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1.
Artículo en Inglés | MEDLINE | ID: mdl-31811350

RESUMEN

RATIONAL: Caloric restriction increases the risk of relapse in abstinent drug users. Hormones involved in the regulation of energy balance and food intake, such as leptin and ghrelin, are implicated in drug-related behaviors. OBJECTIVES: We investigated the role of leptin and ghrelin in the augmentation of heroin seeking induced by chronic food restriction. METHODS: Rats self-administered heroin (0.1 mg/kg/infusion) for 10 days followed by 14 days of drug withdrawal. During withdrawal, rats were food restricted to 90% of their original body weight or were given free access to food. In experiment 1, we measured the plasma concentrations of leptin and ghrelin following heroin self-administration and withdrawal. In experiment 2, leptin was administered centrally (2.0 or 4.0 µg; i.c.v.) prior to a heroin-seeking test under extinction conditions. High density of both leptin and ghrelin receptors was previously identified in the ventral tegmental area (VTA), suggesting a direct effect on reward and motivation. Hence, we administered leptin (experiment 3; 0.125 or 0.250 µg/side), or ghrelin receptor antagonist JMV 2959 (experiment 4; 2.0 or 10.0 µg/side) directly into the VTA prior to the heroin-seeking test. RESULTS: Chronic food restriction significantly decreased plasma levels of leptin and elevated plasma levels of ghrelin. Central administration of leptin had no statistically significant effect on heroin seeking. Intra-VTA administration of either leptin or JMV 2959 dose-dependently and selectively decreased heroin seeking in the food-restricted rats. CONCLUSIONS: Leptin and ghrelin transmission in the VTA can modulate the augmentation of heroin seeking induced by chronic food restriction.

2.
PLoS One ; 14(10): e0223279, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31626659

RESUMEN

Although electrogastrography (EGG) could be a critical tool in the diagnosis of patients with gastrointestinal (GI) disease, it remains under-utilized. The lack of spatial and temporal resolution using current EGG methods presents a significant roadblock to more widespread usage. Human and preclinical studies have shown that GI myoelectric electrodes can record signals containing significantly more information than can be derived from abdominal surface electrodes. The current study sought to assess the efficacy of multi-electrode arrays, surgically implanted on the serosal surface of the GI tract, from gastric fundus-to-duodenum, in recording myoelectric signals. It also examines the potential for machine learning algorithms to predict functional states, such as retching and emesis, from GI signal features. Studies were performed using ferrets, a gold standard model for emesis testing. Our results include simultaneous recordings from up to six GI recording sites in both anesthetized and chronically implanted free-moving ferrets. Testing conditions to produce different gastric states included gastric distension, intragastric infusion of emetine (a prototypical emetic agent), and feeding. Despite the observed variability in GI signals, machine learning algorithms, including k-nearest neighbors and support vector machines, were able to detect the state of the stomach with high overall accuracy (>75%). The present study is the first demonstration of machine learning algorithms to detect the physiological state of the stomach and onset of retching, which could provide a methodology to diagnose GI diseases and symptoms such as nausea and vomiting.

3.
J Clin Invest ; 129(6): 2417-2430, 2019 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-30938715

RESUMEN

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA binding protein (ACBP)-derived endozepines are secreted peptides that modulate the GABAA receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP+ astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. ACBP-astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons and ODN selectively activated POMC neurons through the ODN-GPCR but not GABAA, and supressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN-GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system.

4.
Med Ref Serv Q ; 38(1): 87-96, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30942680

RESUMEN

The primary goal of this project is to understand how each National Cancer Institute-designated cancer center library, and all libraries that support cancer research, function within their institutions. Through an in-depth survey focused on three major areas (staff, content and tools procurement, and user services), the research team hopes to determine how a cancer-centric library can be successful in supporting quality patient care, research excellence, and education. Additionally, the survey will examine the necessary minimum staffing levels for librarians and information professionals based on organizational size and degree of research focus. The survey will seek out the new skills librarians will need to deliver optimal services. The survey will also explore how content libraries purchase reflects and maps to constituents' current medical and research activities. Libraries within a research intense environment have a responsibility to align with researchers and health care professionals to provide resources and services that support their workflows. Cancer libraries need to be attuned to their institutions' missions, whether that includes excellent patient care, research endeavors, or cutting-edge educational programs. The information gathered from the survey will provide data for this research team to define the vision and standards of excellence for a cancer specialized research library.


Asunto(s)
Bases de Datos Bibliográficas/normas , Almacenamiento y Recuperación de la Información/normas , Bibliotecas Médicas/normas , Desarrollo de la Colección de Bibliotecas/normas , Encuestas de Bibliotecas/normas , Neoplasias , Bases de Datos Bibliográficas/tendencias , Predicción , Humanos , Almacenamiento y Recuperación de la Información/tendencias , Bibliotecas Médicas/tendencias , Desarrollo de la Colección de Bibliotecas/tendencias , National Cancer Institute (U.S.) , Estados Unidos
5.
Neuropharmacology ; 151: 55-63, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30946847

RESUMEN

BACKGROUND: Pharmacotherapies targeting motivational aspects of feeding and palatable food reward, while sparing mood and cognitive function, represent an alluring approach to reverse obesity and maintain weight loss in an obesogenic environment. A novel glucagon-like peptide-1/dexamethasone (GLP-1/Dexa) conjugate, developed to selectively activate glucocorticoid receptors in GLP-1 receptor-expressing cells was shown to decrease food intake and lower body weight in obese mice. Here, we investigate if this novel drug candidate modulates the rewarding properties of food and if it affects behavioral indices of mood and memory. METHODS: C57Bl6 mice treated with the GLP-1/Dexa conjugate, GLP-1 or vehicle lever-pressed for high-fat, high sugar (HFHS) food rewards in an operant task. Alterations in food-motivated behavior were also assessed following a HFHS diet withdrawal manipulation (switch to chow). The effects of repeated GLP-1/Dexa conjugate, GLP-1 or vehicle on free-feeding intake, body weight, anxiodepressive behaviors (elevated-plus maze, open field test & forced swim test), memory (novel object recognition) and mRNA expression of reward-relevant markers in the nucleus accumbens were also evaluated in mice fed a HFHS diet for 12 weeks. RESULTS: Mice treated with a GLP-1 analogue displayed a transient (4 h) reduction in their motivation to lever press for HFHS reward, whereas treatment with equimolar doses of GLP-1/Dexa delivered a superior and sustained (20 h) suppression of food-motivated behavior. GLP-1/Dexa also inhibited food reward following withdrawal from the HFHS diet. These benefits coincided with related transcriptional changes of dopaminergic markers in the nucleus accumbens. Importantly, repeated GLP-1/Dexa treatment during a HFHS diet caused weight loss without affecting anxiodepressive behavior and memory. CONCLUSION: Via its actions to blunt the rewarding effects of palatable food without affecting mood and recognition memory, GLP-1-directed targeting of dexamethasone may serve as a promising and safe anti-obesity strategy.


Asunto(s)
Afecto/efectos de los fármacos , Dexametasona/farmacología , Alimentos , Péptido 1 Similar al Glucagón/farmacología , Memoria/efectos de los fármacos , Motivación/efectos de los fármacos , Recompensa , Animales , Condicionamiento Operante/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ratones
7.
Neuron ; 99(6): 1274-1288.e6, 2018 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-30236284

RESUMEN

Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.


Asunto(s)
Neuronas Aferentes/efectos de los fármacos , Dolor/tratamiento farmacológico , Receptores Opioides kappa/antagonistas & inhibidores , Transducción de Señal/fisiología , Animales , Axones/fisiología , Ratones , Ratones Transgénicos , Neuronas/fisiología , Nociceptores/efectos de los fármacos , Nociceptores/metabolismo , Manejo del Dolor , Receptores Opioides kappa/metabolismo
8.
Front Mol Neurosci ; 11: 126, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29706867

RESUMEN

Environmental enrichment (EE) is a powerful stimulus of brain plasticity and is among the most accessible treatment options for brain disease. In rodents, EE is modeled using multi-factorial environments that include running, social interactions, and/or complex surroundings. Here, we show that running and running-independent EE differentially affect the hippocampal dentate gyrus (DG), a brain region critical for learning and memory. Outbred male CD1 mice housed individually with a voluntary running disk showed improved spatial memory in the radial arm maze compared to individually- or socially-housed mice with a locked disk. We therefore used RNA sequencing to perform an unbiased interrogation of DG gene expression in mice exposed to either a voluntary running disk (RUN), a locked disk (LD), or a locked disk plus social enrichment and tunnels [i.e., a running-independent complex environment (CE)]. RNA sequencing revealed that RUN and CE mice showed distinct, non-overlapping patterns of transcriptomic changes versus the LD control. Bio-informatics uncovered that the RUN and CE environments modulate separate transcriptional networks, biological processes, cellular compartments and molecular pathways, with RUN preferentially regulating synaptic and growth-related pathways and CE altering extracellular matrix-related functions. Within the RUN group, high-distance runners also showed selective stress pathway alterations that correlated with a drastic decline in overall transcriptional changes, suggesting that excess running causes a stress-induced suppression of running's genetic effects. Our findings reveal stimulus-dependent transcriptional signatures of EE on the DG, and provide a resource for generating unbiased, data-driven hypotheses for novel mediators of EE-induced cognitive changes.

9.
Mol Metab ; 10: 1-13, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29454579

RESUMEN

OBJECTIVE: The incidence of depression is significantly compounded by obesity. Obesity arising from excessive intake of high-fat food provokes anxiodepressive behavior and elicits molecular adaptations in the nucleus accumbens (NAc), a region well-implicated in the hedonic deficits associated with depression and in the control of food-motivated behavior. To determine the etiology of diet-induced depression, we studied the impact of different dietary lipids on anxiodepressive behavior and metabolic and immune outcomes and the contribution of NAc immune activity. METHODS: Adult C57Bl/6 mice were subjected to isocaloric high-fat/high-sucrose diets (HFD), enriched in either saturated or monounsaturated fat, or a control low-fat diet (LFD). Metabolic responses, anxiodepressive behavior, and plasma and NAc inflammatory markers were assessed after 12 weeks. In separate experiments, an adenoviral construct inhibiting IKKß, an upstream component of the nuclear factor kappa-b (NFkB) pathway, was a priori injected into the NAc. RESULTS: Both HFDs resulted in obesity and hyperleptinemia; however, the saturated HFD uniquely triggered anxiety-like behavior, behavioral despair, hyperinsulinemia, glucose intolerance, peripheral inflammation, and multiple pro-inflammatory signs in the NAc, including reactive gliosis, increased expression of cytokines, antigen-presenting markers and NFкB transcriptional activity. Selective NAc IKKß inhibition reversed the upregulated expression of inflammatory markers, prevented anxiodepressive behavior and blunted compulsive sucrose-seeking in mice fed the saturated HFD. CONCLUSIONS: Metabolic inflammation and NFкB-mediated neuroinflammatory responses in the NAc contribute to the expression of anxiodepressive behavior and heightened food cravings caused by a diet high in saturated fat and sugar.


Asunto(s)
Trastornos de Ansiedad/metabolismo , Trastorno Depresivo/metabolismo , Adicción a la Comida/metabolismo , Núcleo Accumbens/metabolismo , Animales , Trastornos de Ansiedad/etiología , Trastornos de Ansiedad/fisiopatología , Trastorno Depresivo/etiología , Trastorno Depresivo/fisiopatología , Dieta Alta en Grasa/efectos adversos , Sacarosa en la Dieta/efectos adversos , Adicción a la Comida/etiología , Adicción a la Comida/fisiopatología , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Núcleo Accumbens/patología
10.
Mine Water Environ ; 37(1): 31-41, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-31666771

RESUMEN

The exposure of readily soluble components of overburden materials from surface coal mining to air and water results in mineral oxidation and carbonate mineral dissolution, thus increasing coal mine water conductivity. A conductivity benchmark of 300 µS/cm for mine water discharges in the Appalachian region has been suggested to protect aquatic life and the environment. A USGS screening-level leach test was applied to individual strata from three cores collected from a surface mine site in the Central Appalachian region to generate preliminary conductivity rankings, which were used to classify strata for two disposal scenarios: (i) Unmodified Scenario, which included all extracted strata and (ii) Modified Scenario, which excluded 15% (by mass) of the overburden materials with the highest conductivities. We evaluated overburden leaching conductivity using EPA Method 1627 in 18 dry-wet cycles, generating conductivities of 1,020-1,150 µS/cm for the Unmodified Scenario and 624-979 µS/cm for the Modified Scenario. Hence, overburden segregation was successful in reducing the leachate conductivity, but did not reach the proposed benchmark. The leachate was dominated by sulfate in the first four cycles and by bicarbonates in cycles 5-18 in columns with higher sulfur content, while bicarbonates were dominant throughout experiments with lower sulfur content in overburden. The use of conductivity rankings, isolation of potentially problematic overburden strata, and appropriate materials management could reduce conductivity in Central Appalachian streams and other surface mining areas.

11.
Neuropsychopharmacology ; 43(3): 607-616, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28857071

RESUMEN

Long-chain fatty acids (FAs) act centrally to decrease food intake and hepatic glucose production and alter hypothalamic neuronal activity in a manner that depends on FA type and cellular transport proteins. However, it is not known whether FAs are sensed by ventral tegmental area (VTA) dopamine (DA) neurons to control food-motivated behavior and DA neurotransmission. We investigated the impact of the monounsaturated FA oleate in the VTA on feeding, locomotion, food reward, and DA neuronal activity and DA neuron expression of FA-handling proteins and FA uptake. A single intra-VTA injection of oleate, but not of the saturated FA palmitate, decreased food intake and increased locomotor activity. Furthermore, intra-VTA oleate blunted the rewarding effects of high-fat/sugar food in an operant task and inhibited DA neuronal firing. Using sorted DA neuron preparations from TH-eGFP mice we found that DA neurons express FA transporter and binding proteins, and are capable of intracellular transport of long-chain FA. Finally, we demonstrate that a transporter blocker attenuates FA uptake into DA neurons and blocks the effects of intra-VTA oleate to decrease food-seeking and DA neuronal activity. Together, these results suggest that DA neurons detect FA and that oleate has actions in the VTA to suppress DA neuronal activity and food seeking following cellular incorporation. These findings highlight the capacity of DA neurons to act as metabolic sensors by responding not only to hormones but also to FA nutrient signals to modulate food-directed behavior.


Asunto(s)
Dopamina/metabolismo , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Ácido Oléico/metabolismo , Recompensa , Área Tegmental Ventral/metabolismo , Animales , Conducta Apetitiva/fisiología , Células Cultivadas , Condicionamiento Operante/fisiología , Neuronas Dopaminérgicas/metabolismo , Ingestión de Alimentos/psicología , Conducta Alimentaria/psicología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/fisiología , Ratas Wistar
12.
Int J Dev Neurosci ; 64: 8-13, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28919371

RESUMEN

Insufficient dietary intake of essential omega-3 polyunsaturated fatty acids (N-3), especially during critical stages of development, is well-associated with negative neurological and metabolic consequences. The increased availability and intake of foods rich in saturated fat coincides with reduced N-3 consumption, yet how N-3 dietary deficiency during perinatal development modulates motivation for palatable food and interacts with a high-fat diet to affect body weight and emotional states is not clear. Pregnant C57Bl6 mice and pups were subjected to diets either deficient or adequate (control) in N-3 until postnatal day 21. Adult male N-3 deficient or control offspring were tested in a progressive ratio operant task for sucrose motivated behavior or given prolonged access to a saturated high-fat diet or chow followed by measures of energy balance and anxiety-like behavior in the elevated-plus maze and open field test. Brain fatty acid profiles were measured via gas chromatography mass spectrometry. Perinatal dietary N-3 deficiency lowered brain N-3 levels, augmented the rewarding effects of sucrose, heightened diet-induced weight gain and fat mass accumulation and diminished spontaneous physical activity. Finally, perinatal N-3 deficiency increased anxiety-like behaviour independent of diet in the open field but not in the elevated-plus maze test. Insufficient dietary N-3 during critical periods of developmental can amplify the obesogenic effects of saturated fat intake, enhance motivated behaviour for palatable foods and may elicit negative emotional states that can perpetuate overeating and obesity.


Asunto(s)
Dieta , Ácidos Grasos Omega-3/deficiencia , Obesidad/metabolismo , Recompensa , Sacarosa/farmacología , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/fisiología , Encéfalo/metabolismo , Ingestión de Alimentos/fisiología , Ácidos Grasos Omega-3/metabolismo , Femenino , Ratones , Embarazo
13.
Psychoneuroendocrinology ; 83: 142-149, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28623763

RESUMEN

Overconsumption of dietary fat can elicit impairments in emotional processes and the response to stress. While excess dietary lipids have been shown to alter hypothalamus-pituitary-adrenal (HPA) axis function and promote anxiety-like behaviour, it is not known if such changes rely on elevated body weight and if these effects are specific to the type of dietary fat. The objective of this study was to investigate the effect of a saturated and a monounsaturated high-fat diet (HFD) on HPA axis function and anxiety-like behaviour in rats. Biochemical, metabolic and behavioural responses were evaluated following eight weeks on one of three diets: (1) a monounsaturated HFD (50%kcal olive oil), (2) a saturated HFD (50%kcal palm oil), or (3) a control low-fat diet. Weight gain was similar across the three diets while visceral fat mass was elevated by the two HFDs. The saturated HFD had specific actions to increase peak plasma levels of corticosterone and tumour-necrosis-factor-alpha and suppress mRNA expression of glucocorticoid and mineralocorticoid receptors, corticotropin-releasing hormone and 11ß-hydroxysteroid dehydrogenase-1 in the paraventricular nucleus of the hypothalamus. Both HFDs enhanced the corticosterone-suppressing response to dexamethasone administration without affecting the physiological response to a restraint stress and failed to increase anxiety-like behaviour as measured in the elevated-plus maze and open field tests. These findings demonstrate that prolonged intake of saturated fat, without added weight gain, increases CORT and modulates central HPA feedback processes. That saturated HFD failed to affect anxiety-like behaviour can suggest that the anxiogenic effects of prolonged high-fat feeding may rely on more pronounced metabolic dysfunction.


Asunto(s)
Ansiedad/metabolismo , Dieta Alta en Grasa/efectos adversos , Dieta Alta en Grasa/psicología , Animales , Trastornos de Ansiedad/metabolismo , Peso Corporal , Corticosterona/análisis , Corticosterona/sangre , Hormona Liberadora de Corticotropina/metabolismo , Dexametasona/farmacología , Grasas de la Dieta/metabolismo , Modelos Animales de Enfermedad , Ácidos Grasos/efectos adversos , Ácidos Grasos/metabolismo , Ácidos Grasos Monoinsaturados/metabolismo , Glucocorticoides/farmacología , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Obesidad/metabolismo , Obesidad/psicología , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Wistar , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de Glucocorticoides/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/sangre , Aumento de Peso
14.
Cell Rep ; 17(5): 1217-1226, 2016 10 25.
Artículo en Inglés | MEDLINE | ID: mdl-27783937

RESUMEN

α/ß-Hydrolase domain 6 (ABHD6) is a monoacylglycerol hydrolase that degrades the endocannabinoid 2-arachidonoylglycerol (2-AG). Although complete or peripheral ABHD6 loss of function is protective against diet-induced obesity and insulin resistance, the role of ABHD6 in the central control of energy balance is unknown. Using a viral-mediated knockout approach, targeted endocannabinoid measures, and pharmacology, we discovered that mice lacking ABHD6 from neurons of the ventromedial hypothalamus (VMHKO) have higher VMH 2-AG levels in conditions of endocannabinoid recruitment and fail to physiologically adapt to key metabolic challenges. VMHKO mice exhibited blunted fasting-induced feeding and reduced food intake, energy expenditure, and adaptive thermogenesis in response to cold exposure, high-fat feeding, and dieting (transition to a low-fat diet). Our findings identify ABHD6 as a regulator of the counter-regulatory responses to major metabolic shifts, including fasting, nutrient excess, cold, and dieting, thereby highlighting the importance of ABHD6 in the VMH in mediating energy metabolism flexibility.


Asunto(s)
Metabolismo Energético , Hipotálamo/metabolismo , Monoacilglicerol Lipasas/metabolismo , Animales , Ácidos Araquidónicos/farmacología , Frío , Dieta Alta en Grasa , Endocannabinoides/farmacología , Metabolismo Energético/efectos de los fármacos , Eliminación de Gen , Glicéridos/farmacología , Hipotálamo/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Obesidad/metabolismo , Obesidad/patología , Reproducibilidad de los Resultados , Termogénesis/efectos de los fármacos , Pérdida de Peso/efectos de los fármacos
15.
Behav Brain Res ; 313: 201-207, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27363924

RESUMEN

Diazepam is well known for its anxiolytic properties, which are mediated via activation of the GABAA receptor. Diazepam Binding Inhibitor (DBI), also called acyl-CoA binding protein (ACBP), is a ubiquitously expressed protein originally identified based on its ability to displace diazepam from its binding site on the GABAA receptor. Central administration of ACBP or its cleaved fragment, commonly referred to as endozepines, induces proconflict and anxiety-like behaviour in rodents. For this reason, ACBP is known as an anxiogenic peptide. However, the role of endogenous ACBP in anxiety-like behaviour and anxiolytic responses to diazepam has not been investigated. To address this question, we assessed anxiety behaviour and anxiolytic responses to diazepam in two complementary loss-of-function mouse models including astrocyte-specific ACBP KO (ACBP(GFAP) KO) and whole-body KO (ACBP KO) mice. Male and female ACBP(GFAP) KO and ACBP KO mice do not show significant changes in anxiety-like behaviour compared to control littermates during elevated plus maze (EPM) and open field (OF) tests. Surprisingly, ACBP(GFAP) KO and ACBP KO mice were unresponsive to the anxiolytic effect of a low dose of diazepam during EPM tests. In conclusion, our experiments using genetic ACBP loss-of-function models suggest that endozepines deficiency does not affect anxiety-like behaviour in mice and impairs the anxiolytic action of diazepam.


Asunto(s)
Ansiolíticos/farmacología , Ansiedad/fisiopatología , Conducta Animal/efectos de los fármacos , Inhibidor de la Unión a Diazepam/metabolismo , Diazepam/farmacología , Animales , Ansiedad/tratamiento farmacológico , Proteínas Portadoras/genética , Ratones Noqueados , ARN Mensajero/metabolismo , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismo
16.
Cell Rep ; 14(12): 2872-88, 2016 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-26997277

RESUMEN

Suppression of α/ß-domain hydrolase-6 (ABHD6), a monoacylglycerol (MAG) hydrolase, promotes glucose-stimulated insulin secretion by pancreatic ß cells. We report here that high-fat-diet-fed ABHD6-KO mice show modestly reduced food intake, decreased body weight gain and glycemia, improved glucose tolerance and insulin sensitivity, and enhanced locomotor activity. ABHD6-KO mice also show increased energy expenditure, cold-induced thermogenesis, brown adipose UCP1 expression, fatty acid oxidation, and white adipose browning. Adipose browning and cold-induced thermogenesis are replicated by the ABHD6 inhibitor WWL70 and by antisense oligonucleotides targeting ABHD6. Our evidence suggests that one mechanism by which the lipolysis derived 1-MAG signals intrinsic and cell-autonomous adipose browning is via PPARα and PPARγ activation, and that ABHD6 regulates adipose browning by controlling signal competent 1-MAG levels. Thus, ABHD6 regulates energy homeostasis, brown adipose function, and white adipose browning and is a potential therapeutic target for obesity and type 2 diabetes.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Diabetes Mellitus Tipo 2/genética , Monoacilglicerol Lipasas/metabolismo , Obesidad/genética , Células 3T3-L1 , Animales , Compuestos de Bifenilo/farmacología , Carbamatos/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/prevención & control , Dieta Alta en Grasa , Diglicéridos/farmacología , Metabolismo Energético/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/genética , Actividad Motora/efectos de los fármacos , Obesidad/etiología , Obesidad/metabolismo , Obesidad/prevención & control , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , PPAR gamma/metabolismo , Termogénesis , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
17.
Artículo en Inglés | MEDLINE | ID: mdl-26888796

RESUMEN

BACKGROUND: GPR120 (FFAR4) is a G-protein coupled receptor implicated in the development of obesity and the antiinflammatory and insulin-sensitizing effects of omega-3 (ω-3) polyunsaturated fatty acids. Increasing central ω-3 polyunsaturated fatty acid levels has been shown to have both anorectic and anxiolytic actions. Despite the strong clinical interest in GPR120, its role in the brain is largely unknown, and thus we sought to determine the impact of central GPR120 pharmacological activation on energy balance, food reward, and anxiety-like behavior. METHODS: Male C57Bl/6 mice with intracerebroventricular cannulae received a single injection (0.1 or 1 µM) or continuous 2-week infusion (1 µM/d; mini-pump) of a GPR120 agonist or vehicle. Free-feeding intake, operant lever-pressing for palatable food, energy expenditure (indirect calorimetry), and body weight were measured. GPR120 mRNA expression was measured in pertinent brain areas. Anxiety-like behavior was assessed in the elevated-plus maze and open field test. RESULTS: GPR120 agonist injections substantially reduced chow intake during 4 hours postinjection, suppressed the rewarding effects of high-fat/-sugar food, and blunted approach-avoidance behavior in the open field. Conversely, prolonged central GPR120 agonist infusions reduced anxiety-like behavior in the elevated-plus maze and open field, yet failed to affect free-feeding intake, energy expenditure, and body weight on a high-fat diet. CONCLUSION: Acute reductions in food intake and food reward suggest that GPR120 could mediate the effects of central ω-3 polyunsaturated fatty acids to inhibit appetite. The anxiolytic effect elicited by GPR120 agonist infusions favors the testing of compounds that can enter the brain to activate GPR120 for the mitigation of anxiety.


Asunto(s)
Ansiedad/prevención & control , Ingestión de Alimentos/fisiología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/fisiología , Recompensa , Animales , Benzofuranos/administración & dosificación , Benzofuranos/farmacología , Peso Corporal/efectos de los fármacos , Condicionamiento Operante/fisiología , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético/efectos de los fármacos , Infusiones Intraventriculares , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Actividad Motora/efectos de los fármacos , Receptores Acoplados a Proteínas G/biosíntesis , Sulfonas/administración & dosificación , Sulfonas/farmacología
18.
Neuropsychopharmacology ; 41(3): 811-21, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26171719

RESUMEN

Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.


Asunto(s)
Dieta Alta en Grasa/efectos adversos , Dopamina/metabolismo , Núcleo Accumbens/metabolismo , Aceite de Oliva/administración & dosificación , Aceites Vegetales/administración & dosificación , Receptores de Dopamina D1/metabolismo , Anfetamina/farmacología , Animales , Benzazepinas/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , /fisiología , Dieta Alta en Grasa/métodos , Agonistas de Dopamina/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Núcleo Accumbens/efectos de los fármacos , Aceite de Palma , Distribución Aleatoria , Ratas Wistar , Receptores AMPA/metabolismo , Receptores de Dopamina D1/agonistas , Recompensa , Transducción de Señal , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiología
19.
Cell Metab ; 22(4): 741-9, 2015 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-26341832

RESUMEN

The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food.


Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Leptina/farmacología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Inmunohistoquímica , Ratones , Ratones Noqueados , Microscopía Confocal , Actividad Motora/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Leptina/metabolismo , Factor de Transcripción STAT3/deficiencia , Factor de Transcripción STAT3/genética , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo
20.
Stress ; 18(4): 381-99, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26303312

RESUMEN

This manuscript summarizes the proceedings of the symposium entitled, "Stress, Palatable Food and Reward", that was chaired by Drs. Linda Rinaman and Yvonne Ulrich-Lai at the 2014 Neurobiology of Stress Workshop held in Cincinnati, OH. This symposium comprised research presentations by four neuroscientists whose work focuses on the biological bases for complex interactions among stress, food intake and emotion. First, Dr Ulrich-Lai describes her rodent research exploring mechanisms by which the rewarding properties of sweet palatable foods confer stress relief. Second, Dr Stephanie Fulton discusses her work in which excessive, long-term intake of dietary lipids, as well as their subsequent withdrawal, promotes stress-related outcomes in mice. Third, Dr Mark Wilson describes his group's research examining the effects of social hierarchy-related stress on food intake and diet choice in group-housed female rhesus macaques, and compared the data from monkeys to results obtained in analogous work using rodents. Finally, Dr Gorica Petrovich discusses her research program that is aimed at defining cortical-amygdalar-hypothalamic circuitry responsible for curbing food intake during emotional threat (i.e. fear anticipation) in rats. Their collective results reveal the complexity of physiological and behavioral interactions that link stress, food intake and emotional state, and suggest new avenues of research to probe the impact of genetic, metabolic, social, experiential and environmental factors on these interactions.


Asunto(s)
Conducta de Elección , Ingestión de Alimentos/psicología , Emociones , Conducta Alimentaria/psicología , Estrés Psicológico/psicología , Animales , Dieta , Grasas de la Dieta , Sacarosa en la Dieta , Ingestión de Alimentos/fisiología , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Macaca mulatta , Ratones , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Recompensa , Estrés Psicológico/metabolismo
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