RESUMEN
Neuromodulatory neurons located in the brain can influence activity in locomotor networks residing in the spinal cord or ventral nerve cords of invertebrates. How inputs to and outputs of neuromodulatory descending neurons affect walking activity is largely unknown. With the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and immunohistochemistry, we show that a population of dorsal unpaired median (DUM) neurons descending from the gnathal ganglion to thoracic ganglia of the stick insect Carausius morosus contains the neuromodulatory amine octopamine. These neurons receive excitatory input coupled to the legs' stance phases during treadmill walking. Inputs did not result from connections with thoracic central pattern-generating networks, but, instead, most are derived from leg load sensors. In excitatory and inhibitory retractor coxae motor neurons, spike activity in the descending DUM (desDUM) neurons increased depolarizing reflexlike responses to stimulation of leg load sensors. In these motor neurons, descending octopaminergic neurons apparently functioned as components of a positive feedback network mainly driven by load-detecting sense organs. Reflexlike responses in excitatory extensor tibiae motor neurons evoked by stimulations of a femur-tibia movement sensor either are increased or decreased or were not affected by the activity of the descending neurons, indicating different functions of desDUM neurons. The increase in motor neuron activity is often accompanied by a reflex reversal, which is characteristic for actively moving animals. Our findings indicate that some descending octopaminergic neurons can facilitate motor activity during walking and support a sensory-motor state necessary for active leg movements.NEW & NOTEWORTHY We investigated the role of descending octopaminergic neurons in the gnathal ganglion of stick insects. The neurons become active during walking, mainly triggered by input from load sensors in the legs rather than pattern-generating networks. This report provides novel evidence that octopamine released by descending neurons on stimulation of leg sense organs contributes to the modulation of leg sensory-evoked activity in a leg motor control system.
Asunto(s)
Ganglios de Invertebrados/fisiología , Neuronas Motoras/fisiología , Red Nerviosa/fisiología , Neuronas Eferentes/fisiología , Octopamina/metabolismo , Caminata/fisiología , Animales , Conducta Animal/fisiología , InsectosRESUMEN
Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty.
Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismo , Neuronas Dopaminérgicas/metabolismo , Conducta Exploratoria , Locomoción , Potenciales de Acción , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Animales , Neuronas Dopaminérgicas/fisiología , Femenino , Globo Pálido/citología , Globo Pálido/metabolismo , Globo Pálido/fisiología , Masculino , Ratones , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , RecompensaRESUMEN
Adaptation of liver to the postprandial state requires coordinated regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR signaling, Xbp1 splicing, increased expression of ER-stress genes, and phosphatidylcholine synthesis, which translate into a rapid morphological ER remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increased upon nutrient supply. Sensory food perception activates POMC neurons in the hypothalamus, optogenetic activation of POMC neurons activates hepatic mTOR signaling and Xbp1 splicing, whereas lack of MC4R expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and in liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinately primes postprandial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s axis. VIDEO ABSTRACT.
Asunto(s)
Retículo Endoplásmico/metabolismo , Preferencias Alimentarias , Melanocortinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Animales , Femenino , Regulación de la Expresión Génica , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Norepinefrina/farmacología , Fosfatidilcolinas/análisis , Fosfatidilcolinas/metabolismo , Análisis de Componente Principal , Receptor de Melanocortina Tipo 4/deficiencia , Receptor de Melanocortina Tipo 4/genética , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
The integrated stress response (ISR) facilitates cellular adaptation to stress conditions via the common target eIF2α. During ISR, the selective translation of stress-related mRNAs often relies on alternative mechanisms, such as leaky scanning or reinitiation, but the underlying mechanism remains incompletely understood. Here we report that, in response to amino acid starvation, the reinitiation of ATF4 is not only governed by the eIF2α signaling pathway, but is also subjected to regulation by mRNA methylation in the form of N6-methyladenosine (m6A). While depleting m6A demethylases represses ATF4 reinitiation, knocking down m6A methyltransferases promotes ATF4 translation. We demonstrate that m6A in the 5' UTR controls ribosome scanning and subsequent start codon selection. Global profiling of initiating ribosomes reveals widespread alternative translation events influenced by dynamic mRNA methylation. Consistently, Fto transgenic mice manifest enhanced ATF4 expression, highlighting the critical role of m6A in translational regulation of ISR at cellular and organismal levels.
Asunto(s)
Adenosina/análogos & derivados , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/fisiología , Factor 2 Eucariótico de Iniciación/metabolismo , Iniciación de la Cadena Peptídica Traduccional , ARN Mensajero/genética , Ribosomas/fisiología , Estrés Fisiológico , Regiones no Traducidas 5' , Adenosina/farmacología , Animales , Células Cultivadas , Codón Iniciador , Factor 2 Eucariótico de Iniciación/genética , Fibroblastos , Regulación de la Expresión Génica , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Fosforilación , ARN Mensajero/metabolismoRESUMEN
Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP â LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP â anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP â aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Regulación del Apetito , Glucosa/metabolismo , Resistencia a la Insulina , Neuronas/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Conducta Alimentaria , Ratones , Miostatina/genética , Optogenética , TranscriptomaRESUMEN
Variations in the fat mass and obesity associated (FTO) gene are currently the strongest known genetic factor predisposing humans to non-monogenic obesity. Recent experiments have linked these variants to a broad spectrum of behavioural alterations, including food choice and substance abuse. Yet, the underlying neurobiological mechanisms by which these genetic variations influence body weight remain elusive. Here, we explore the brain structural substrate of the obesity-predisposing rs9939609 T/A variant of the FTO gene in non-obese subjects by means of multivariate classification and use fMRI to investigate genotype-specific differences in neural food-cue reactivity by analysing correlates of a visual food perception task. Our findings demonstrate that MRI-derived measures of morphology along middle and posterior fusiform gyrus (FFG) are highly predictive for FTO at-risk allele carriers, who also show enhanced neural responses elicited by food cues in the same posterior FFG area. In brief, these findings provide first-time evidence for FTO-specific differences in both brain structure and function already in non-obese individuals, thereby contributing to a mechanistic understanding of why FTO is a predisposing factor for obesity.
Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Obesidad/genética , Lóbulo Temporal/fisiología , Percepción Visual , Adulto , Femenino , Alimentos , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Máquina de Vectores de SoporteRESUMEN
Variations in the fat mass and obesity-associated (FTO) gene are linked to obesity. However, the underlying neurobiological mechanisms by which these genetic variants influence obesity, behavior, and brain are unknown. Given that Fto regulates D2/3R signaling in mice, we tested in humans whether variants in FTO would interact with a variant in the ANKK1 gene, which alters D2R signaling and is also associated with obesity. In a behavioral and fMRI study, we demonstrate that gene variants of FTO affect dopamine (D2)-dependent midbrain brain responses to reward learning and behavioral responses associated with learning from negative outcome in humans. Furthermore, dynamic causal modeling confirmed that FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic predisposition alters reward processing not only in obesity, but also in other disorders with altered D2R-dependent impulse control, such as addiction. Significance statement: Variations in the fat mass and obesity-associated (FTO) gene are associated with obesity. Here we demonstrate that variants of FTO affect dopamine-dependent midbrain brain responses and learning from negative outcomes in humans during a reward learning task. Furthermore, FTO variants modulate the connectivity in a basic reward circuit of meso-striato-prefrontal regions, suggesting a mechanism by which genetic vulnerability in reward processing can increase predisposition to obesity.
Asunto(s)
Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Proteínas/genética , Receptores de Dopamina D2/metabolismo , Recompensa , Adulto , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Conectoma , Femenino , Humanos , Masculino , Mesencéfalo/metabolismo , Mesencéfalo/fisiologíaRESUMEN
Genome wide association studies undoubtedly linked variants of the fat mass and obesity-associated protein (FTO) to obesity. To date, however, knowledge on the mechanisms coupling variants in the intron of the FTO gene to its expression or enzymatic activity to alter metabolism remains scarce. Until recently, the investigation of the molecular function of FTO had not led to conclusive results concerning the 'where', 'when' and 'how' of FTO activity. Finally, since FTO was identified as a RNA modifying enzyme, demethylating N6-methyladenosine on single stranded RNA, novel understanding of the molecular function is gathered. These and other studies suggest the requirement for a further reaching approach to further investigate FTO function, since the phenotype of aberrant FTO function may encompass more than just obesity. Taking these new insights and translating them into appropriate paradigms for functional research in humans may lead to a deeper understanding of the human physiology and disease. This article is part of a Special Issue entitled: From Genome to Function.
RESUMEN
Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO "obesity-risk" rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.
Asunto(s)
Apetito , Ghrelina/sangre , Proteínas/genética , Aciltransferasas/genética , Aciltransferasas/metabolismo , Adolescente , Adulto , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Animales , Encéfalo/fisiología , Ingestión de Alimentos/psicología , Alimentos , Neuroimagen Funcional , Expresión Génica , Regulación de la Expresión Génica , Estudios de Asociación Genética , Células HEK293 , Humanos , Imagen por Resonancia Magnética , Masculino , Metilación , Ratones , Ratones Noqueados , Polimorfismo de Nucleótido Simple , Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Recompensa , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Adulto JovenRESUMEN
Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.