RESUMO
Hypothalamic obesity represents a rare diagnosis applicable to only a small subset of obese patients. It is important to identify, diagnose, and treat these patients. This article reviews the physiology of the hypothalamus, focusing on its role in regulation of hunger, feeding, and metabolism. The causes of hypothalamic obesity are discussed including genetic, anatomic, and iatrogenic etiologies. The complex hormonal environment leading to obesity is explored for each etiology and treatment strategies are discussed. Reproductive consequences are also reviewed.
Assuntos
Doenças Hipotalâmicas/complicações , Hipotálamo/fisiopatologia , Obesidade/etiologia , Apetite/fisiologia , Depressores do Apetite/uso terapêutico , Cirurgia Bariátrica , Craniofaringioma/complicações , Craniofaringioma/cirurgia , Metabolismo Energético/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Humanos , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Hipogonadismo/etiologia , Hipogonadismo/fisiopatologia , Doenças Hipotalâmicas/diagnóstico , Doenças Hipotalâmicas/genética , Doenças Hipotalâmicas/fisiopatologia , Doenças Hipotalâmicas/cirurgia , Hormônios Hipotalâmicos/fisiologia , Hipotálamo/lesões , Doença Iatrogênica , Infertilidade/etiologia , Infertilidade/fisiopatologia , Leptina/deficiência , Leptina/genética , Leptina/fisiologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/cirurgia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/cirurgia , Complicações Pós-Operatórias/fisiopatologia , Pró-Opiomelanocortina/deficiência , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/fisiologia , Puberdade Tardia/etiologia , Puberdade Tardia/fisiopatologia , Receptores para Leptina/deficiência , Receptores para Leptina/genética , Receptores para Leptina/fisiologia , Receptores de Melanocortina/deficiência , Receptores de Melanocortina/genética , Receptores de Melanocortina/fisiologia , Comportamento SedentárioRESUMO
Beta-thymosins are actin monomer-binding polypeptides that are expressed in a neuronal growth-specific manner during embryonic development. Here, we show that regenerating retinal ganglion cells and non-neuronal cells of the optic nerve transiently activate beta-thymosin transcription after optic nerve lesion in the zebrafish. In retinal cell cultures, beta-thymosin is found at highest concentration in growth cones, branching points and varicosities of neurite-extending retinal ganglion cells. These places often exhibit reduced phalloidin staining, indicating that beta-thymosin promotes the disassembly of actin filaments. Beta-thymosin distribution within neurons in culture is distinct from actin, tubulin and the actin-severing protein gelsolin. Ectopic expression of beta-thymosin in a central nervous system (CNS) catecholaminergic cell line leads to alterations in the shape of the cell bodies and neurites. Beta-thymosin-positive cells spread more fully and exhibit an excessive degree of branching. We partially cloned two other actin-binding proteins, profilin and gelsolin, and analysed their expression patterns. Profilin is constitutively expressed in virtually all cells. Gelsolin, like beta-thymosin, is selectively increased in regenerating retinal ganglion cells. During development, however, gelsolin mRNA is not detected in the nervous system. These findings indicate that distinct mechanisms control the actin cytoskeleton in embryonic and regenerating neurons, and that beta-thymosin may be a major regulator of actin dynamics in the zebrafish CNS.
Assuntos
Actinas/metabolismo , Proteínas Contráteis , Citoesqueleto/metabolismo , Regeneração Nervosa/fisiologia , Células Ganglionares da Retina/metabolismo , Timosina/análogos & derivados , Ubiquitinas/genética , Acetilação , Actinas/análise , Animais , Northern Blotting , Catecolaminas/fisiologia , Linhagem Celular , Gelsolina/análise , Gelsolina/genética , Expressão Gênica/fisiologia , Cones de Crescimento/química , Cones de Crescimento/metabolismo , Proteínas dos Microfilamentos/genética , Nervo Óptico/citologia , Nervo Óptico/fisiologia , Profilinas , RNA Mensageiro/análise , RNA Mensageiro/genética , Células Ganglionares da Retina/ultraestrutura , Timosina/análise , Timosina/genética , Timosina/metabolismo , Tubulina (Proteína)/análise , Tubulina (Proteína)/metabolismo , Ubiquitinas/análise , Ubiquitinas/metabolismo , Peixe-ZebraRESUMO
beta-Thymosins are polypeptides that bind monomeric actin and thereby function as actin buffers in many cells. We show that during zebrafish development, &bgr;-thymosin expression is tightly correlated with neuronal growth and differentiation. It is transiently expressed in a subset of axon-extending neurons, essentially primary neurons that extend long axons, glia and muscle. Non-neuronal expression in the brain is restricted to a subset of glia surrounding newly forming axonal tracts. Skeletal muscle cells in somites, jaw and fin express beta-thymosin during differentiation, coinciding with the time of innervation. Injection of beta-thymosin antisense RNA into zebrafish embryos results in brain defects and impairment of the development of beta-thymosin-associated axon tracts. Furthermore, irregularities in somite formation can be seen in a subset of embryos. Compared to wild-type, antisense-injected embryos show slightly weaker and more diffuse engrailed staining at the midbrain-hindbrain boundary and a strong reduction of Isl-1 labeling in Rohon Beard and trigeminal neurons. The decreased expression is not based on a loss of neurons indicating that beta-thymosin may be involved in the maintenance of the expression of molecules necessary for neuronal differentiation. Taken together, our results strongly indicate that beta-thymosin is an important regulator of development.
Assuntos
Proteínas do Tecido Nervoso , Timosina/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Sequência de Bases , Encéfalo/embriologia , Clonagem Molecular , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Hibridização In Situ , Proteínas com Homeodomínio LIM , Dados de Sequência Molecular , Músculos/embriologia , Sistema Nervoso/embriologia , RNA/genética , RNA Antissenso/farmacologia , Alinhamento de Sequência , Timosina/química , Fatores de Transcrição , Peixe-Zebra/embriologiaRESUMO
Axotomy of vertebrate neurons leads to the transient upregulation of GAP-43 and alpha-tubulin. In adult zebrafish retina, mRNA levels of both genes were increased in retinal ganglion cells after optic nerve lesion following a similar time course. At 5 days after crush, the mRNA level of GAP-43 was increased nearly 20 times, whereas a 6-fold increase was observed for alpha-tubulin. Subsequently, upon target reinnervation, mRNA levels of both genes were downregulated and were 2-fold higher than normal at 25 days after crush. Stretching the optic nerve that results in diffuse axonal lesions led to the expression of both genes in identical subsets of retinal ganglion cells. When regeneration was prevented by removing a piece of the optic nerve, mRNA levels remained elevated. Disruption of axonal transport by colchicine and vinblastine led to the induction of both genes in normal retina. Blocking electrical activity with tetrodotoxin had no effect. This indicates that retrogradely transported signals induced by target contact regulate GAP-43 and alpha-tubulin transcription. Furthermore, the joint regulation of GAP-43 and alpha-tubulin mRNA levels after different kinds of lesion suggests that a common pathway underlies the regulation of neuronal GAP-43 and alpha-tubulin gene expression. In contrast, distinct mechanisms may control the extent and maintenance of increased mRNA levels of these genes.
Assuntos
Proteína GAP-43/genética , Regeneração Nervosa/genética , RNA Mensageiro/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/fisiologia , Tubulina (Proteína)/genética , Animais , Citoesqueleto/fisiologia , DNA Complementar/biossíntese , DNA Complementar/isolamento & purificação , Proteína GAP-43/biossíntese , Regulação da Expressão Gênica , Isomerismo , Dados de Sequência Molecular , Nervo Óptico/fisiologia , Retina/metabolismo , Sinapses/fisiologia , Tubulina (Proteína)/biossíntese , Tubulina (Proteína)/isolamento & purificação , Peixe-ZebraRESUMO
zfNLRR is a novel transmembrane protein that is most prominently expressed during regeneration of the zebrafish central nervous system. Retinal ganglion cells and descending spinal cord neurons strongly increase zfNLRR mRNA levels after axotomy in the adult. In contrast, during development expression is hardly detectable and is restricted to a few sensory systems. In the adult brain, zfNLRR mRNA is found at low levels in several motor and premotor systems. Sequence analysis reveals that zfNLRR contains in its extracellular region 12 leucine-rich repeats, 1 immunoglobulin-like domain and 1 fibronectin type III-like domain. The same protein binding motifs were identified in transmembrane proteins from frog, mouse, and human. Together, they constitute a novel family of vertebrate neuronal leucine-rich repeat proteins. Three distinct isoforms are identified so far. On the basis of its structural features and expression pattern, we propose that zfNLRR functions as a neuronal-specific adhesion molecule or soluble ligand binding receptor, primarily during restoration of the nervous system after injury.