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1.
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
2.
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
3.
Pesqui. vet. bras ; 39(11): 909-914, Nov. 2019. tab, ilus
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1056917

RESUMO

The Labrador Retriever is among the main breeds with the greatest predisposition to obesity. Several factors, especially the interrelationships between food management, exercise and social factors; influence the likelihood of a dog becoming obese. Furthermore, genetic factors are also responsible for obesity in dogs, and in Labrador Retriever, a frameshift mutation (P187fs) in pro-opiomelanocortin (POMC) gene is strongly associated with obesity. There is no knowledge of studies that have previously evaluated the prevalence of the canine POMC deletion (P187fs) in Brazilian Labrador Retriever. Therefore, the objective of this study was to investigate this mutation in Labrador Retriever dogs in Brazil. Of the 108 Labrador Retrievers that were assessed in this study, 59 were from a previous study, composed by animals assisted in a veterinary hospital with unknown lineage, and 49 were from a prospective study, composed of 19 pet and 30 assistance/rescue Labrador Retriever dogs. The obesity risk and appetite questionnaire were applied, with some modifications, to tutors of the animals used in the prospective study. Fragments of the DNA, containing the mutation, were amplified by PCR and submitted to direct gene sequencing. The allele frequency of the mutation was 21.3% and was out of Hardy-Weinberg equilibrium (P<0.05). Using only the data of animals with known lineage, the presence of the mutated allele was higher in the Assistance/rescue Group than Pet Group (P<0.01), furthermore, the allele frequencies observed in Assistance Group (31.7%) was out of Hardy-Weinberg equilibrium (P<0.05), while that in the Pet Group (18.4%) was in equilibrium (P>0.05). Although the mutation has increased the food-motivation in the assistance/rescue dogs, other variables, especially frequent exercising, favored that these animals maintained the ideal body weight (body condition score = 5). In summary, the Hardy-Weinberg disequilibrium observed in the allele distribution of the deletion POMC_P187fs in this study, independently of the Labrador Retriever group assessed, suggesting the possibility of positive selection of the mutated allele, which may lead to the maintenance of this deleterious allele in the studied population.(AU)


O Labrador Retriever é uma das principais raças caninas com maior predisposição à obesidade. Vários fatores, especialmente as interrelações entre a alimentação, exercício e fatores sociais, influenciam a probabilidade de um cão se tornar obeso. Além disso, fatores genéticos são também responsáveis pela obesidade em cães, e no Labrador Retriever a mutação "frameshift" P187fs no gene pró-opiomelanocortina (POMC) está fortemente associada à obesidade. Não existem estudos prévios de prevalência da deleção P187fs no gene POMC em cães Labrador Retriever no Brasil. Portanto, o objetivo deste estudo foi investigar esta mutação em cães da raça Labrador Retriever no Brasil. Dos 108 Labradores Retrievers avaliados neste estudo, 59 eram de um estudo retrospectivo (composto por animais atendido no hospital veterinário e sem linhagem conhecida) e 49 eram de um estudo prospectivo (composto por 19 cães pet e 30 cães de assistência/resgate). Um questionário de risco de obesidade modificado foi aplicado nos tutores dos animais usados no estudo prospectivo. Fragmentos de DNA, contendo a mutação, foram amplificados por PCR e submetidos ao sequenciamento gênico direto. A frequência alélica da mutação foi de 21,3% e estava fora do equilíbrio de Hardy-Weinberg (P<0,05). Usando somente os dados dos animais de linhagem conhecida, a presença do alelo mutado foi maior no Grupo de cães de Assistência/resgate que no Grupo de Pets (P<0,01), além disso, as frequências alélicas nos Grupos de Assistência/resgate (31,7%) e no de pets (18,4%) estavam fora e em equilíbrio de Hardy-Weinberg (P<0,05), respectivamente. Embora a mutação tenha aumentado a motivação pelo alimento em cães Labrador Retriever do Grupo de Assistência/resgate, outras variáveis, especialmente o frequente exercício, favoreceu a manutenção o peso corporal ideal (peso corporal = 5). Em resumo, o desequilíbrio de Hardy-Weinberg observado na distribuição do alelo POMC_P187fs observado neste estudo, independentemente do grupo de Labrador Retriever avaliado, sugere a possibilidade de uma seleção positiva para o alelo mutado, o qual poderá levar a manutenção desse alelo deletério nesta população.(AU)


Assuntos
Animais , Masculino , Feminino , Cães , Pró-Opiomelanocortina/genética , Obesidade/genética , Obesidade/veterinária
4.
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
5.
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
6.
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
7.
Anim Sci J ; 90(9): 1293-1302, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31310043

RESUMO

The molecular mechanism underlying in the onset and maintenance of incubation behavior are not fully understood, and it is still unknown the reason why White Leghorn, a layer strain, hens never display incubation behavior. Therefore, to explore specific hypothalamic genes regulating incubation behavior, cap analysis of gene expression (CAGE) were applied to comparison between incubating Silkie and laying White Leghorn hens. In addition, mRNA expression of some differentially expressed genes (DEGs) and melanocortinergic appetite genes including agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) was also analyzed on Silkie hens under natural anorexia and starvation. The CAGE identified 217 hypothalamic DEGs in incubating Silkie hens, and that of two, transthyretin (TTR) and prolactin-releasing peptide (PrRP), suggested as appetite gene, were markedly up- and down-regulated in incubating hens, respectively. In addition, AgRP and POMC expression also increased in incubating bird. mRNA expression of TTR, PrRP, and appetite genes were not differed significantly by starvation, although TTR mRNA expression was relatively high in fasting hens. Consequently, transcriptome by CAGE identified a number of hypothalamic genes differentially expressed by incubation behavior in Silkie hens. Of these, it is suggested that TTR and PrRP may, at least in part, be related to adaptation to natural anorexia in incubating Silkie chickens.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Ingestão de Alimentos/genética , Comportamento Materno/fisiologia , Pré-Albumina/metabolismo , Pró-Opiomelanocortina/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Galinhas , Feminino , Perfilação da Expressão Gênica , Genética Comportamental , Hipotálamo/metabolismo , Pré-Albumina/genética , Pró-Opiomelanocortina/genética , Hormônio Liberador de Prolactina/genética , Inanição
8.
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
9.
Pharmacol Biochem Behav ; 181: 28-36, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30991059

RESUMO

A fixed dose combination of bupropion (BPP) and naltrexone (NTX), Contrave®, is an FDA approved pharmacotherapy for the treatment of obesity. A recent study found that combining BPP with low-dose NTX reduced alcohol drinking in alcohol-preferring male rats. To explore potential pharmacological effects of the BPP + NTX combination on alcohol drinking, both male and female C57Bl/6J mice were tested on one-week drinking-in-the dark (DID) and three-week intermittent access (IA) models. Neuronal proopiomelanocortin (POMC) enhancer knockout (nPE-/-) mice with hypothalamic-specific deficiency of POMC, and its bioactive peptides melanocyte stimulating hormone and beta-endorphin, were used as a genetic control for the effects of the BPP + NTX. A single administration of BPP + NTX (10 mg/kg + 1 mg/kg) decreased alcohol intake after DID in C57Bl/6J males, but not females. Also in C57Bl/6J males, BPP + NTX reduced intake of the caloric reinforcer sucrose, but not the non-caloric reinforcer saccharin. In contrast, BPP + NTX had no effect on alcohol DID in nPE-/- males. Pretreatment with the selective melanocortin 4 receptor (MC4R) antagonist HS014 reversed the anti-dipsogenic effect of BPP + NTX on alcohol DID in C57Bl/6J males. In the 3-week chronic IA model, single or repeated administrations for four days of BPP + NTX reduced alcohol intake and preference in C57Bl/6J males only. The behavioral measures observed in C57Bl/6J mice provide clear evidence that BPP + NTX profoundly reduced alcohol drinking in males, but the doses tested were not effective in females. Furthermore, our results suggest a hypothalamic POMC/MC4R-dependent mechanism for the observed BPP + NTX effects on alcohol drinking in male mice.


Assuntos
Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Bupropiona/farmacologia , Bupropiona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Bupropiona/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Etanol/administração & dosagem , Feminino , Técnicas de Inativação de Genes , Hipotálamo/metabolismo , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naltrexona/administração & dosagem , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Fotoperíodo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Receptor Tipo 4 de Melanocortina/metabolismo , Sacarina/farmacologia , Fatores Sexuais , Sacarose/farmacologia
11.
Endocrinology ; 160(5): 1081-1096, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30997487

RESUMO

Mice with a targeted mutation in the pro-opiomelanocortin (Pomc) gene (Pomctm1/tm1 mice) are unable to synthesize desacetyl-α-MSH and α-MSH and they develop obesity when fed chow diet. In this study, we hypothesized that a chronic high-fat (HF) diet exacerbates Pomctm1/tm1 mouse obesity. Male and female Pomcwt/wt and Pomctm1/tm1 mice were fed low-fat (LF) (10 kcal percent fat) or HF (45 kcal percent fat) diets from weaning for 23 weeks. We show that Pomctm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomctm1/tm1 mice develop obesity because they are hyperphagic compared with Pomcwt/wt mice when fed an LF or HF diet. Female Pomctm1/tm1 mice develop obesity when feeding on an LF or HF diet because they exhibit signs of reduced energy expenditure (no change in feed efficiency; body weight gained exceeding energy intake) compared with Pomcwt/wt mice. A chronic HF diet exacerbates male Pomctm1/tm1 and Pomcwt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomcwt/wt mice are protected from chronic HF diet-induced obesity because they reduce the amount of HF diet eaten, and they appear to increase their energy expenditure (no change in feed efficiency but energy intake exceeding body weight gained). A chronic HF diet exacerbates female Pomctm1/tm1 mouse obesity due to impaired ability to reduce the amount of HF diet eaten and apparent impaired HF diet-induced adaptive thermogenesis. Our data show that desacetyl-α-MSH and α-MSH are required for sexually dimorphic HF diet-induced C57BL/6J obesity. In conclusion, desacetyl-α-MSH and α-MSH play salutary roles in sexually dimorphic melanocortin obesity and sexually dimorphic HF diet-induced C57BL/6J obesity.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Mutação , Obesidade/genética , Pró-Opiomelanocortina/genética , Animais , Gorduras na Dieta/administração & dosagem , Ingestão de Energia/genética , Metabolismo Energético/genética , Feminino , Masculino , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Fatores Sexuais , Termogênese/genética , Ganho de Peso/genética , alfa-MSH/metabolismo
12.
Biosci Biotechnol Biochem ; 83(7): 1336-1342, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30916623

RESUMO

Leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) suppresses food intake after its activation by binding of its ligands, R-spondins. We investigated the mechanism of food intake suppression by R-spondin1 in a region-specific Lgr4 gene knockout (LGR4 cKO) mouse model, generated by deletion of the Lgr4 gene in arcuate nucleus (ARC) using Lgr4fx/fx mice combined with infection of an AAV-Cre vector. After R-spondin1 administration, LGR4 cKO mice didn't exhibit a suppressed appetite, compared to that in control mice, which received a vehicle. In ARC of LGR4 cKO mice, Pomc mRNA expression was reduced, leading to suppressed food intake. On the other hand, neurons-specific LGR4 KO mice exhibited no differences in Pomc expression, and no structural differences were observed in the ARC of mutant mice. These results suggest that LGR4 is an essential part of the mechanism, inducing Pomc gene expression with R-spondin1 in ARC neurons in mice, thereby regulating feeding behavior. Abbreviations: LGR4: Leucine-rich repeat-containing G-protein coupled receptor 4; RSPOs: roof plate-specific spondins; ARC: arcuate nucleus; AAV: adeno associated virus; POMC: pro-opiomelanocortin; CART: cocaine and amphetamine-regulated transcript; NPY: neuropeptide Y; AgRP: agouti-related peptide; Axin2: axis inhibition protein 2; Lef1: lymphoid enhancer binding factor 1; ccnd1: cyclin D1.


Assuntos
Comportamento Alimentar , Pró-Opiomelanocortina/fisiologia , Receptores Acoplados a Proteínas-G/fisiologia , Trombospondinas/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Opiomelanocortina/genética , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Proteínas Wnt/metabolismo
13.
Pigment Cell Melanoma Res ; 32(4): 510-527, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30791235

RESUMO

Different camouflages work best with some background matching colour. Our understanding of the evolution of skin colour is based mainly on the genetics of pigmentation ("background matching"), with little known about the evolution of the neuroendocrine systems that facilitate "background adaptation" through colour phenotypic plasticity. To address the latter, we studied the evolution in vertebrates of three genes, pomc, pmch and pmchl, that code for α-MSH and two melanin-concentrating hormones (MCH and MCHL). These hormones induce either dispersion/aggregation or the synthesis of pigments. We find that α-MSH is highly conserved during evolution, as is its role in dispersing/synthesizing pigments. Also conserved is the three-exon pmch gene that encodes MCH, which participates in feeding behaviours. In contrast, pmchl (known previously as pmch), is a teleost-specific intron-less gene. Our data indicate that in zebrafish, pmchl-expressing neurons extend axons to the pituitary, supportive of an MCHL hormonal role, whereas zebrafish and Xenopus pmch+ neurons send axons dorsally in the brain. The evolution of these genes and acquisition of hormonal status for MCHL explain different mechanisms used by vertebrates to background-adapt.


Assuntos
Adaptação Fisiológica , Evolução Molecular , Pró-Opiomelanocortina/genética , Pigmentação da Pele/genética , Proteínas de Xenopus/genética , Xenopus/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Sequência Conservada/genética , Células HEK293 , Hormônios/metabolismo , Humanos , Filogenia , Pró-Opiomelanocortina/química , Xenopus/fisiologia , Proteínas de Xenopus/química , Peixe-Zebra/fisiologia , Proteínas de Peixe-Zebra/química
15.
J Biol Chem ; 294(13): 4946-4955, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30709906

RESUMO

Hypoxia-inducible factor-2α (HIF2α) is a nuclear transcription factor that plays a critical role in cell survival including metabolic adaptation under hypoxia as well as normoxia, but whether HIF2α contributes to the control of whole-body metabolic balance is unclear. In this study, we found that the hypothalamic HIF2α protein level rapidly increases in young mice that are centrally stimulated with insulin. However, this insulin-induced HIF2α up-regulation is substantially attenuated in mice of advanced age. This attenuation is comparable with the effect of high-calorie feeding in young mice. Of note, unlike high-calorie feeding conditions, age-dependent HIF2α attenuation occurs without impaired activation of the hypothalamic IR/IRS-2/AKT/FOXO1 pathway in response to insulin. Molecular and physiological analyses revealed that hypothalamic HIF2α contributes to the action of central insulin in regulation of proopiomelanocortin (Pomc) gene expression and food intake. HIF2α knockout in POMC neurons led to age-dependent excess weight gain and fat increase, a phenotype that was associated with a mild degree of glucose intolerance and insulin resistance. In conclusion, hypothalamic HIF2α responds to insulin, and the up-regulation is involved in adaptive metabolic regulation as age increases, whereas impairment of HIF2α in the hypothalamus contributes to weight gain and glucose disorders in age-dependent manners.


Assuntos
Envelhecimento/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Intolerância à Glucose/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Transdução de Sinais , Envelhecimento/genética , Envelhecimento/patologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Regulação da Expressão Gênica , Intolerância à Glucose/genética , Intolerância à Glucose/patologia , Hipotálamo/patologia , Insulina/genética , Camundongos , Camundongos Transgênicos , Pró-Opiomelanocortina/biossíntese , Pró-Opiomelanocortina/genética
16.
Mol Metab ; 20: 194-204, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30503832

RESUMO

OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. METHODS: To test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. RESULTS: Stimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. CONCLUSION: In conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes.


Assuntos
Hipoglicemia/metabolismo , Hipotálamo/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismo , Animais , Epinefrina/metabolismo , Glucagon/metabolismo , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pró-Opiomelanocortina/deficiência , Pró-Opiomelanocortina/genética , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/genética
17.
Mol Cell Endocrinol ; 479: 12-19, 2019 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-30149043

RESUMO

Endocrine disrupting chemicals, such as bisphenol A (BPA), have been linked to obesity. However, the direct effect of BPA on the hypothalamic pro-opiomelanocortin (POMC) neurons, which regulate energy homeostasis, remains unexplored. We define the effect of BPA on functionally characterized, POMC-expressing cell models, mHypoA-POMC/GFP-2 and mHypoE-43/5. Exposure to BPA significantly induced the mRNA levels of Pomc in both primary culture and the cell lines. Neuroinflammatory and steroid receptor mRNA levels were assessed to delineate the potential mechanisms, including inflammatory markers Nfκb, Il6 and Iκba, and steroid receptors Esr1, Esr2, Gpr30, Esrrg, and Pparg. Pre-treatment with anti-inflammatory compounds gonadotropin-releasing hormone, and PS1145, an IκB kinase inhibitor, abrogated the BPA-mediated Pomc induction. Furthermore, T0070907, a PPARγ antagonist, abolished Pomc induction, while the GPR30 antagonist G15 had no effect. These findings indicate that BPA may have direct effects on POMC neurons in the hypothalamus, utilizing neuroinflammatory mechanisms and through PPARγ nuclear receptors.


Assuntos
Compostos Benzidrílicos/toxicidade , Regulação da Expressão Gênica/genética , Hipotálamo/patologia , Inflamação/genética , Modelos Biológicos , Neurônios/patologia , PPAR gama/metabolismo , Fenóis/toxicidade , Pró-Opiomelanocortina/genética , Animais , Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Biomarcadores/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inflamação/patologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , PPAR gama/antagonistas & inibidores , Pró-Opiomelanocortina/metabolismo , Piridinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
18.
Ann Endocrinol (Paris) ; 80(2): 117-121, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30243475

RESUMO

BACKGROUND: Endogenous ß-endorphin is delivered exclusively from the pituitary gland in various stressful conditions and plays an essential role in the nervous system. Recently, a few studies demonstrated peripheral endogenous opioid secretion from immune cells at inflammatory sites. Here, we investigated the expression of ß-endorphin, the most powerful endogenous opioid peptide, in peripheral tissues in response to systemic administration of lipopolysaccharide in mice. METHODS: Male C57BL/6N mice received intravenously administered lipopolysaccharide to induce an endotoxic shock-like condition. mRNA for proopiomelanocortin, a precursor of ß-endorphin, was quantified in peripheral blood cells, liver and spleen. ß-endorphin peptide was measured in the liver and spleen. RESULTS: Expression of proopiomelanocortin mRNA was detected in peripheral tissues after systemic administration of lipopolysaccharide. Lipopolysaccharide also induced ß-endorphin expression in the liver and spleen. CONCLUSION: Expression of proopiomelanocortin mRNA and ß-endorphin was detected in peripheral tissues after systemic administration of lipopolysaccharide. These results provide new evidence that peripheral endogenous opioids can be produced not only as a result of local inflammation but also by severe systemic stress such as endotoxic shock. Further study is required to clarify the role of peripheral ß-endorphin during endotoxic shock.


Assuntos
Lipopolissacarídeos/administração & dosagem , Choque Séptico/induzido quimicamente , Choque Séptico/genética , beta-Endorfina/genética , Animais , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Choque Séptico/metabolismo , Choque Séptico/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Distribuição Tecidual/efeitos dos fármacos , beta-Endorfina/metabolismo
19.
Biochem Biophys Res Commun ; 508(3): 811-817, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528733

RESUMO

Constant light exposure is widespread in the intensive care unit (ICU) and could increase the rate of brain dysfunction as delirium and sleep disorders in critical patients. And the activation of hypothalamic neuropeptides is proved to play a crucial role in regulating hypercatabolism, especially skeletal muscle wasting in critical patients, which could lead to serious complications and poor prognosis. Here we investigated the hypothesis that constant light exposure could aggravate skeletal muscle wasting in endotoxemia rats and whether it was associated with alterations of circadian clock and hypothalamic proopiomelanocortin(POMC) expression. Fifty-four adult male Sprague-Dawley rats were intraperitoneally injected with lipopolysaccharide(LPS) or saline, subjected to constant light or a 12:12 h light-dark cycle for 7 days. On day 8, rats were sacrificed across six time points in 24 h and hypothalamus tissues and skeletal muscle were obtained. Rates of muscle wasting were measured by 3-methylhistidine(3-MH) and tyrosine release as well as expression of two muscle atrophic genes, muscle ring finger 1(MuRF-1) and muscle atrophy F-box(MAFbx). The expression of circadian clock genes, silent information regulator 1(SIRT1), POMC and hypothalamic inflammatory cytokines were also detected. Results showed that LPS administration significantly increased hypothalamic POMC expression, inflammatory cytokine levels and muscle wasting rates. Meanwhile constant light exposure disrupted the circadian rhythm, declined the expression of SIRT1 as well as aggravated hypothalamic POMC overexpression and skeletal muscle wasting in rats with endotoxemia. Taken together, the results demonstrated that constant light exposure could aggravate POMC-mediated skeletal muscle wasting in endotoxemia rats, which is associated with alteration of circadian clocks and SIRT1 in the hypothalamus.


Assuntos
Relógios Circadianos/genética , Endotoxemia/metabolismo , Hipotálamo/metabolismo , Músculo Esquelético/metabolismo , Pró-Opiomelanocortina/metabolismo , Sirtuína 1/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Citocinas/metabolismo , Endotoxemia/genética , Expressão Gênica , Luz , Masculino , Proteínas Musculares/metabolismo , Pró-Opiomelanocortina/genética , Ratos , Ratos Sprague-Dawley , Proteínas Ligases SKP Culina F-Box/metabolismo , Sirtuína 1/genética
20.
Dev Psychopathol ; 31(2): 433-438, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30009717

RESUMO

The proopiomelanocortin (POMC) molecule has been implicated in models of self-injurious behavior (SIB) in neurodevelopmental disorders, but it has never been specifically sequenced in search of base specific polymorphisms. The empirical focus of this preliminary study was to sequence the POMC gene in 11 children (mean age = 41.8 months, range = 12-60 months; 73% male) with clinical concerns regarding global developmental delay, 5 with reported self-injury. Genomic DNA was extracted from blood samples, and the POMC gene was amplified by specific oligonucleotide primers via polymerase chain reaction. The amplified gene products were sequenced by the University of Minnesota Genomic Center, and the results were analyzed using Sequencher software. A single nucleotide polymorphism (SNP), 1130 C>T, was found in the 3' untranslated region (UTR) of two samples (one of whom had SIB). The program TargetScanHuman was used to predict the function of this mutation. Variant c.1130 C<T was predicted to be located in the target site of two microRNAs (miRNAs; hsa-mir-3715 and hsa-mir-1909), and the variant allele T may result in an increased minimum free energy for the two miRNAs. Further work with much larger samples is needed to continue the investigation of POMC's possible function as a risk factor for the development of SIB in children with developmental delay/disability. The findings presented in this study show that the SNP found in the 3' UTR could alter the binding of miRNAs to POMC 3'UTR, thus, increasing POMC expression and affecting several biological systems with high relevance to the biology of self-injury. There was a significant difference in ß-endorphin levels between SIB (M = 169.25 pg/mL) and no SIB (M = 273.5 pg/mL, SD = 15.2) cases (p < .01). Intervention implications are tied to prior observations of individual differences among SIB responders and nonresponders to treatment with the opioid antagonist naltrexone. Stratifying individuals with SIB by POMC mutation status may provide a potential tailoring-like variable to guide the selection of who is more (or less) likely to respond to opiate antagonist treatment. Currently, opioid antagonistic treatment for SIB is empiric (trial and error).


Assuntos
Deficiências do Desenvolvimento/genética , Polimorfismo de Nucleotídeo Único , Pró-Opiomelanocortina/genética , Comportamento Autodestrutivo/genética , Regiões 3' não Traduzidas , Alelos , Pré-Escolar , Deficiências do Desenvolvimento/sangue , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Comportamento Autodestrutivo/sangue , beta-Endorfina/sangue
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