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Osteoporosis predisposes to fractures, which affect the quality of life and can be life-threatening. However, the knowledge, attitudes and preventive behaviors of osteoporosis in older adults are insufficient. The aim of this paper was to develop and test the effect of a bone-preserving board game program among older adults. A convenience sample of 85 older adults recruited from two community activity centers in southern Taiwan were assigned to either an experimental group or a control group. The experimental group played a bone-preserving board game for 4 weeks, and the control group participated in routine community center activities. The generalized estimating equation showed significantly larger improvements in knowledge, attitudes, and preventive behaviors in the experimental group than in the control group. Board games designed for older adults can support public health education and help prevent osteoporosis. Our results provide a reference for educators, clinical practitioners and researchers.
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Conocimientos, Actitudes y Práctica en Salud , Osteoporosis , Humanos , Anciano , Calidad de Vida , Osteoporosis/prevención & control , Educación en Salud , Conductas Relacionadas con la SaludRESUMEN
Exercise can effectively slow aging and prevent the onset and reduce the complications of chronic diseases in the elderly. However, roughly one-third of older adults are inactive. Joyful learning is an effective method for promoting physical activity, while using games is a feasible strategy for achieving joyful learning that enables individuals to fully immerse themselves in and enjoy an activity. Therefore, exploring gaming strategies to enhance physical activity among the elderly is worthwhile. In this paper, a set of gaming strategies based on the literature and practical experience is proposed. The name of this strategy, GAME, is an acronym of the following: goal setting and educational content development (G), activity design and game content creation (A), mechanics and dynamics implementation (M), and evaluation of qualitative and quantitative health outcomes (E). This systematic descriptive approach helps clearly demonstrate how gamification strategies can promote physical activity and health in older adults. The aim of this paper is to provide a reference and guide for education, research, and clinical practice in health promotion programs targeting older adults.
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Ejercicio Físico , Humanos , Ejercicio Físico/psicología , Anciano , AprendizajeRESUMEN
Older people living in long-term care facilities remain largely inactive, and therefore promoting exercise in this population is necessary. This study evaluated the efficacy of a mindfulness-based exercise program in older residents of a long-term care facility in Taiwan. A convenience sample of 72 older residents of a long-term care facility were recruited and assigned to either an experimental group or a control group. The experimental group (nâ¯=â¯36) participated in an 8-week mindfulness-based exercise program, and the control group (nâ¯=â¯36) received routine care. The generalized estimating equation showed significantly larger improvements in a fear of falling, exercise self-efficacy, dynamic balance, and muscle strength in the experimental group than in the control group from baseline to the end of the intervention and 3 months after the end of the intervention. This study provides a reference for how to improve exercise practice in older people living in long-term care facilities.
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Cuidados a Largo Plazo , Atención Plena , Humanos , Anciano , Taiwán , Miedo , Terapia por EjercicioRESUMEN
There is a growing prevalence of inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract, among the aging population. Ghrelin is a gut hormone that, in addition to controlling feeding and energy metabolism, has been shown to exert anti-inflammatory effects; however, the effect of ghrelin in protecting against colitis in old mice has not been assessed. Here, we subjected old female C57BL/6J mice to dextran sulfate sodium (DSS) in drinking water for six days, then switched back to normal drinking water, administered acyl-ghrelin or vehicle control from day 3 to 13, and monitored disease activities throughout the disease course. Our results showed that treatment of old mice with acyl-ghrelin attenuated DSS-induced colitis. Compared to the DSS group, ghrelin treatment decreased levels of the inflammation marker S100A9 in the colons collected on day 14 but not on day 8, suggesting that the anti-inflammatory effect was more prominent in the recovery phase. Ghrelin treatment also significantly reduced F4/80 and interleukin-17A on day 14. Moreover, acyl-ghrelin increased mitochondrial respiration and activated transcriptional activity of the peroxisome proliferator-activated receptor gamma (PPARγ) in Caco-2 cells. Together, our data show that ghrelin alleviated DSS-induced colitis, suggesting that ghrelin may promote tissue repair in part through regulating epithelial metabolism via PPARγ mediated signaling.
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Colitis Ulcerosa , Animales , Femenino , Ratones , Antiinflamatorios/farmacología , Células CACO-2 , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Sulfato de Dextran , Modelos Animales de Enfermedad , Ghrelina/farmacología , Ratones Endogámicos C57BL , PPAR gamma/genética , PPAR gamma/metabolismoRESUMEN
Chronic low-grade inflammation is a hallmark of aging, which is now coined as inflamm-aging. Inflamm-aging contributes to many age-associated diseases such as obesity, type 2 diabetes, cardiovascular disease, and inflammatory bowel disease (IBD). We have shown that gut hormone ghrelin, via its receptor growth hormone secretagogue receptor (GHS-R), regulates energy metabolism and inflammation in aging. Emerging evidence suggests that gut microbiome has a critical role in intestinal immunity of the host. To determine whether microbiome is an integral driving force of GHS-R mediated immune-metabolic homeostasis in aging, we assessed the gut microbiome profiles of young and old GHS-R global knockout (KO) mice. While young GHS-R KO mice showed marginal changes in Bacteroidetes and Firmicutes, aged GHS-R KO mice exhibited reduced Bacteroidetes and increased Firmicutes, featuring a disease-susceptible microbiome profile. To further study the role of GHS-R in intestinal inflammation in aging, we induced acute colitis in young and aged GHS-R KO mice using dextran sulfate sodium (DSS). The GHS-R KO mice showed more severe disease activity scores, higher proinflammatory cytokine expression, and decreased expression of tight junction markers. These results suggest that GHS-R plays an important role in microbiome homeostasis and gut inflammation during aging; GHS-R suppression exacerbates intestinal inflammation in aging and increases vulnerability to colitis. Collectively, our finding reveals for the first time that GHS-R is an important regulator of intestinal health in aging; targeting GHS-R may present a novel therapeutic strategy for prevention/treatment of aging leaky gut and inflammatory bowel disease.
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Envejecimiento/metabolismo , Colitis/metabolismo , Disbiosis/metabolismo , Receptores de Ghrelina/metabolismo , Animales , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/fisiología , Microbioma Gastrointestinal/fisiología , Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microbiota/fisiología , Obesidad/metabolismoRESUMEN
OBJECTIVE: To evaluate the effect of an enterovirus board game on improving knowledge of enterovirus for elementary school children in Taiwan. DESIGN: A pilot study with a one-group pretest-posttest design. SAMPLE: Using convenience sampling, 27 children were recruited from a single elementary school in Taiwan in June 2020. MEASUREMENTS: Demographic data were collected and the children completed an enterovirus knowledge questionnaire. Statistical analyses included descriptive statistics, McNemar test, and Wilcoxon test. INTERVENTION: Each experimental group of four to five children participated in a 40-min enterovirus board game. RESULTS: After using the board game, the children had significantly higher mean scores for enterovirus knowledge. Specifically, the children had a higher proportion of correct answers for seven questions related to enterovirus after playing the game compared to before. CONCLUSIONS: Board games designed for elementary school-aged children can support public health education and help prevent outbreaks of infectious diseases such as enterovirus.
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Enterovirus , Niño , Educación en Salud , Humanos , Proyectos Piloto , Instituciones Académicas , Encuestas y CuestionariosRESUMEN
BACKGROUND/OBJECTIVES: Ghrelin is an orexigenic hormone that increases food intake, adiposity, and insulin resistance through its receptor Growth Hormone Secretagogue Receptor (GHS-R). We previously showed that ghrelin/GHS-R signaling has important roles in regulation of energy homeostasis, and global deletion of GHS-R reduces obesity and improves insulin sensitivity by increasing thermogenesis. However, it is unknown whether GHS-R regulates thermogenic activation in adipose tissues directly. METHODS: We generated a novel adipose tissue-specific GHS-R deletion mouse model and characterized the mice under regular diet (RD) and high-fat diet (HFD) feeding. Body composition was measured by Echo MRI. Metabolic profiling was determined by indirect calorimetry. Response to environmental stress was assessed using a TH-8 temperature monitoring system. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Tissue histology was analyzed by hematoxylin/eosin and immunofluorescent staining. Expression of genes involved in thermogenesis, angiogenesis and fibrosis in adipose tissues were analyzed by real-time PCR. RESULTS: Under RD feeding, adipose tissue-specific GHS-R deletion had little or no impact on metabolic parameters. However, under HFD feeding, adipose tissue-specific GHS-R deletion attenuated diet-induced obesity and insulin resistance, showing elevated physical activity and heat production. In addition, adipose tissue-specific GHS-R deletion increased expression of master adipose transcription regulator of peroxisome proliferator-activated receptor (PPAR) γ1 and adipokines of adiponectin and fibroblast growth factor (FGF) 21; and differentially modulated angiogenesis and fibrosis evident in both gene expression and histological analysis. CONCLUSIONS: These results show that GHS-R has cell-autonomous effects in adipocytes, and suppression of GHS-R in adipose tissues protects against diet-induced obesity and insulin resistance by modulating adipose angiogenesis and fibrosis. These findings suggest adipose GHS-R may constitute a novel therapeutic target for treatment of obesity and metabolic syndrome.
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Tejido Adiposo/metabolismo , Resistencia a la Insulina/genética , Obesidad/metabolismo , Receptores de Ghrelina , Termogénesis/genética , Adipocitos/citología , Adipocitos/metabolismo , Adiponectina/metabolismo , Tejido Adiposo/irrigación sanguínea , Animales , Dieta Alta en Grasa , Fibrosis/metabolismo , Masculino , Ratones , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismoRESUMEN
Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in ß and α cells. We then generated ß-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic ß and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, ß cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.
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Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Receptores de Ghrelina/metabolismo , Animales , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Ratones , Ratones Noqueados , Receptores de Ghrelina/genéticaRESUMEN
BACKGROUND: Clinical placements play an important role in helping nursing students to achieve clinical competence, but these placements can be highly challenging and stressful. It has been shown that stress can be either a trigger or aggravating factor for ill-health in general, but studies have seldom differentiated the impact of general health status on perceived stress. This study examined factors associated with perceived stress of clinical practice among nursing students with a particular focus on the effect of general health status on stress. METHODS: This was a cross-sectional quantitative study conducted among 724 associate nursing degree students in Southern Taiwan. RESULTS: Health status scores varied from 28 to 139, with an average of 68.40 (SD = 25.75). Health status was reported to be 'good' (scores 28-55) in 35.5% of participants, moderate (scores 56-83) in 24.6%, and poor (Scores ⧠84) in 39.9% of participants. Perceived stress scores ranged from 0 to 95 points with an average score of 36.65 (SD ± 15.95). The classification and regression tree (CART) analysis showed health status as the most important factor linked to perceived stress with a Normalized Importance value of 100%. Those who reported general health status (measured through General Health Questionnaire (GHQ)-28) score of ≤34.5 perceived mild stress and those with a score of > 34.5-< 84.5 perceived moderate stress. A score of 84.5 was found to be the point of transition to perceptions of severe stress. When health status score was greater than 84.5, perceived stress was at a severe or extremely severe level. CONCLUSIONS: Our findings indicated health status as a potential measure to identify students who were most vulnerable to perceived stress. Given the cross-sectional design of this study and the bidirectional relationship between health and stress, more studies are needed to fully establish the predictive link between general health status and vulnerability to stress.
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BACKGROUND: Relocation to a long-term care (LTC) facility is a major life change for most elderly people. Following relocation, many elderly experience difficulties in adapting to changes in the living environment. Taiwan is increasingly becoming an "aging society" and the numbers of those who relocate from family residences to long-term residential care facilities have increased over years. However, in-depth evidence on the experiences of the elderly of their stay in LTC facilities in Taiwan is relatively sparse. This study aimed to explore the relocation experiences of the elderly to a LTC facility to inform policy and practice to address their needs effectively. METHODS: A qualitative study, using semi-structured in-depth interviews, was conducted to explore the experiences of 16 elderly people who have relocated to and lived in a LTC facility in Taiwan for up to a period of 12 months. All interviews were recorded, transcribed, and analyzed using grounded theory approach. RESULTS: Participants' accounts reflected four interrelated key themes: wish to minimize the burden, but stay connected with the family; perceived barriers to adaptation; valuing tailored care; and acceptance and engagement. Each theme included interrelated subthemes that influenced one another and represented the different stages in the relocation journey. Most participants viewed relocation as a way of minimizing the burden of their care from family members, but desired to keep a close connection with family and friends. Participants recounted experiences of psychological resistance while making the decision to relocate. Fear of losing autonomy and the ability to perform self-care was a major reason for resistance to adapt. Provision of tailored care was accorded much value by the participants. The decision to accept the relocation and to adapt themselves to the new environment due to their needs for constant care was explicit in some accounts. CONCLUSIONS: Relocation to LTC facility is a dynamic process in the first year of moving into the facility, and involves a range of emotions, feelings and experiences. Adaptation of the elderly into the LTC facility can be maximized if the relocation is well planned with provisions for individually tailored care and family involvement.
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Cuidados a Largo Plazo , Casas de Salud , Anciano , Familia , Humanos , Investigación Cualitativa , TaiwánRESUMEN
Bitter melon (Momordica charantia) has been used to manage diabetes and related conditions in various parts of the world. In the present study, ten compounds were isolated from acetone and methanol extracts of bitter melon. The chemical structures of compounds were unambiguously elucidated by 1D, 2D NMR, and high-resolution mass spectra. Identified compounds 1-7 exhibited significant inhibition of α-amylase and moderate inhibition of α-glucosidase activities. Momordicoside G and gentisic acid 5-O-ß-d-xyloside showed the highest inhibition of α-amylase (70.5%), and α-glucosidase (56.4%), respectively. Furthermore, molecular docking studies of isolated compounds 1-7 were able to bind to the active sites of both enzymes. Additionally, the isolated compounds 1-7 significantly attenuated lipopolysaccharide (LPS)-induced inflammation, downregulating the expression of pro-inflammatory markers NF-κB, INOS, IL-6, IL-1ß, TNF-α, and Cox-2 in murine macrophage RAW 264.7 cells. One phenolic derivative, gentisic acid 5-O-ß-d-xyloside, was isolated and identified for the first time from bitter melon, and significantly suppressed the expression of Cox-2 and IL-6 compared to the LPS-treated group. α-Amylase and α-glucosidase are targets of anti-diabetes drugs, our findings suggest that compounds purified from bitter melon may have potential to use as functional food ingredients for the prevention of type 2 diabetes and related inflammatory conditions.
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Antiinflamatorios/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Inflamación/tratamiento farmacológico , Momordica charantia/química , Antiinflamatorios/farmacología , Simulación por Computador , Hipoglucemiantes/farmacologíaRESUMEN
BACKGROUND: Thermogenic impairment promotes obesity and insulin resistance. Adiponectin is an important regulator of energy homeostasis. While many beneficial metabolic effects of adiponectin resemble that of activated thermogenesis, the role of adiponectin in thermogenesis is not clear. In this study, we investigated the role of adiponectin in thermogenesis using adiponectin-null mice (Adipoq -/-). METHODS: Body composition was measured using EchoMRI. Metabolic parameters were determined by indirect calorimetry. Insulin sensitivity was evaluated by glucose- and insulin- tolerance tests. Core body temperature was measured by a TH-8 temperature monitoring system. Gene expression was assessed by real-time PCR and protein levels were analyzed by Western blotting and immunohistochemistry. The mitochondrial density of brown adipose tissue was quantified by calculating the ratio of mtDNA:total nuclear DNA. RESULTS: Under normal housing temperature of 24 °C and ad libitum feeding condition, the body weight, body composition, and metabolic profile of Adipoq -/- mice were unchanged. Under fasting condition, Adipoq -/- mice exhibited reduced energy expenditure. Conversely, under cold exposure, Adipoq -/- mice exhibited reduced body temperature, and the expression of thermogenic regulatory genes was significantly reduced in brown adipose tissue (BAT) and subcutaneous white adipose tissue (WAT). Moreover, we observed that mitochondrial content was reduced in BAT and subcutaneous WAT, and the expression of mitochondrial fusion genes was decreased in BAT of Adipoq -/- mice, suggesting that adiponectin ablation diminishes mitochondrial biogenesis and altered mitochondrial dynamics. Our study further revealed that adiponectin deletion suppresses adrenergic activation, and down-regulates ß3-adrenergic receptor, insulin signaling, and the AMPK-SIRT1 pathway in BAT. CONCLUSIONS: Our findings demonstrate that adiponectin is an essential regulator of thermogenesis, and adiponectin is required for maintaining body temperature under cold exposure.
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Adiponectina/fisiología , Frío , Termogénesis , Adiponectina/genética , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Conducta Animal , ADN Mitocondrial/metabolismo , Ambiente , Ayuno , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés FisiológicoRESUMEN
High fructose corn syrup (HFCS) is widely used as sweetener in processed foods and soft drinks in the United States, largely substituting sucrose (SUC). The orexigenic hormone ghrelin promotes obesity and insulin resistance; ghrelin responds differently to HFCS and SUC ingestion. Here we investigated the roles of ghrelin in HFCS- and SUC-induced adiposity and insulin resistance. To mimic soft drinks, 10-week-old male wild-type (WT) and ghrelin knockout (Ghrelin-/-) mice were subjected to ad lib. regular chow diet supplemented with either water (RD), 8% HFCS (HFCS), or 10% sucrose (SUC). We found that SUC-feeding induced more robust increases in body weight and body fat than HFCS-feeding. Comparing to SUC-fed mice, HFCS-fed mice showed lower body weight but higher circulating glucose and insulin levels. Interestingly, we also found that ghrelin deletion exacerbates HFCS-induced adiposity and inflammation in adipose tissues, as well as whole-body insulin resistance. Our findings suggest that HFCS and SUC have differential effects on lipid metabolism: while sucrose promotes obesogenesis, HFCS primarily enhances inflammation and insulin resistance, and ghrelin confers protective effects for these metabolic dysfunctions.
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Adiposidad/efectos de los fármacos , Ghrelina/efectos de los fármacos , Jarabe de Maíz Alto en Fructosa/efectos adversos , Resistencia a la Insulina , Obesidad/etiología , Sacarosa/efectos adversos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Glucemia/análisis , Composición Corporal , Peso Corporal/efectos de los fármacos , Peso Corporal/etnología , Dieta/efectos adversos , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Ghrelina/genética , Ghrelina/metabolismo , Prueba de Tolerancia a la Glucosa , Jarabe de Maíz Alto en Fructosa/metabolismo , Inflamación , Insulina/sangre , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/metabolismo , Sacarosa/metabolismo , Edulcorantes/efectos adversosRESUMEN
Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsrf/f). Our data showed that GHS-R in AgRP neurons is required for ghrelin's stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.
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Proteína Relacionada con Agouti/metabolismo , Neuronas/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Fragmentos de Péptidos/metabolismo , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Termogénesis , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Metabolismo Energético , Conducta Alimentaria , Eliminación de Gen , Hormona del Crecimiento/metabolismo , Homeostasis , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Noqueados , Modelos BiológicosRESUMEN
Cholinergic neurons in the basal forebrain and the brainstem form extensive projections to a number of thalamic nuclei. Activation of cholinergic afferents during distinct behavioral states can regulate neuronal firing, transmitter release at glutamatergic and GABAergic synapses, and synchrony in thalamic networks, thereby controlling the flow of sensory information. These effects are thought to be mediated by slow and persistent increases in extracellular ACh levels, resulting in the modulation of populations of thalamic neurons over large temporal and spatial scales. However, the synaptic mechanisms underlying cholinergic signaling in the thalamus are not well understood. Here, we demonstrate highly reliable cholinergic transmission in the mouse thalamic reticular nucleus (TRN), a brain structure essential for sensory processing, arousal, and attention. We find that ACh release evoked by low-frequency stimulation leads to biphasic excitatory-inhibitory (E-I) postsynaptic responses, mediated by the activation of postsynaptic α4ß2 nicotinic ACh receptors (nAChRs) and M2 muscarinic ACh receptors (mAChRs), respectively. In addition, ACh can bind to mAChRs expressed near cholinergic release sites, resulting in autoinhibition of release. We show that the activation of postsynaptic nAChRs by transmitter release from only a small number of individual axons is sufficient to trigger action potentials in TRN neurons. Furthermore, short trains of cholinergic synaptic inputs can powerfully entrain ongoing TRN neuronal activity. Our study demonstrates fast and precise synaptic E-I signaling mediated by ACh, suggesting novel computational mechanisms for the cholinergic control of neuronal activity in thalamic circuits.
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Acetilcolina/metabolismo , Potenciales de Acción/fisiología , Núcleos Talámicos Intralaminares/fisiología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Inhibidores de la Colinesterasa/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Núcleos Talámicos Intralaminares/efectos de los fármacos , Masculino , Ratones , Neuronas/efectos de los fármacos , Fisostigmina/farmacología , Receptores Colinérgicos/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Transmisión Sináptica/efectos de los fármacosRESUMEN
Tauopathies, characterized by neurofibrillary tangles (NFTs) of phosphorylated tau proteins, are a group of neurodegenerative diseases, including frontotemporal dementia and both sporadic and familial Alzheimer's disease. Forebrain-specific over-expression of human tau(P301L), a mutation associated with frontotemporal dementia with parkinsonism linked to chromosome 17, in rTg4510 mice results in the formation of NFTs, learning and memory impairment and massive neuronal death. Here, we show that the mRNA and protein levels of NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), a recently identified survival factor for maintaining neuronal health in peripheral nerves, are reduced in rTg4510 mice prior to the onset of neurodegeneration or cognitive deficits. Two functional cAMP-response elements (CREs) were identified in the nmnat2 promoter region. Both the total amount of phospho-CRE binding protein (CREB) and the pCREB bound to nmnat2 CRE sites in the cortex and the hippocampus of rTg4510 mice are significantly reduced, suggesting that NMNAT2 is a direct target of CREB under physiological conditions and that tau(P301L) overexpression down-regulates CREB-mediated transcription. We found that over-expressing NMNAT2 or its homolog NMNAT1, but not NMNAT3, in rTg4510 hippocampi from 6 weeks of age using recombinant adeno-associated viral vectors significantly reduced neurodegeneration caused by tau(P301L) over-expression at 5 months of age. In summary, our studies strongly support a protective role of NMNAT2 in the mammalian central nervous system. Decreased endogenous NMNAT2 function caused by reduced CREB signaling during pathological insults may be one of underlying mechanisms for neuronal death in tauopathies.
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Proteína de Unión a CREB/genética , Regulación hacia Abajo , Nicotinamida-Nucleótido Adenililtransferasa/genética , Tauopatías/genética , Transcripción Genética , Animales , Secuencia de Bases , Western Blotting , Cartilla de ADN , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Hipocampo/patología , Humanos , Ratones , Ratones Transgénicos , Regiones Promotoras Genéticas , Reacción en Cadena en Tiempo Real de la Polimerasa , Tauopatías/patologíaRESUMEN
The proneural protein neurogenin 2 (NGN2) is a key transcription factor in regulating both neurogenesis and neuronal radial migration in the embryonic cerebral cortex. However, the co-factors that support the action of NGN2 in the cortex remain unclear. Here, we show that the LIM-only protein LMO4 functions as a novel co-factor of NGN2 in the developing cortex. LMO4 and its binding partner nuclear LIM interactor (NLI/LDB1/CLIM2) interact with NGN2 simultaneously, forming a multi-protein transcription complex. This complex is recruited to the E-box containing enhancers of NGN2-target genes, which regulate various aspects of cortical development, and activates NGN2-mediated transcription. Correspondingly, analysis of Lmo4-null embryos shows that the loss of LMO4 leads to impairments of neuronal differentiation in the cortex. In addition, expression of LMO4 facilitates NGN2-mediated radial migration of cortical neurons in the embryonic cortex. Our results indicate that LMO4 promotes the acquisition of cortical neuronal identities by forming a complex with NGN2 and subsequently activating NGN2-dependent gene expression.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Corteza Cerebral/embriología , Corteza Cerebral/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Técnica del Anticuerpo Fluorescente , Regulación del Desarrollo de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas de Homeodominio/genética , Hibridación in Situ , Proteínas con Dominio LIM , Ratones , Proteínas del Tejido Nervioso/genética , Unión Proteica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). METHODS: LysM-Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. RESULTS: We found that Ghsr expression in PMs was increased under HFD feeding. In vivo, HFD-fed LysM-Cre;Ghsrf/f mice exhibited significantly attenuated systemic inflammation and insulin resistance without affecting food intake or body weight. Tissue analysis showed that HFD-fed LysM-Cre;Ghsrf/f mice have significantly decreased monocyte/macrophage infiltration, pro-inflammatory activation, and lipid accumulation, showing elevated lipid-associated macrophages (LAMs) in eWAT and liver. Ex vivo, Ghsr-deficient macrophages protected against PA- or LPS-induced pro-inflammatory polarization, showing reduced glycolysis, increased fatty acid oxidation, and decreased NF-κB nuclear translocation. At molecular level, GHSR metabolically programs macrophage polarization through PKA-CREB-IRS2-AKT2 signaling pathway. CONCLUSIONS: These novel results demonstrate that macrophage GHSR plays a key role in the pathogenesis of meta-inflammation, and macrophage GHSR promotes macrophage infiltration and induces pro-inflammatory polarization. These exciting findings suggest that GHSR may serve as a novel immunotherapeutic target for the treatment of obesity and its associated comorbidity.
Asunto(s)
Resistencia a la Insulina , Receptores de Ghrelina , Ratones , Animales , Receptores de Ghrelina/genética , Receptores de Ghrelina/metabolismo , Resistencia a la Insulina/fisiología , Lipopolisacáridos/metabolismo , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones Noqueados , Obesidad/metabolismo , NutrientesRESUMEN
Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the major regions regulating cognitive and emotional behaviors, and found that the neuronal deletion of GHSR reduced DIO-induced neuroinflammation by suppressing proinflammatory chemokines/cytokines and decreasing microglial activation. Furthermore, our data showed that neuronal GHSR deletion suppresses neuroinflammation by downregulating AMPK-autophagy signaling in neurons. In conclusion, our data reveal that neuronal GHSR inhibition protects against DIO-induced depressive-like behavior and spatial cognitive dysfunction, at least in part, through AMPK-autophagy signaling-mediated neuroinflammation.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Receptores de Ghrelina , Animales , Ratones , Depresión/genética , Dieta Alta en Grasa/efectos adversos , Inflamación/complicaciones , Enfermedades Neuroinflamatorias , Neuronas , Obesidad/complicaciones , Receptores de Ghrelina/genéticaRESUMEN
GABAergic neurons in the thalamic reticular nucleus (TRN) form powerful inhibitory connections with several dorsal thalamic nuclei, thereby controlling attention, sensory processing, and synchronous oscillations in the thalamocortical system. TRN neurons are interconnected by a network of GABAergic synapses, but their properties and their role in shaping TRN neuronal activity are not well understood. Using recording techniques aimed to minimize changes in the intracellular milieu, we show that synaptic GABA(A) receptor activation triggers postsynaptic depolarizations in mouse TRN neurons. Immunohistochemical data indicate that TRN neurons express very low levels of the Cl(-) transporter KCC2. In agreement, perforated-patch recordings show that intracellular Cl(-) levels are high in TRN neurons, resulting in a Cl(-) reversal potential (E(Cl)) significantly depolarized from rest. Additionally, we find that GABA(A) receptor-evoked depolarizations are amplified by the activation of postsynaptic T-type Ca(2+) channels, leading to dendritic Ca(2+) increases and the generation of burst firing in TRN neurons. In turn, GABA-evoked burst firing results in delayed and long-lasting feedforward inhibition in thalamic relay cells. Our results show that GABA-evoked depolarizations can interact with T-type Ca(2+) channels to powerfully control spike generation in TRN neurons.