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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Brain-derived neurotrophic factor has been associated previously with the regulation of food intake. To help elucidate the role of this neurotrophin in weight regulation, we have generated conditional mutants in which brain-derived neurotrophic factor has been eliminated from the brain after birth through the use of the cre-loxP recombination system. Brain-derived neurotrophic factor conditional mutants were hyperactive after exposure to stressors and had higher levels of anxiety when evaluated in the light/dark exploration test. They also had mature onset obesity characterized by a dramatic 80-150% increase in body weight, increased linear growth, and elevated serum levels of leptin, insulin, glucose, and cholesterol. In addition, the mutants had an abnormal starvation response and elevated basal levels of POMC, an anorexigenic factor and the precursor for alpha-MSH. Our results demonstrate that brain derived neurotrophic factor has an essential maintenance function in the regulation of anxiety-related behavior and in food intake through central mediators in both the basal and fasted state.
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PMID:Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity. 1157 7

In addition to their stimulatory action on neuronal differentiation and survival, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) improve glucose and lipid metabolism and control energy balance and feeding behavior. These latter activities are referred to here as the metabotrophic potential of neurotrophins. We recently reported that circulating NGF and BDNF levels are reduced in the metabolic syndrome and in acute coronary syndromes, and that the tissue content of NGF is reduced in atherosclerotic coronary arteries. Thus we hypothesize that a metabotrophic deficit due to reduction of neurotrophin availability may be implicated in the pathogenesis of obesity and related metabolic diseases, such as metabolic syndrome, type 2 diabetes, and atherosclerosis. The metabotrophic deficit hypothesis also considers metabolism-related beneficial effects exerted by other neurotrophic factors, particularly ciliary neurotrophic factor, leukemia inhibitory factor, and bone morphogenetic proteins.
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PMID:Metabotrophic potential of neurotrophins:implication in obesity and related diseases? 1452 35

An 8-year-old male with a complex developmental syndrome and severe obesity was heterozygous for a de novo missense mutation resulting in a Y722C substitution in the neurotrophin receptor TrkB. This mutation markedly impaired receptor autophosphorylation and signaling to MAP kinase. Mutation of NTRK2, which encodes TrkB, seems to result in a unique human syndrome of hyperphagic obesity. The associated impairment in memory, learning and nociception seen in the proband reflects the crucial role of TrkB in the human nervous system.
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PMID:A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. 1549 31

An increasing number of researchers of the metabolic syndrome assume that many mechanisms are involved in its complex pathophysiology such as an increased sympathetic activity, disorders of the hypothalamo-pituitary-adrenal axis, the action of chronic subclinical infections, proinflammatory cytokines, and the effect of adipocytokines or psychoemotional stress. An increasing body of scientific research in this field confirms the role of the neurotrophins and mastocytes in the pathogenesis of inflammatory and immune diseases. Recently it has been proved that neurotrophins and mastocytes have metabotrophic effects and take part in the carbohydrate and lipid metabolism. In the early stage of the metabolic syndrome we established a statistically significant increase in the plasma levels of the nerve growth factor. In the generalized stage the plasma levels of the neutrophines were statistically decreased in comparison to those in the healthy controls. We consider that the neurotrophin deficit is likely to play a significant pathogenic role in the development of the metabolic anthropometric and vascular manifestations of the generalized stage of MetSyn. We suggest a hypothesis for the etiopathogenesis of the metabolic syndrome based on the neuro-immuno-endocrine interactions. The specific pathogenic pathways of MetSyn development include: (1) increased tissue and plasma levels of proinflammatory cytokines Interleukin-1(IL-1), Interleukin-6 (IL-6 ) and tumor necrosis factor - alpha (TNF-alpha) caused by inflammatory and/or emotional distress; (2) increased plasma levels of neurotrophin - nerve growth factor (NGF) caused by the high IL-1, IL-6 and TNFalpha levels; (3) high plasma levels of NGF which enhance activation of: the autonomous nerve system--vegetodystonia (disbalance of neurotransmitters); Neuropeptide Y (NPY)--enhanced feeding, obesity and increased leptin plasma levels; hypothalamo-pituitary-adrenal axis--increased corticotropin-releasing hormone (CRH) and cortisol (hormonal disbalance); immune cells--increased number and degranulation of mastocytes (MC)--immunological disbalance; (4) as a result of 1-3 insulin resistance is exhibited leading to diabetes mellitus. The hypothesis is confirmed by results obtained after 6-month nonsteroid anti-inflammatory treatment of patients with MetSyn. These results are reported in a separate publication.
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PMID:Metabolic syndrome--neurotrophic hypothesis. 1654 15

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5' end of the BDNF gene. The patient's genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.
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PMID:Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. 1713 Apr 81

Signal specificity of multifunctional enzymes is achieved through protein-protein interactions involving specific domains on scaffold proteins. p62 (also known as sequestosome 1) is such a scaffold protein that possesses PB1 and UBA domains, and the TRAF6 binding sequence. Proteins recruited to these domains enable p62 to integrate kinase-activated and ubiquitin-mediated signaling pathways. The biological function of p62 has been studied in diverse systems and processes such as osteoclastogenesis, inflammation, differentiation, neurotrophin biology and obesity. The availability of mice in which p62 has been genetically inactivated is providing new insight into the mechanism and function of p62 at a whole-organism level.
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PMID:Signal integration and diversification through the p62 scaffold protein. 1717 52

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are expressed in several hypothalamic and hindbrain nuclei involved in regulating energy homeostasis, developmentally and in the adult animal. Their depletion during the fetal or early postnatal periods when developmental processes are still ongoing elicits hyperphagic behavior and obesity in mice. Whether BDNF is a chief element in appetite control in the mature brain remains controversial. The required sources of this neurotrophin are also unknown. We show that glucose administration rapidly induced BDNF mRNA expression, mediated by Bdnf promoter 1, and TrkB transcription in the ventromedial hypothalamus (VMH) of adult mice, consistent with a role of this pathway in satiety. Using viral-mediated selective knock-down of BDNF in the VMH and dorsomedial hypothalamus (DMH) of adult mice, we were able to elucidate the physiological relevance of BDNF in energy balance regulation. Site-specific mutants exhibited hyperphagic behavior and obesity but normal energy expenditure. Furthermore, intracerebroventricular administration of BDNF triggered an immediate neuronal response in multiple hypothalamic nuclei in wild-type mice, suggesting that its anorexigenic actions involve short-term mechanisms. Locomotor, aggressive, and depressive-like behaviors, all of which are associated with neural circuits involving the VMH, were not altered in VMH/DMH-specific BDNF mutants. These findings demonstrate that BDNF is an integral component of central mechanisms mediating satiety in the adult mouse and, moreover, that its synthesis in the VMH and/or DMH is required for the suppression of appetite.
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PMID:Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. 1816 Jun 34

Neuronal cell death and its regulation have been extensively studied as an essential process of both neurodevelopment and neurodegenerative conditions. However it is not clear how circulating hormones influence such processes. Therefore we aimed to determine whether the anti-obesity hormone leptin could promote the survival of murine central and peripheral neurons in vitro. Thus we established primary neuronal cultures of dopaminergic midbrain neurons and trigeminal sensory neurons and induced cell death via either toxic insult or growth factor withdrawal. We demonstrate that leptin promotes the survival of developing peripheral and central neurons via activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3-kinase)/Akt/nuclear factor kappa B (NF-kappaB) -dependent signaling cascades. Specifically, leptin protects dopaminergic midbrain neurons from the apoptotic stimuli, tumor necrosis factor alpha (TNF-alpha) and 6-hydroxydopamine (6-OHDA). In addition, it promotes the survival of postnatal, but not embryonic, trigeminal sensory neurons following neurotrophin withdrawal. Our data reveal a novel neuroprotective role for leptin in the peripheral nervous system while expanding on the known anti-apoptotic role of leptin in the CNS. These findings have important implications for our understanding of neuronal viability.
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PMID:Neuroprotective actions of leptin on central and peripheral neurons in vitro. 1855 Feb 92

Obesity is the commonest nutritional disorder of companion animals. In rodents and humans, white adipose tissue is a major endocrine and secretory organ, releasing adipokines linked to inflammation. In this study, we examined whether nerve growth factor (NGF), a target-derived neurotrophin central to the development/maintenance of sympathetic innervation and an inflammatory response protein, is synthesized and secreted by canine adipocytes. NGF mRNA was detected in each of the major fat depots (the subcutaneous, inguinal, gonadal, perirenal, and falciform ligaments) of dogs at similar levels. Canine adipocytes, differentiated from preadipocytes (inguinal depot) in primary culture, expressed the NGF gene and secreted NGF both pre- and post-differentiation. Treatment of the differentiated adipocytes with LPS resulted in a dramatic increase in NGF mRNA levels (20-fold at 24 h) and in NGF protein in the medium (60-fold at 24 h). The proinflammatory cytokine TNFalpha also led to a substantial increase in NGF mRNA levels (11-fold) and protein secretion (16-fold), while IL-6 had little effect. In contrast, dexamethasone decreased both NGF mRNA levels (80%) and protein release (60%). The PPARgamma agonist rosiglitazone also reduced NGF secretion. These results demonstrate that canine white adipocytes synthesize and secrete NGF, the powerful upregulation by LPS and TNFalpha indicating that the neurotrophin is strongly linked to the inflammatory response in canine WAT. Canine adipocytes appear highly sensitive to inflammatory stimuli.
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PMID:NGF gene expression and secretion by canine adipocytes in primary culture: upregulation by the inflammatory mediators LPS and TNFalpha. 1879 83

Brain-derived neurotrophic factor and neurotrophin-4 high-affinity receptor tropomyosine related kinase (Trk) B is required for the differentiation and maintenance of specific neuron populations. Misregulation of TrkB has been reported in many human diseases, including cancer, obesity and neurological and psychiatric disorders. Alternative splicing that generates receptor isoforms with different functional properties also regulates TrkB function. Here, we describe numerous novel isoforms of TrkB proteins, including isoforms generated by alternative splicing of cassette exons in the regions encoding both the extracellular and intracellular domain and also N-terminally truncated isoforms encoded by novel 5' exon-containing transcripts. We also characterize the intracellular localization and phosphorylation potential of novel TrkB isoforms and find that these proteins have unique properties. In addition, we describe the expression profiles of all the known human TrkB transcripts in adult tissues and also during postnatal development in the human prefrontal cortex. We show that transcripts encoding the full-length TrkB receptor and the C-terminally truncated TrkB-T1 have different expression profiles as compared to the proteins they encode. Identification of 36 potential TrkB protein isoforms suggests high complexity in the synthesis, regulation and function of this important neurotrophin receptor emphasizing the need for further study of these novel TrkB variants.
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PMID:Human TrkB gene: novel alternative transcripts, protein isoforms and expression pattern in the prefrontal cerebral cortex during postnatal development. 2019 39


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