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1.
J Biol Chem ; 291(11): 5844-5859, 2016 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-26755731

RESUMO

Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Pró-Proteína Convertase 2/metabolismo , Precursores de Proteínas/metabolismo , Sirtuína 1/metabolismo , Animais , Metabolismo Energético , Masculino , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley
2.
J Biol Chem ; 288(24): 17675-88, 2013 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-23640886

RESUMO

It was shown previously that abnormal prohormone processing or inactive proconverting enzymes that are responsible for this processing cause profound obesity. Our laboratory demonstrated earlier that in the diet-induced obesity (DIO) state, the appetite-suppressing neuropeptide α-melanocyte-stimulating hormone (α-MSH) is reduced, yet the mRNA of its precursor protein proopiomelanocortin (POMC) remained unaltered. It was also shown that the DIO condition promotes the development of endoplasmic reticulum (ER) stress and leptin resistance. In the current study, using an in vivo model combined with in vitro experiments, we demonstrate that obesity-induced ER stress obstructs the post-translational processing of POMC by decreasing proconverting enzyme 2, which catalyzes the conversion of adrenocorticotropin to α-MSH, thereby decreasing α-MSH peptide production. This novel mechanism of ER stress affecting POMC processing in DIO highlights the importance of ER stress in regulating central energy balance in obesity.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Estresse do Retículo Endoplasmático , Obesidade/metabolismo , Pró-Opiomelanocortina/metabolismo , Processamento de Proteína Pós-Traducional , Hormônio Adrenocorticotrópico/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/patologia , Linhagem Celular , Dieta Hiperlipídica/efeitos adversos , Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica , Leptina/fisiologia , Masculino , Camundongos , Obesidade/etiologia , Obesidade/patologia , Pró-Opiomelanocortina/genética , Pró-Proteína Convertase 2/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , alfa-MSH/metabolismo , eIF-2 Quinase/genética , eIF-2 Quinase/metabolismo
3.
Am J Physiol Endocrinol Metab ; 306(8): E904-15, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24518677

RESUMO

Hypothalamic proopiomelanocortin (POMC) neurons constitute a critical anorexigenic node in the central nervous system (CNS) for maintaining energy balance. These neurons directly affect energy expenditure and feeding behavior by releasing bioactive neuropeptides but are also subject to signals directly related to nutritional state such as the adipokine leptin. To further investigate the interaction of diet and leptin on hypothalamic POMC peptide levels, we exposed 8- to 10-wk-old male POMC-Discosoma red fluorescent protein (DsRed) transgenic reporter mice to either 24-48 h (acute) or 2 wk (chronic) food restriction, high-fat diet (HFD), or leptin treatment. Using semiquantitative immunofluorescence and radioimmunoassays, we discovered that acute fasting and chronic food restriction decreased the levels of adrenocorticotropic hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH), and ß-endorphin in the hypothalamus, together with decreased DsRed fluorescence, compared with control ad libitum-fed mice. Furthermore, acute but not chronic HFD or leptin administration selectively increased α-MSH levels in POMC fibers and increased DsRed fluorescence in POMC cell bodies. HFD and leptin treatments comparably increased circulating leptin levels at both time points, suggesting that transcription of Pomc and synthesis of POMC peptide products are not modified in direct relation to the concentration of plasma leptin. Our findings indicate that negative energy balance persistently downregulated POMC peptide levels, and this phenomenon may be partially explained by decreased leptin levels, since these changes were blocked in fasted mice treated with leptin. In contrast, sustained elevation of plasma leptin by HFD or hormone supplementation did not significantly alter POMC peptide levels, indicating that enhanced leptin signaling does not chronically increase Pomc transcription and peptide synthesis.


Assuntos
Hipotálamo/metabolismo , Leptina/metabolismo , Estado Nutricional/fisiologia , Pró-Opiomelanocortina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Dieta , Ingestão de Alimentos/efeitos dos fármacos , Leptina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pró-Opiomelanocortina/genética , Fatores de Tempo
4.
Am J Physiol Endocrinol Metab ; 304(6): E640-50, 2013 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-23321476

RESUMO

Protein posttranslational processing is a cellular mechanism fundamental to the generation of bioactive peptides, including the anorectic α-melanocyte-stimulating hormone (α-MSH) and thyrotropin-releasing hormone (TRH) peptides produced in the hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, respectively. Neuropeptide Y (NPY) promotes positive energy balance in part by suppressing α-MSH and TRH. The mechanism by which NPY regulates α-MSH output, however, is not well understood. Our results reveal that NPY inhibited the posttranslational processing of α-MSH's inactive precursor proopiomelanocortin (POMC) by decreasing the prohormone convertase-2 (PC2). We also found that early growth response protein-1 (Egr-1) and NPY-Y1 receptors mediated the NPY-induced decrease in PC2. NPY given intra-PVN also decreased PC2 in PVN samples, suggesting a reduction in PC2-mediated pro-TRH processing. In addition, NPY attenuated the α-MSH-induced increase in TRH production by two mechanisms. First, NPY decreased α-MSH-induced CREB phosphorylation, which normally enhances TRH transcription. Second, NPY decreased the amount of α-MSH in the PVN. Collectively, these results underscore the significance of the interaction between NPY and α-MSH in the central regulation of energy balance and indicate that posttranslational processing is a mechanism that plays a specific role in this interaction.


Assuntos
Regulação do Apetite , Núcleo Arqueado do Hipotálamo/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , alfa-MSH/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Infusões Intraventriculares , Masculino , Modelos Biológicos , Neuropeptídeo Y/administração & dosagem , Fosforilação , Pró-Opiomelanocortina/metabolismo , Pró-Proteína Convertase 2/metabolismo , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo
5.
Cell Metab ; 5(3): 181-94, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17339026

RESUMO

Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Leptina/farmacologia , Neurônios/metabolismo , Obesidade/metabolismo , Proteína Relacionada com Agouti , Animais , Núcleo Arqueado do Hipotálamo/citologia , Composição Corporal , Dieta , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/metabolismo , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leptina/administração & dosagem , Masculino , Melanocortinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/metabolismo , RNA Mensageiro , Transdução de Sinais , Redução de Peso , alfa-MSH/metabolismo
6.
Am J Physiol Endocrinol Metab ; 300(6): E1002-11, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21406615

RESUMO

The adipose tissue-derived hormone leptin regulates energy balance through catabolic effects on central circuits, including proopiomelanocortin (POMC) neurons. Leptin activation of POMC neurons increases thermogenesis and locomotor activity. Protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of leptin signaling. POMC neuron-specific deletion of PTP1B in mice results in reduced high-fat diet-induced body weight and adiposity gain due to increased energy expenditure and greater leptin sensitivity. Mice lacking the leptin gene (ob/ob mice) are hypothermic and cold intolerant, whereas leptin delivery to ob/ob mice induces thermogenesis via increased sympathetic activity to brown adipose tissue (BAT). Here, we examined whether POMC PTP1B mediates the thermoregulatory response of CNS leptin signaling by evaluating food intake, body weight, core temperature (T(C)), and spontaneous physical activity (SPA) in response to either exogenous leptin or 4-day cold exposure (4°C) in male POMC-Ptp1b-deficient mice compared with wild-type controls. POMC-Ptp1b(-/-) mice were hypersensitive to leptin-induced food intake and body weight suppression compared with wild types, yet they displayed similar leptin-induced increases in T(C). Interestingly, POMC-Ptp1b(-/-) mice had increased BAT weight and elevated plasma triiodothyronine (T(3)) levels in response to a 4-day cold challenge, as well as reduced SPA 24 h after cold exposure, relative to controls. These data show that PTP1B in POMC neurons plays a role in short-term cold-induced reduction of SPA and may influence cold-induced thermogenesis via enhanced activation of the thyroid axis.


Assuntos
Temperatura Baixa , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Homeostase/genética , Homeostase/fisiologia , Neurônios/metabolismo , Pró-Opiomelanocortina/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Animais , Grelina/sangue , Hipotálamo/metabolismo , Luz , Camundongos , Camundongos Knockout , Atividade Motora/fisiologia , Neurônios/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/deficiência , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , RNA/biossíntese , RNA/genética , RNA/isolamento & purificação , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Grelina/biossíntese , Transdução de Sinais/fisiologia , Telemetria , Termogênese/fisiologia , Hormônios Tireóideos/sangue , Tireotropina/metabolismo
7.
Front Neuroendocrinol ; 31(2): 134-56, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20074584

RESUMO

The hypothalamic-pituitary-thyroid (HPT) axis plays a critical role in mediating changes in metabolism and thermogenesis. Thus, the central regulation of the thyroid axis by Thyrotropin Releasing Hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) is of key importance for the normal function of the axis under different physiological conditions including cold stress and changes in nutritional status. Before the TRH peptide becomes biologically active, a series of tightly regulated processes occur including the proper folding of the prohormone for targeting to the secretory pathway, its post-translational processing, and targeting of the processed peptides to the secretory granules near the plasma membrane of the cell ready for secretion. Multiple inputs coming from the periphery or from neurons present in different areas of the brain including the hypothalamus are responsible for the activation or inhibition of the TRH neuron and in turn affect the output of TRH and the set point of the axis.


Assuntos
Sistema Hipotálamo-Hipofisário/fisiologia , Neurônios/fisiologia , Hormônios Liberadores de Hormônios Hipofisários/fisiologia , Glândula Tireoide/fisiologia , Hormônio Liberador de Tireotropina/fisiologia , Animais , Temperatura Baixa , Neuropeptídeo Y/fisiologia , Obesidade/fisiopatologia , Núcleo Hipotalâmico Paraventricular , Precursores de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Hormônios Tireóideos/fisiologia
8.
Am J Physiol Endocrinol Metab ; 299(6): E976-89, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20858755

RESUMO

The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintaining energy expenditure and body weight, and the adipocyte hormone leptin regulates this axis by increasing TRH levels in the fed state. Leptin stimulates TRH directly in the hypothalamic paraventricular nucleus (PVN; direct pathway) and indirectly by regulating proopiomelnocortin neurons in the hypothalamic arcuate nucleus (ARC; indirect pathway). Whereas the indirect pathway is fully functional in lean animals, it is inactive during diet-induced obesity (DIO) because of the establishment of leptin resistance. Despite this, the HPT axis activity in obese humans and rodents remains within the normal levels or slightly higher. Therefore, in this study, we aimed to determine the mechanism(s) by which the HPT axis is still active despite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears a mutation in the leptin receptor, we were able to demonstrate that under DIO conditions the HPT axis is regulated at the central level, but only through the direct pathway of leptin action on TRH neurons. Deiodinase enzymes, which are present in many tissues and responsible for converting thyroid hormones, were not statistically different between lean and DIO animals. These data suggest that the increase in T(4/3) seen in obese animals is due mostly to central leptin action. We also found that T(3) feedback inhibition on the prepro-TRH gene is controlled partially by leptin-induced pSTAT3 signaling via the TRH promoter. This interactive relationship between T(3) and pSTAT3 signaling appears essential to maintain the HPT axis at normal levels in conditions such as obesity.


Assuntos
Hipotálamo/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiopatologia , Análise de Variância , Animais , Western Blotting , Temperatura Corporal , Dieta , Metabolismo Energético , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Hipotálamo/fisiopatologia , Imuno-Histoquímica , Modelos Lineares , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Obesidade/etiologia , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Receptores para Leptina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Hormônio Liberador de Tireotropina/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangue
9.
Neurobiol Dis ; 37(1): 130-40, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19815072

RESUMO

Mammalian genomes encode only a small number of cuproenzymes. The many genes involved in coordinating copper uptake, distribution, storage and efflux make gene/nutrient interactions especially important for these cuproenzymes. Copper deficiency and copper excess both disrupt neural function. Using mice heterozygous for peptidylglycine alpha-amidating monooxygenase (PAM), a cuproenzyme essential for the synthesis of many neuropeptides, we identified alterations in anxiety-like behavior, thermoregulation and seizure sensitivity. Dietary copper supplementation reversed a subset of these deficits. Wildtype mice maintained on a marginally copper-deficient diet exhibited some of the same deficits observed in PAM(+/-) mice and displayed alterations in PAM metabolism. Altered copper homeostasis in PAM(+/-) mice suggested a role for PAM in the cell type specific regulation of copper metabolism. Physiological functions sensitive to genetic limitations of PAM that are reversed by supplemental copper and mimicked by copper deficiency may serve as indicators of marginal copper deficiency.


Assuntos
Transtornos de Ansiedade/metabolismo , Regulação da Temperatura Corporal/fisiologia , Cobre/metabolismo , Oxigenases de Função Mista/metabolismo , Complexos Multienzimáticos/metabolismo , Peptídeos/metabolismo , Convulsões/metabolismo , Animais , Transtornos de Ansiedade/dietoterapia , Regulação da Temperatura Corporal/efeitos dos fármacos , Cobre/deficiência , Cobre/uso terapêutico , Dieta , Suplementos Nutricionais , Feminino , Heterozigoto , Homeostase/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Oxigenases de Função Mista/sangue , Oxigenases de Função Mista/genética , Complexos Multienzimáticos/sangue , Complexos Multienzimáticos/genética , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Vasoconstrição/fisiologia
10.
Exp Neurol ; 330: 113327, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32387398

RESUMO

Numerous genes, and alterations in their expression, have been identified as risk factors for developing levodopa-induced dyskinesia (LID). However, our understanding of the complexities of molecular changes remains insufficient for development of clinical treatment. In the current study we used gene array, in situ hybridization, immunohistochemistry, and microdialysis to provide a unique compare and contrast assessment of the relationship of four candidate genes to LID, employing three genetically distinct rat strains (Sprague-Dawley (SD), Fischer-344 (F344) and Lewis-RT.1) showing differences in dyskinesia susceptibility and 'first-ever LID' versus 'chronic LID' expression in subjects displaying equal dyskinesia severity. In these studies, rat strains were easily distinguishable for their LID propensity with: 1) a majority of SD rats expressing LID (LID+) and a subset being resistant (LID-); 2) all F344 rats readily developing (LID+); and 3) all Lewis rats being LID-resistant (LID-). Following chronic levodopa, LID+ SD rats showed significant increases in candidate gene expression: Nr4a2/(Nurr1) > > Trh > Inhba = Fosb. However, SD rats with long-standing striatal dopamine (DA) depletion treated with first-ever versus chronic high-dose levodopa revealed that despite identical levels of LID severity: 1) Fosb and Nurr1 transcripts but not protein were elevated with acute LID expression; 2) FOSB/ΔFOSB and NURR1 proteins were elevated only with chronic LID; and 3) Trh transcript and protein were elevated only with chronic LID. Strikingly, despite similar levodopa-induced striatal DA release in both LID-expressing F344 and LID-resistant Lewis rats, Fosb, Trh, Inhba transcripts were significantly elevated in both strains; however, Nurr1 mRNA was significantly increased only in LID+ F344 rats. These findings suggest a need to reevaluate currently accepted genotype-to-phenotype relationships in the expression of LID, specifically that of Fosb, a transcription factor generally assumed to play a causal role, and Nurr1, a transcription factor that has received significant attention in PD research linked to its critical role in the survival and function of midbrain DA neurons but who's striatal expression, generally below levels of detection, has remained largely unexplored as a regulator of LID. Finally these studies introduce a novel 'model' (inbred F344 vs inbred Lewis) that may provide a powerful tool for investigating the role for 'dyskinesia-resistance' genes downstream of 'dyskinesia-susceptibility' genes in modulating LID expression, a concept that has received considerably less attention and offers a new ways of thinking about antidyskinetic therapies.


Assuntos
Antiparkinsonianos/toxicidade , Discinesia Induzida por Medicamentos/genética , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Genótipo , Masculino , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/metabolismo , Fenótipo , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew
11.
Trends Endocrinol Metab ; 30(3): 163-176, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30691778

RESUMO

Overweight and obesity pose significant health problems globally, and are causatively linked to metabolic dysregulation. The hypothalamus integrates neural, nutritional, and hormonal cues to regulate homeostasis, including circadian rhythm, body temperature, thirst, food intake, energy expenditure, and glucose metabolism. Hypothalamic neuropeptides play a fundamental role in these processes. Studies during the past two decades suggest a role of central endoplasmic reticulum (ER) stress in the pathophysiology of obesity. This review covers recent findings on the role of ER stress and neuropeptide processing in the central regulation of energy homeostasis, with special emphasis on proopiomelanocortin (POMC)-encoding neurons. In addition, the role of neuroinflammation in the context of obesity is briefly discussed.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Hipotálamo/metabolismo , Animais , Metabolismo Energético/fisiologia , Humanos , Resposta a Proteínas não Dobradas/fisiologia
12.
Neuron ; 37(4): 649-61, 2003 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-12597862

RESUMO

The gastrointestinal peptide hormone ghrelin stimulates appetite in rodents and humans via hypothalamic actions. We discovered expression of ghrelin in a previously uncharacterized group of neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These neurons send efferents onto key hypothalamic circuits, including those producing neuropeptide Y (NPY), Agouti-related protein (AGRP), proopiomelanocortin (POMC) products, and corticotropin-releasing hormone (CRH). Within the hypothalamus, ghrelin bound mostly on presynaptic terminals of NPY neurons. Using electrophysiological recordings, we found that ghrelin stimulated the activity of arcuate NPY neurons and mimicked the effect of NPY in the paraventricular nucleus of the hypothalamus (PVH). We propose that at these sites, release of ghrelin may stimulate the release of orexigenic peptides and neurotransmitters, thus representing a novel regulatory circuit controlling energy homeostasis.


Assuntos
Sistema Nervoso Central/metabolismo , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Hipotálamo/metabolismo , Rede Nervosa/metabolismo , Hormônios Peptídicos/metabolismo , Proteínas , Proteína Relacionada com Agouti , Animais , Sistema Nervoso Central/citologia , Hormônio Liberador da Corticotropina/biossíntese , Feminino , Grelina , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas Luminescentes/biossíntese , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeo Y/biossíntese , Especificidade de Órgãos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Técnicas de Patch-Clamp , Hormônios Peptídicos/farmacologia , Terminações Pré-Sinápticas/metabolismo , Pró-Opiomelanocortina/biossíntese , Ligação Proteica/fisiologia , Biossíntese de Proteínas , Ratos
13.
J Clin Invest ; 128(3): 1125-1140, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29457782

RESUMO

Pro-opiomelanocortin (POMC) neurons function as key regulators of metabolism and physiology by releasing prohormone-derived neuropeptides with distinct biological activities. However, our understanding of early events in prohormone maturation in the ER remains incomplete. Highlighting the significance of this gap in knowledge, a single POMC cysteine-to-phenylalanine mutation at position 28 (POMC-C28F) is defective for ER processing and causes early onset obesity in a dominant-negative manner in humans through an unclear mechanism. Here, we report a pathologically important role of Sel1L-Hrd1, the protein complex of ER-associated degradation (ERAD), within POMC neurons. Mice with POMC neuron-specific Sel1L deficiency developed age-associated obesity due, at least in part, to the ER retention of POMC that led to hyperphagia. The Sel1L-Hrd1 complex targets a fraction of nascent POMC molecules for ubiquitination and proteasomal degradation, preventing accumulation of misfolded and aggregated POMC, thereby ensuring that another fraction of POMC can undergo normal posttranslational processing and trafficking for secretion. Moreover, we found that the disease-associated POMC-C28F mutant evades ERAD and becomes aggregated due to the presence of a highly reactive unpaired cysteine thiol at position 50. Thus, this study not only identifies ERAD as an important mechanism regulating POMC maturation within the ER, but also provides insights into the pathogenesis of monogenic obesity associated with defective prohormone folding.


Assuntos
Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático/patologia , Hipotálamo/patologia , Obesidade/patologia , Pró-Opiomelanocortina/metabolismo , Animais , Axônios , Cisteína/química , Comportamento Alimentar , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Inflamação , Peptídeos e Proteínas de Sinalização Intracelular , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Neurônios/metabolismo , Fenilalanina/química , Pró-Opiomelanocortina/genética , Proteínas/metabolismo , Compostos de Sulfidrila , Ubiquitina/química , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
14.
Elife ; 72018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29761783

RESUMO

The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight.


Assuntos
Regulação da Temperatura Corporal , Metabolismo Energético , Homeostase , Leptina/metabolismo , Área Pré-Óptica/fisiologia , Transdução de Sinais , Animais , Peso Corporal , Camundongos
15.
Endocrinology ; 148(9): 4191-200, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17584972

RESUMO

Recent evidence demonstrated that posttranslational processing of neuropeptides is critical in the pathogenesis of obesity. Leptin or other physiological changes affects the biosynthesis and processing of many peptides hormones as well as the regulation of the family of prohormone convertases responsible for the maturation of these hormones. Regulation of energy balance by leptin involves regulation of several proneuropeptides such as proTRH and proopiomelanocortin. These proneuropeptide precursors require for their maturation proteolytic cleavage by the prohormone convertases 1 and 2 (PC1/3 and PC2). Because biosynthesis of mature peptides in response to leptin requires prohormone processing, it is hypothesized that leptin might regulate hypothalamic PC1/3 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Leptin has been shown to increase PC1/3 and PC2 promoter activities, and starvation of rats, leading to low serum leptin levels, resulted in a decrease in PC1/3 and PC2 gene and protein expression in the paraventricular and arcuate nucleus of the hypothalamus. Changes in nutritional status also changes proopiomelanocortin processing in the nucleus of the solitary tract, but this is not reversed by leptin. The PCs are also physiologically regulated by states of hyperthyroidism, hyperglycemia, inflammation, and suckling, and a recently discovered nescient helix-loop-helix-2 transcription factor is the first one to show an ability to regulate the transcription of PC1/3 and PC2. Therefore, the coupled regulation of proneuropeptide/processing enzymes may be a common process, by which cells generate more effective processing of prohormones into mature peptides.


Assuntos
Hipotálamo/enzimologia , Leptina/fisiologia , Neurônios/enzimologia , Obesidade/fisiopatologia , Pró-Opiomelanocortina/biossíntese , Pró-Proteína Convertases/metabolismo , Hormônio Liberador de Tireotropina/biossíntese , Animais , Sequências Hélice-Alça-Hélice , Sistema Hipotálamo-Hipofisário/fisiologia , Glândula Tireoide/fisiologia
16.
Endocrinology ; 148(10): 4952-64, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17584968

RESUMO

Different physiological conditions affect the biosynthesis and processing of hypophysiotropic proTRH in the hypothalamic paraventricular nucleus, and consequently the output of TRH. Early studies suggest that norepinephrine (NE) mediates the cold-induced activation of the hypothalamic-pituitary-thyroid axis at a central level. However, the specific role of NE on the biosynthesis and processing of proTRH has not been fully investigated. In this study, we found that NE affects gene transcription, protein biosynthesis, and secretion in TRH neurons in vitro; these changes were coupled with an up-regulation of prohormone convertase enzymes (PC) 1/3 and PC2. In vivo, NE is the main mediator of the cold-induced activation of the hypothalamic-pituitary-thyroid axis at the hypothalamic level, in which it potently stimulates the biosynthesis and proteolytic processing of proTRH through a coordinated up-regulation of the PCs. This activation occurs via beta-adrenoreceptors and phosphorylated cAMP response element binding signaling. In contrast, alpha-adrenoreceptors regulate TRH secretion but not proTRH biosynthesis and processing. Therefore, this study provides novel information on the molecular mechanisms of control of hypophysiotropic TRH biosynthesis.


Assuntos
Temperatura Baixa , Núcleo Hipotalâmico Paraventricular/metabolismo , Peptídeo Hidrolases/metabolismo , Precursores de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Ácido Pirrolidonocarboxílico/análogos & derivados , Receptores Adrenérgicos beta/fisiologia , Hormônio Liberador de Tireotropina/metabolismo , Animais , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Norepinefrina/farmacologia , Núcleo Hipotalâmico Paraventricular/citologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo , Precursores de Proteínas/biossíntese , Precursores de Proteínas/química , Precursores de Proteínas/genética , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Hormônio Liberador de Tireotropina/biossíntese , Hormônio Liberador de Tireotropina/química , Hormônio Liberador de Tireotropina/genética
17.
Endocrinology ; 148(4): 1550-60, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17194736

RESUMO

The central melanocortin 4 receptor (MC4R) plays a critical role in energy homeostasis, although little is known regarding its role in the regulation of adaptive thermogenesis of brown adipose tissue (BAT). Here we show using retrograde transsynaptic tracing with attenuated pseudorabies virus coupled with dual-label immunohistochemistry that specific subsets of MC4R-expressing neurons in multiple nuclei of the central nervous system known to regulate sympathetic outflow polysynaptically connect with interscapular BAT (IBAT). Furthermore, we show that MC4R-/- and agouti-related peptide-treated mice are defective in HF diet-induced up-regulation of uncoupling protein 1 in IBAT. Additionally, MC4R-/- mice exposed to 4 C for 4 h exhibit a defect in up-regulation of uncoupling protein 1 levels in IBAT. Our results provide a neuroanatomic substrate for MC4R regulating sympathetically mediated IBAT thermogenesis and demonstrate that the MC4R is critically required for acute high-fat- and cold-induced IBAT thermogenesis.


Assuntos
Aclimatação/fisiologia , Tecido Adiposo Marrom/fisiologia , Receptor Tipo 4 de Melanocortina/fisiologia , Termogênese/fisiologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Proteína Relacionada com Agouti , Animais , Sistema Nervoso Central/química , Temperatura Baixa , Dieta Aterogênica , Herpesvirus Suídeo 1 , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Canais Iônicos/metabolismo , Masculino , Melanocortinas/metabolismo , Melanocortinas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Proteína Desacopladora 1
18.
J Clin Invest ; 114(3): 357-69, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15286802

RESUMO

Regulation of energy balance by leptin involves regulation of several neuropeptides, including thyrotropin-releasing hormone (TRH). Synthesized from a larger inactive precursor, its maturation requires proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). Since this maturation in response to leptin requires prohormone processing, we hypothesized that leptin might regulate hypothalamic PC1 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Using hypothalamic neurons, we found that leptin stimulated PC1 and PC2 mRNA and protein expression and also increased PC1 and PC2 promoter activities in transfected 293T cells. Starvation of rats, leading to low serum leptin levels, decreased PC1 and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Exogenous administration of leptin to fasted animals restored PC1 levels in the median eminence (ME) and the PVN to approximately the level found in fed control animals. Consistent with this regulation of PCs in the PVN, concentrations of TRH in the PVN and ME were substantially reduced in the fasted animals relative to the fed animals, and leptin reversed this decrease. Further analysis showed that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH) at known PC cleavage sites was reduced by fasting and increased in animals given leptin. Combined, these findings suggest that leptin-dependent stimulation of hypothalamic TRH expression involves both activation of trh transcription and stimulation of PC1 and PC2 expression, which lead to enhanced processing of proTRH into mature TRH.


Assuntos
Regulação Enzimológica da Expressão Gênica , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 2/genética , Processamento de Proteína Pós-Traducional , Hormônio Liberador de Tireotropina/metabolismo , Animais , Células Cultivadas , Ingestão de Energia , Feminino , Hipotálamo/citologia , Hipotálamo/embriologia , Imuno-Histoquímica , Injeções Intraperitoneais , Leptina/administração & dosagem , Leptina/farmacologia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Pró-Proteína Convertase 1/biossíntese , Pró-Proteína Convertase 1/efeitos dos fármacos , Pró-Proteína Convertase 2/biossíntese , Pró-Proteína Convertase 2/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Hormônio Liberador de Tireotropina/genética , Tiroxina/sangue , Tri-Iodotironina/sangue
19.
Front Biosci ; 12: 3545-53, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17485320

RESUMO

A complex network of peptide hormones secreted from the gut, adipose tissue, the brain, and other tissues regulate energy balance. Intensive investigation has uncovered the role of many of the major players in energy balance. However, many of these peptide hormones are derived from precursor proteins whose in vivo processing have not been fully studied. In this review we highlight the importance of fully understanding the processing of prohormones and highlight a particular case of why this is important with the recent discovery of the peptide obestatin.


Assuntos
Metabolismo Energético , Hormônios/metabolismo , Peptídeos/metabolismo , Grelina , Hormônios Peptídicos/metabolismo , Pró-Opiomelanocortina/metabolismo , Processamento de Proteína Pós-Traducional , Hormônio Liberador de Tireotropina/metabolismo
20.
Front Biosci ; 12: 3554-65, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17485321

RESUMO

The biosynthesis of prohormone-derived peptides is a complex cellular process, which requires specific cleavage, sorting, and modifications of the peptides before the final generation of the bioactive products. In this review, we describe the current knowledge of the cell biology of a key prohormone: proThyrotropin Releasing Hormone (proTRH), which is the precursor of the TRH peptide. In particular, we focus on the biosynthesis of the hypophysiotropic TRH, which is produced in the hypothalamic paraventricular nucleus (PVN) and is the main activator of the hypothalamic-pituitary-thyroid (HPT) axis. Recently, we showed that the regulation of the biosynthesis of TRH in the PVN also occurs at post-translational level through coordinated changes in proTRH processing, by the action of the prohormone convertase (PC1/3 and PC2) processing enzymes. Such regulation, which represents a novel aspect in the regulation of the neuropeptide biosynthesis, ultimately would lead to a more effective processing of prohormones into mature peptides.


Assuntos
Neuropeptídeos/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Animais , Humanos , Neuropeptídeos/biossíntese , Núcleo Hipotalâmico Paraventricular/metabolismo , Hormônio Liberador de Tireotropina/biossíntese
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