ; 103(5): 891-908.e6, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277924

RESUMO

Motivated behavior is influenced by neural networks that integrate physiological needs. Here, we describe coordinated regulation of hypothalamic feeding and midbrain reward circuits in awake behaving mice. We find that alcohol and other non-nutritive drugs inhibit activity in hypothalamic feeding neurons. Interestingly, nutrients and drugs utilize different pathways for the inhibition of hypothalamic neuron activity, as alcohol signals hypothalamic neurons in a vagal-independent manner, while fat and satiation signals require the vagus nerve. Concomitantly, nutrients, alcohol, and drugs also increase midbrain dopamine signaling. We provide evidence that these changes are interdependent, as modulation of either hypothalamic neurons or midbrain dopamine signaling influences reward-evoked activity changes in the other population. Taken together, our results demonstrate that (1) food and drugs can engage at least two peripheral→central pathways to influence hypothalamic neuron activity, and (2) hypothalamic and dopamine circuits interact in response to rewards.


Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Etanol/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Recompensa , Proteína Relacionada com Agouti/metabolismo , Anfetamina/farmacologia , Animais , Cocaína/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Hipotálamo/metabolismo , Camundongos , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nicotina/farmacologia , Pró-Opiomelanocortina/metabolismo , Vagotomia , Nervo Vago/fisiologia
19.
Genes Brain Behav ; 18(8): e12600, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31339663

RESUMO

Persistent alterations of proopiomelanocortin (Pomc) and mu-opioid receptor (Oprm1) activity and stress responses after alcohol are critically involved in vulnerability to alcohol dependency. Gene transcriptional regulation altered by alcohol may play important roles. Mice with genome-wide deletion of neuronal Pomc enhancer1 (nPE1-/- ), had hypothalamic-specific partial reductions of beta-endorphin and displayed lower alcohol consumption, compared to wildtype littermates (nPE1+/+ ). We used RNA-Seq to measure steady-state nuclear mRNA transcripts of opioid and stress genes in hypothalamus of nPE1+/+ and nPE1-/- mice after 1-day acute withdrawal from chronic excessive alcohol drinking or after water. nPE1-/- had lower basal Pomc and Pdyn (prodynorphin) levels compared to nPE1+/+ , coupled with increased basal Oprm1 and Oprk1 (kappa-opioid receptor) levels, and low alcohol drinking increased Pomc and Pdyn to the basal levels of nPE1+/+ in the water group, without significant effects on Oprm1 and Oprk1. In nPE1+/+ , excessive alcohol intake increased Pomc and Oprm1, with no effect on Pdyn or Oprk1. For stress genes, nPE1-/- had lowered basal Oxt (oxytocin) and Avp (arginine vasopressin) that were restored by low alcohol intake to basal levels of nPE1+/+ . In nPE1+/+ , excessive alcohol intake decreased Oxt and Avpi1 (AVP-induced protein1). Functionally examining the effect of pharmacological blockade of mu-opioid receptor, we found that naltrexone reduced excessive alcohol intake in nPE1+/+ , but not nPE1-/- . Our results provide evidence relevant to the transcriptional profiling of the critical genes in mouse hypothalamus: enhanced opioid and reduced stress gene transcripts after acute withdrawal from excessive alcohol may contribute to altered reward and stress responses.


Assuntos
Bebedeira/genética , Elementos Facilitadores Genéticos/genética , Hipotálamo/metabolismo , Pró-Opiomelanocortina/genética , Animais , Arginina Vasopressina/metabolismo , Bebedeira/metabolismo , Encefalinas/genética , Encefalinas/metabolismo , Etanol/farmacologia , Hipotálamo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/metabolismo , Pró-Opiomelanocortina/metabolismo , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Transcriptoma
20.
Front Neuroendocrinol ; 54: 100773, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31344387

RESUMO

Proopiomelanocortin (POMC) is a key mediator of satiety. Epigenetic marks such as DNA methylation may modulate POMC expression and provide a biological link between early life exposures and later phenotype. Animal studies suggest epigenetic marks at POMC are influenced by maternal energy excess and restriction, prenatal stress and Triclosan exposure. Postnatal factors including energy excess, folate, vitamin A, conjugated linoleic acid and leptin may also affect POMC methylation. Recent human studies suggest POMC DNA methylation is influenced by maternal nutrition in early pregnancy and associated with childhood and adult obesity. Studies in children propose a link between POMC DNA methylation and elevated lipids and insulin, independent of body habitus. This review brings together evidence from animal and human studies and suggests that POMC is sensitive to nutritional programming and is associated with a wide range of weight-related and metabolic outcomes.


Assuntos
Metilação de DNA , Epigênese Genética , Transtornos do Metabolismo de Glucose/metabolismo , Fenômenos Fisiológicos da Nutrição , Obesidade/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Feminino , Transtornos do Metabolismo de Glucose/etiologia , Transtornos do Metabolismo de Glucose/genética , Humanos , Obesidade/etiologia , Obesidade/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Pró-Opiomelanocortina/genética
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