RESUMEN
Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the NF1 tumor suppressor gene, a negative regulator of RAS-mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and Prss56-Nf1 knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified NF1-deficient Schwann cells and skeletal stem/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas NF1-deficient SSPCs adopted a fibrotic fate, NF1-deficient Schwann cells produced critical paracrine factors including transforming growth factor-ß and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both NF1-deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the Prss56-Nf1 knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.
Asunto(s)
Ratones Noqueados , Neurofibromina 1 , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Seudoartrosis , Células de Schwann , Animales , Femenino , Humanos , Masculino , Ratones , Diferenciación Celular/efectos de los fármacos , Fibrosis , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neurofibromatosis 1/patología , Neurofibromatosis 1/metabolismo , Neurofibromatosis 1/complicaciones , Neurofibromina 1/metabolismo , Neurofibromina 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Seudoartrosis/patología , Seudoartrosis/metabolismo , Seudoartrosis/congénito , Células de Schwann/metabolismo , Células de Schwann/efectos de los fármacos , Células de Schwann/patología , Células Madre/metabolismo , Células Madre/efectos de los fármacos , Tibia/patologíaRESUMEN
Cutaneous neurofibromas (cNFs) are a hallmark of patients with the neurofibromatosis type 1 (NF1) genetic disorder. These benign nerve sheath tumors, which can amount to thousands, develop from puberty onward, often cause pain and are considered by patients to be the primary burden of the disease. Mutations of NF1, encoding a negative regulator of the RAS signaling pathway, in the Schwann cell (SCs) lineage are considered to be at the origin of cNFs. The mechanisms governing cNFs development are poorly understood, and therapeutics to reduce cNFs are missing, mainly due to the lack of appropriate animal models. To address this, we designed the Nf1-KO mouse model that develops cNFs. Using this model, we found that cNFs development is a singular event and goes through 3 successive stages: initiation, progression, and stabilization characterized by changes in the proliferative and MAPK activities of tumor SCs. We found that skin trauma accelerated the development of cNFs and further used this model to explore the efficacy of the MEK inhibitor binimetinib to cure these tumors. We showed that while topically delivered binimetinib has a selective and minor effect on mature cNFs, the same drug prevents their development over long periods.
Asunto(s)
Neurofibroma , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Ratones , Animales , Neurofibromatosis 1/tratamiento farmacológico , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibroma/tratamiento farmacológico , Neurofibroma/genética , Bencimidazoles , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/prevención & control , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas Activadas por MitógenosRESUMEN
Patients carrying an inactive NF1 allele develop tumors of Schwann cell origin called neurofibromas (NF). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNF). However, this has not been the case for cutaneous neurofibromas (cNF), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs and provides insights on disease mechanisms, revealing a long, multistep pathologic process in which inflammation-related signals play a pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas. SIGNIFICANCE: Patients affected by NF1 develop numerous cNFs. We present a mouse model that faithfully recapitulates cNFs, identify a candidate cell type at their origin, analyze the steps involved in their formation, and show that their development is dramatically accelerated by skin injury. These findings have important clinical/therapeutic implications.This article is highlighted in the In This Issue feature, p. 1.
Asunto(s)
Neurofibroma/metabolismo , Neurofibromatosis 1/metabolismo , Neurofibromina 1/genética , Células de Schwann/metabolismo , Neoplasias Cutáneas/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Noqueados , Mutación , Neurofibroma/etiología , Neurofibroma/genética , Neurofibroma/fisiopatología , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/genética , Neurofibromatosis 1/fisiopatología , Células de Schwann/fisiología , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/fisiopatologíaRESUMEN
Broad plasticity of the peripheral glia is an emerging concept during development of the peripheral nervous system (PNS). Recent studies have identified the neural crest-derived boundary caps (BCs), as a multitask stem cell population of the developing PNS. BC progeny migrate along the nerves to provide the major glial component of nerve roots and nerve terminals in the skin. Strikingly, those two locations constitute the privileged sites for development of benign peripheral nerve sheath tumors called neurofibromas in patients with neurofibromatosis type 1 (NF1), making BCs attractive candidates for the 'cell of origin' of this disease. Here, we review these exciting findings, focusing on the origin and novel functions of BCs. We further discuss the heterogeneity of BCs, and address their implication in the pathogenesis of NF1.
Asunto(s)
Cresta Neural/citología , Células-Madre Neurales/citología , Neurofibromatosis 1/fisiopatología , Neuroglía/citología , Sistema Nervioso Periférico/citología , Animales , Humanos , Cresta Neural/patología , Cresta Neural/fisiología , Células-Madre Neurales/patología , Células-Madre Neurales/fisiología , Neuroglía/patología , Neuroglía/fisiología , Sistema Nervioso Periférico/patología , Sistema Nervioso Periférico/fisiologíaRESUMEN
Quaking (QKI) is an RNA-binding protein involved in post-transcriptional mRNA processing. This gene is found to be associated with several human neurological disorders. Early expression of QKI proteins in the developing mouse neuroepithelium, together with neural tube defects in Qk mouse mutants, suggest the functional requirement of Qk for the establishment of the nervous system. As a knockout of Qk is embryonic lethal in mice, other model systems like the zebrafish could serve as a tool to study the developmental functions of qki. In the present study we sought to characterize the evolutionary relationship and spatiotemporal expression of qkia, qki2, and qkib; zebrafish homologs of human QKI. We found that qkia is an ancestral paralog of the single tetrapod Qk gene that was likely lost during the fin-to-limb transition. Conversely, qkib and qki2 are orthologs, emerging at the root of the vertebrate and teleost lineage, respectively. Both qki2 and qkib, but not qkia, were expressed in the progenitor domains of the central nervous system, similar to expression of the single gene in mice. Despite having partially overlapping expression domains, each gene has a unique expression pattern, suggesting that these genes have undergone subfunctionalization following duplication. Therefore, we suggest the zebrafish could be used to study the separate functions of qki genes during embryonic development.
Asunto(s)
Proteínas de Unión al ARN/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Evolución Biológica , Cordados/anatomía & histología , Cordados/genética , Secuencia Conservada , Evolución Molecular , Extremidades/embriología , Regulación del Desarrollo de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Ratones , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Sistema Nervioso/embriología , Sistema Nervioso/metabolismo , Tubo Neural/metabolismo , Filogenia , Proteínas de Unión al ARN/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Alineación de Secuencia , Homología de Secuencia , Especificidad de la Especie , Sintenía , Pez Cebra/embriología , Pez Cebra/metabolismo , Proteínas de Pez Cebra/biosíntesisRESUMEN
The γ-aminobutyric acid (GABA) type B receptor has been implicated in glial cell development in the peripheral nervous system (PNS), although the exact function of GABA signaling is not known. To investigate GABA and its B receptor in PNS development and degeneration, we studied the expression of the GABAB receptor, GABA, and glutamic acid decarboxylase GAD65/67 in both development and injury in fetal dissociated dorsal root ganglia (DRG) cell cultures and in the rat sciatic nerve. We found that GABA, GAD65/67, and the GABAB receptor were expressed in premyelinating and nonmyelinating Schwann cells throughout development and after injury. A small population of myelinated sensory fibers displayed all of these molecules at the node of Ranvier, indicating a role in axon-glia communication. Functional studies using GABAB receptor agonists and antagonists were performed in fetal DRG primary cultures to study the function of this receptor during development. The results show that GABA, via its B receptor, is involved in the myelination process but not in Schwann cell proliferation. The data from adult nerves suggest additional roles in axon-glia communication after injury.
Asunto(s)
Vaina de Mielina/metabolismo , Nódulos de Ranvier/metabolismo , Receptores de GABA-B/metabolismo , Nervio Ciático , Ácido gamma-Aminobutírico/metabolismo , Animales , Animales Recién Nacidos , Proliferación Celular/efectos de los fármacos , Embrión de Mamíferos , GABAérgicos/farmacología , Ganglios Espinales/citología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Básica de Mielina/genética , Proteína Básica de Mielina/metabolismo , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Glicoproteína Asociada a Mielina/genética , Glicoproteína Asociada a Mielina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/genética , Nervio Ciático/citología , Nervio Ciático/embriología , Nervio Ciático/crecimiento & desarrollo , Neuropatía Ciática/metabolismo , Neuropatía Ciática/patologíaRESUMEN
Linkage, association and expression studies previously pointed to the human QKI, KH domain containing, RNA-binding (QKI) as a candidate gene for schizophrenia. Functional studies of the mouse orthologue Qk focused mainly on its role in oligodendrocyte development and myelination, while its function in astroglia remained unexplored. Here, we show that QKI is highly expressed in human primary astrocytes and that its splice forms encode proteins targeting different subcellular localizations. Uncovering the role of QKI in astrocytes is of interest in light of growing evidence implicating astrocyte dysfunction in the pathogenesis of several disorders of the central nervous system. We selectively silenced QKI splice variants in human primary astrocytes and used RNA sequencing to identify differential expression and splice variant composition at the genome-wide level. We found that an mRNA expression of Glial fibrillary acidic protein (GFAP), encoding a major component of astrocyte intermediate filaments, was down-regulated after QKI7 splice variant silencing. Moreover, we identified a potential QKI-binding site within the 3' untranslated region of human GFAP. This sequence was not conserved between mice and humans, raising the possibility that GFAP is a target for QKI in humans but not rodents. Haloperidol treatment of primary astrocytes resulted in coordinated increases in QKI7 and GFAP expression. Taken together, our results provide the first link between QKI and GFAP, two genes with alterations previously observed independently in schizophrenic patients. Our findings for QKI, together with its well-known role in myelination, suggest that QKI is a hub regulator of glia function in humans.
Asunto(s)
Astrocitos/metabolismo , Regulación de la Expresión Génica , Proteína Ácida Fibrilar de la Glía/genética , Proteínas de Unión al ARN/fisiología , Secuencia de Aminoácidos , Antipsicóticos/farmacología , Células Cultivadas , Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Proteína Ácida Fibrilar de la Glía/metabolismo , Haloperidol/farmacología , Humanos , Datos de Secuencia Molecular , Cultivo Primario de Células , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas/fisiología , Transporte de Proteínas , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Proteínas de Unión al ARN/química , Esquizofrenia/metabolismo , Análisis de Secuencia de ARN , TranscriptomaRESUMEN
BACKGROUND: Empirical evaluations of sexually dimorphic expression of genes on the mammalian X-chromosome are needed to understand the evolutionary forces and the gene-regulatory mechanisms controlling this chromosome. We performed a large-scale sex-bias expression analysis of genes on the X-chromosome in six different somatic tissues from mouse. RESULTS: Our results show that the mouse X-chromosome is enriched with female-biased genes and depleted of male-biased genes. This suggests that feminisation as well as de-masculinisation of the X-chromosome has occurred in terms of gene expression in non-reproductive tissues. Several mechanisms may be responsible for the control of female-biased expression on chromosome X, and escape from X-inactivation is a main candidate. We confirmed escape in case of Tmem29 using RNA-FISH analysis. In addition, we identified novel female-biased non-coding transcripts located in the same female-biased cluster as the well-known coding X-inactivation escapee Kdm5c, likely transcribed from the transition-region between active and silenced domains. We also found that previously known escapees only partially explained the overrepresentation of female-biased X-genes, particularly for tissue-specific female-biased genes. Therefore, the gene set we have identified contains tissue-specific escapees and/or genes controlled by other sexually skewed regulatory mechanisms. Analysis of gene age showed that evolutionarily old X-genes (>100 myr, preceding the radiation of placental mammals) are more frequently female-biased than younger genes. CONCLUSION: Altogether, our results have implications for understanding both gene regulation and gene evolution of mammalian X-chromosomes, and suggest that the final result in terms of the X-gene composition (masculinisation versus feminisation) is a compromise between different evolutionary forces acting on reproductive and somatic tissues.
Asunto(s)
Regulación de la Expresión Génica , Genes Ligados a X , Proteínas de la Membrana/genética , Oxidorreductasas N-Desmetilantes/genética , Cromosoma X , Animales , Sesgo , Evolución Biológica , Encéfalo/metabolismo , Ojo/metabolismo , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Histona Demetilasas , Hibridación Fluorescente in Situ , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Oxidorreductasas N-Desmetilantes/metabolismo , Caracteres SexualesRESUMEN
Single nucleotide polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. Alterations in Fto expression in transgenic animals affect body weight, energy expenditure and food intake. Fto, a nuclear protein and proposed transcription co-factor, has been speculated to affect energy balance through a functional relationship with specific genes encoding feeding-related peptides. Herein, we employed double immunohistochemistry and showed that the majority of neurons synthesizing a satiety mediator, oxytocin, coexpress Fto in the brain of male and female mice. We then overexpressed Fto in a murine hypothalamic cell line and, using qPCR, detected a 50% increase in the level of oxytocin mRNA. Expression levels of several other feeding-related genes, including neuropeptide Y (NPY) and Agouti-related protein (AgRP), were unaffected by the FTO transfection. Addition of 10 and 100 nmol oxytocin to the cell culture medium did not affect Fto expression in hypothalamic cells. We conclude that Fto, a proposed transcription co-factor, influences expression of the gene encoding a satiety mediator, oxytocin.
Asunto(s)
Encéfalo/metabolismo , Regulación de la Expresión Génica , Oxo-Ácido-Liasas/metabolismo , Oxitocina/genética , Oxitocina/metabolismo , Respuesta de Saciedad , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Oxigenasas de Función Mixta , Neuronas/metabolismoRESUMEN
A single nucleotide polymorphism in the FTO gene is associated with obesity in humans. Evidence gathered in animals mainly relates energy homeostasis to the central FTO mRNA levels, but our knowledge of the Fto protein distribution and regulation is limited. Fto, a demethylase and transcriptional coactivator, is thought to regulate expression of other genes. Herein, we examined Fto immunoreactivity (IR) in the mouse and rat brain with emphasis on sites governing energy balance. We also studied whether energy status affects central Fto IR. We report that Fto IR, limited to nuclear profiles, is widespread in the brain, in- and outside feeding circuits; it shows a very similar distribution in feeding-related sites in mice and rats. Several areas regulating energy homeostasis display enhanced intensity of Fto staining: the arcuate, paraventricular, supraoptic, dorsomedial, ventromedial nuclei, and dorsal vagal complex. Some regions mediating feeding reward, including the bed nucleus of the stria terminalis, have ample Fto IR. We found that differences in energy status between rats fed ad libitum, deprived or refed following deprivation, did not affect the number of Fto-positive nuclei in 10 sites governing consumption for energy or reward. We conclude that Fto IR, widespread in the rodent brain, is particularly abundant in feeding circuits, but the number of Fto-positive neurons is unaffected by changes in energy balance.
Asunto(s)
Encéfalo/anatomía & histología , Encéfalo/metabolismo , Metabolismo Energético/fisiología , Conducta Alimentaria/fisiología , Neuronas/metabolismo , Oxo-Ácido-Liasas/metabolismo , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Animales , Encéfalo/fisiología , Homeostasis/fisiología , Inmunohistoquímica/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Oxigenasas de Función Mixta , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Sexual dimorphism in brain gene expression has been recognized in several animal species. However, the relevant regulatory mechanisms remain poorly understood. To investigate whether sex-biased gene expression in mammalian brain is globally regulated or locally regulated in diverse brain structures, and to study the genomic organisation of brain-expressed sex-biased genes, we performed a large scale gene expression analysis of distinct brain regions in adult male and female mice. RESULTS: This study revealed spatial specificity in sex-biased transcription in the mouse brain, and identified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampus and 31 in the eye. Genes located on sex chromosomes were consistently over-represented in all brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealed Y-encoded male-biased transcripts and X-encoded female-biased transcripts known to escape X-inactivation. In addition, we identified novel coding and non-coding X-linked genes with female-biased expression in multiple tissues. Interestingly, the chromosomal positions of all of the female-biased non-coding genes are in close proximity to protein-coding genes that escape X-inactivation. This defines X-chromosome domains each of which contains a coding and a non-coding female-biased gene. Lack of repressive chromatin marks in non-coding transcribed loci supports the possibility that they escape X-inactivation. Moreover, RNA-DNA combined FISH experiments confirmed the biallelic expression of one such novel domain. CONCLUSION: This study demonstrated that the amount of genes with sex-biased expression varies between individual brain regions in mouse. The sex-biased genes identified are localized on many chromosomes. At the same time, sexually dimorphic gene expression that is common to several parts of the brain is mostly restricted to the sex chromosomes. Moreover, the study uncovered multiple female-biased non-coding genes that are non-randomly co-localized on the X-chromosome with protein-coding genes that escape X-inactivation. This raises the possibility that expression of long non-coding RNAs may play a role in modulating gene expression in domains that escape X-inactivation in mouse.
Asunto(s)
Regulación de la Expresión Génica/genética , ARN no Traducido/genética , Caracteres Sexuales , Inactivación del Cromosoma X/genética , Cromosoma X/genética , Animales , Encéfalo/metabolismo , Femenino , Perfilación de la Expresión Génica , Genes Ligados a X/genética , Histonas/metabolismo , Lisina/metabolismo , Masculino , Metilación , Ratones , Familia de Multigenes , Análisis de Secuencia por Matrices de Oligonucleótidos , Sistemas de Lectura Abierta/genética , Especificidad de Órganos/genética , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: The human QKI gene, called quaking homolog, KH domain RNA binding (mouse), is a candidate gene for schizophrenia encoding an RNA-binding protein. This gene was shown to be essential for myelination in oligodendrocytes. QKI is also highly expressed in astrocytes, but its function in these cells is not known. METHODS/PRINCIPAL FINDINGS: We studied the effect of small interference RNA (siRNA)-mediated QKI depletion on global gene expression in human astrocyte glioma cells. Microarray measurements were confirmed with real-time quantitative polymerase chain reaction (qPCR). The presence of QKI binding sites (QRE) was assessed by a bioinformatic approach. Viability and cell morphology were also studied. The most significant alteration after QKI silencing was the decreased expression of genes involved in interferon (IFN) induction (P = 6.3E-10), including IFIT1, IFIT2, MX1, MX2, G1P2, G1P3, GBP1 and IFIH1. All eight genes were down-regulated after silencing of the splice variant QKI-7, but were not affected by QKI-5 silencing. Interestingly, four of them were up-regulated after treatment with the antipsychotic agent haloperidol that also resulted in increased QKI-7 mRNA levels. CONCLUSIONS/SIGNIFICANCE: The coordinated expression of QKI-7 splice variant and IFN-related genes supports the idea that this particular splice variant has specific functions in astrocytes. Furthermore, a role of QKI-7 as a regulator of an inflammatory gene pathway in astrocytes is suggested. This hypothesis is well in line with growing experimental evidence on the role of inflammatory components in schizophrenia.
Asunto(s)
Astrocitos/metabolismo , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Proteínas de Unión al ARN/metabolismo , Línea Celular , Glioma/genética , Humanos , Interferones/genética , Interferones/metabolismo , Unión Proteica , Proteínas de Unión al ARN/genéticaRESUMEN
BACKGROUND: Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short- and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward- and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal. RESULTS: Deprivation upregulated FTO mRNA, while leucine downregulated it. Consumption of palatable diets or macronutrient preference did not affect FTO expression. However, the propensity to ingest more energy without an effect on body weight was associated with lower FTO mRNA levels. We found that 4-fold higher number of FTO cells displayed c-Fos at meal termination as compared to initiation in the paraventricular and arcuate nuclei of re-fed mice. Moreover, ISH showed that FTO is present mainly in hunger-related sites and it shows a high degree of colocalization with anorexigenic oxytocin. CONCLUSION: We conclude that FTO mRNA is present mainly in sites related to hunger/satiation control; changes in hypothalamic FTO expression are associated with cues related to energy intake rather than feeding reward. In line with that, neurons involved in feeding termination express FTO. Interestingly, baseline FTO expression appears linked not only with energy intake but also energy metabolism.