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Sodium-glucose cotransporter 2 (SGLT2) inhibitors regulate plasma glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption. This study investigated the impact of empagliflozin (EMPA), an SGLT2 inhibitor, on hypothalamic energy regulation. To directly investigate the role of SGLT2 inhibitors in the hypothalamus, we administered EMPA through intracerebroventricular (i.c.v.) injections into the murine ventricles. After dental cementing the i.c.v. cannula onto the skull, the mice were given 5 days to recover before receiving vehicle or EMPA (50 nM/2 µL) injections. In a high-fat diet (HFD)-induced obesity model, we determined the gene expression levels of agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) in the hypothalamus. Additionally, we assessed FoxO1 expression, which regulates AgRP and POMC gene transcription in hypothalamic cell lines. We found that EMPA directly influenced the expression of endogenous mRNA of POMC and AgRP, which are critical for energy homeostasis, and modulated their transcription in high-fat diet-induced obese mice. Additionally, EMPA affected the expression of FoxO1, a key transcriptional regulator of glucose homeostasis, thereby regulating the transcriptional activity of POMC and AgRP. These results indicate that EMPA significantly influences hypothalamic energy homeostasis, highlighting its potential as a regulator in obesity and T2DM management.
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TTF-1 stimulates appetite by regulating the expression of agouti-related peptide (AgRP) and proopiomelanocortin (POMC) genes in the hypothalamus of starving animals. However, the mechanism underlying TTF-1's response to decreased energy levels remains elusive. Here, we provide evidence that the NAD+-dependent deacetylase, sirtuin1 (Sirt1), activates TTF-1 in response to energy deficiency. Energy deficiency leads to a twofold increase in the expression of both Sirt1 and TTF-1, leading to the deacetylation of TTF-1 through the interaction between the two proteins. The activation of Sirt1, induced by energy deficiency or resveratrol treatment, leads to a significant increase in the deacetylation of TTF-1 and promotes its nuclear translocation. Conversely, the inhibition of Sirt1 prevents these Sirt1 effects. Notably, a point mutation in a lysine residue of TTF-1 significantly disrupts its deacetylation and thus nearly completely hinders its ability to regulate AgRP and POMC gene expression. These findings highlight the importance of energy-deficiency-induced deacetylation of TTF-1 in the control of AgRP and POMC gene expression.
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Proopiomelanocortina , Sirtuina 1 , Animales , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Hipotálamo/metabolismoRESUMEN
Eukaryotic translation initiation factor 2α (eIF2α) is a key mediator of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR). In mammals, eIF2α is phosphorylated by overnutrition-induced ER stress and is related to the development of obesity. Here, we studied the function of phosphorylated eIF2α (p-eIF2α) in agouti-related peptide (AgRP) neurons using a mouse model (AgRPeIF2αA/A) with an AgRP neuron-specific substitution from Ser 51 to Ala in eIF2α, which impairs eIF2α phosphorylation in AgRP neurons. These AgRPeIF2αA/A mice had decreases in starvation-induced AgRP neuronal activity and food intake and an increased responsiveness to leptin. Intriguingly, impairment of eIF2α phosphorylation produced decreases in the starvation-induced expression of UPR and autophagy genes in AgRP neurons. Collectively, these findings suggest that eIF2α phosphorylation regulates AgRP neuronal activity by affecting intracellular responses such as the UPR and autophagy during starvation, thereby participating in the homeostatic control of whole-body energy metabolism. ARTICLE HIGHLIGHTS: This study examines the impact of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, triggered by an energy deficit, on hypothalamic AgRP neurons and its subsequent influence on whole-body energy homeostasis. Impaired eIF2α phosphorylation diminishes the unfolded protein response and autophagy, both of which are crucial for energy deficit-induced activation of AgRP neurons. This study highlights the significance of eIF2α phosphorylation as a cellular marker indicating the availability of energy in AgRP neurons and as a molecular switch that regulates homeostatic feeding behavior.
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Factor 2 Eucariótico de Iniciación , eIF-2 Quinasa , Animales , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , eIF-2 Quinasa/metabolismo , Estrés del Retículo Endoplásmico , Factor 2 Eucariótico de Iniciación/metabolismo , Conducta Alimentaria , Mamíferos/metabolismo , Neuronas/metabolismo , Péptidos/metabolismo , Fosforilación , RatonesRESUMEN
OBJECTIVE: Thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is predominantly expressed in discrete areas of the hypothalamus, which acts as the central unit for the regulation of whole-body energy homeostasis. Current study designed to identify the roles of TTF-1 on the responsiveness of the hypothalamic circuit activity to circulating leptin and the development of obesity linked to the insensitivity of leptin. METHODS: We generated conditional knock-out mice by crossing TTF-1flox/flox mice with leptin receptor (ObRb)Cre or proopiomelanocortin (POMC)Cre transgenic mice to interrogate the contributions of TTF-1 in leptin signaling and activity. Changes of food intake, body weight and energy expenditure were evaluated in standard or high fat diet-treated transgenic mice by using an indirect calorimetry instrument. Molecular mechanism was elucidated with immunohistochemistry, immunoblotting, quantitative PCR, and promoter assays. RESULTS: The selective deletion of TTF-1 gene expression in cells expressing the ObRb or POMC enhanced the anorexigenic effects of leptin as well as the leptin-induced phosphorylation of STAT3. We further determined that TTF-1 inhibited the transcriptional activity of the ObRb gene. In line with these findings, the selective deletion of the TTF-1 gene in ObRb-positive cells led to protective effects against diet-induced obesity via the amelioration of leptin resistance. CONCLUSIONS: Collectively, these results suggest that hypothalamic TTF-1 participates in the development of obesity as a molecular component involved in the regulation of cellular leptin signaling and activity. Thus, TTF-1 may represent a therapeutic target for the treatment, prevention, and control of obesity.
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Leptina , Proopiomelanocortina , Factor Nuclear Tiroideo 1 , Animales , Ratones , Hipotálamo/metabolismo , Leptina/genética , Leptina/metabolismo , Ratones Noqueados , Obesidad/genética , Obesidad/metabolismo , Proopiomelanocortina/metabolismo , Factor Nuclear Tiroideo 1/genética , Factor Nuclear Tiroideo 1/metabolismoRESUMEN
Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-likelike 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.
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Factor de Crecimiento Epidérmico , Proteínas del Tejido Nervioso , Animales , Encefalinas , Factor de Crecimiento Epidérmico/genética , Factor de Crecimiento Epidérmico/farmacología , Expresión Génica , Ratones , Células 3T3 NIH , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Precursores de Proteínas , RatasRESUMEN
Nutrient availability and utilization in hypothalamic cells are directly associated with the regulation of whole-body energy homeostasis. Thus, establishing metabolic profiling in the hypothalamus in response to metabolic shift is valuable to better understand the underlying mechanism of appetite regulation. In the present study, we evaluate the alteration of lipophilic and hydrophilic metabolites in both the hypothalamus and serum of fasted mice. Fasted mice displayed an elevated ketone body and decreased lactate levels in the hypothalamus. In support of the metabolite data, we further confirmed that short-term food deprivation resulted in the altered expression of genes involved in cellular metabolic processes, including the shuttling of fuel sources and the production of monocarboxylates in hypothalamic astrocytes. Overall, the current study provides useful information to close the gap in our understanding of the molecular and cellular mechanisms underlying hypothalamic control of whole-body energy metabolism.
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BACKGROUND & AIMS: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous neoplasms. Although some have a relatively benign and indolent natural history, others can be aggressive and ultimately fatal. Somatostatin analogues (SSAs) improve both quality of life and survival for these patients once they develop metastatic disease. However, these drugs are costly and their cost-effectiveness is not known. METHODS: A decision-analytic model was developed and analyzed to compare two treatment strategies for patients with Stage IV GEP-NETs. The first strategy had all patients start SSA immediately while the second strategy waited, reserving SSA initiation until the patient showed signs of progression. Sensitivity analysis was performed to explore model parameter uncertainty. RESULTS: Our model of patients age 60 with metastatic GEP-NETs suggests empiric initiation of SSA led to an increase 0.62 unadjusted life-years and incremental increase in quality-adjusted life years (QALYs) of 0.44. The incremental costs were $388,966 per QALY and not cost-effective at a willingness-to-pay threshold of $100,000. Death was attributed to GEP-NETs for 94.1% of patients in the SSA arm vs. 94.9% of patients in the DELAY SSA arm. Sensitivity analysis found that the model was most sensitive to costs of SSAs. Using probabilistic sensitivity analysis, the SSA strategy was only cost-effective 1.4% of the time at a WTP threshold of $100,000 per QALY. CONCLUSIONS: Our modeling study finds it is not cost-effective to initiate SSAs at time of presentation for patients with metastatic GEP-NETs. Further clinical studies are needed to identify the optimal timing to initiate these drugs.
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Costos de los Medicamentos , Neoplasias Intestinales/tratamiento farmacológico , Tumores Neuroendocrinos/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Calidad de Vida , Somatostatina/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Simulación por Computador , Análisis Costo-Beneficio/estadística & datos numéricos , Toma de Decisiones , Progresión de la Enfermedad , Humanos , Neoplasias Intestinales/economía , Neoplasias Intestinales/mortalidad , Cadenas de Markov , Modelos Económicos , Tumores Neuroendocrinos/economía , Tumores Neuroendocrinos/mortalidad , Neoplasias Pancreáticas/economía , Neoplasias Pancreáticas/mortalidad , Años de Vida Ajustados por Calidad de Vida , Somatostatina/análogos & derivados , Somatostatina/economía , Neoplasias Gástricas/economía , Neoplasias Gástricas/mortalidadRESUMEN
Immunocompetent hosts with toxoplasmosis are usually asymptomatic. However, T. gondii can present as an acute systemic infection. Symptomatic patients usually have a benign, self-limited course that typically lasts from a few weeks to months. Herein, we present a 66-year-old immunocompetent female who developed dysphagia and new-onset cervical lymphadenopathy during pulmonary Mycobacterium avium complex treatment.
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Neurons have multiple dendrites and single axon. This neuronal polarity is gradually established during early processes of neuronal differentiation: generation of multiple neurites (stages 1-2); differentiation (stage 3) and maturation (stages 4-5) of an axon and dendrites. In this study, we demonstrated that the neuron-specific n-glycosylated protein NELL2 is important for neuronal polarization and axon growth using cultured rat embryonic hippocampal neurons. Endogenous NELL2 expression was gradually increased in parallel with the progression of developmental stages of hippocampal neurons, and overexpression of NELL2 stimulated neuronal polarization and axon growth. In line with these results, knockdown of NELL2 expression resulted in deterioration of neuronal development, including inhibition of neuronal development progression, decreased axon growth and increased axon branching. Inhibitor against extracellular signal-regulated kinase (ERK) dramatically inhibited NELL2-induced progression of neuronal development and axon growth. These results suggest that NELL2 is an important regulator for the morphological development for neuronal polarization and axon growth.
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Axones/metabolismo , Hipocampo/citología , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis , Animales , Diferenciación Celular , Polaridad Celular , Células Cultivadas , ARN Interferente Pequeño/metabolismo , Ratas , Transducción de SeñalRESUMEN
BACKGROUND: A growing body of evidence shows that hypothalamic inflammation is an important factor in the initiation of obesity. In particular, reactive gliosis accompanied by inflammatory responses in the hypothalamus are pivotal cellular events that elicit metabolic abnormalities. In this study, we examined whether MyD88 signaling in hypothalamic astrocytes controls reactive gliosis and inflammatory responses, thereby contributing to the pathogenesis of obesity. METHODS: To analyze the role of astrocyte MyD88 in obesity pathogenesis, we used astrocyte-specific Myd88 knockout (KO) mice fed a high-fat diet (HFD) for 16 weeks or injected with saturated free fatty acids. Astrocyte-specific gene expression in the hypothalamus was determined using real-time PCR with mRNA purified by the Ribo-Tag system. Immunohistochemistry was used to detect the expression of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, phosphorylated signal transducer and activator of transcription 3, and α-melanocyte-stimulating hormone in the hypothalamus. Animals' energy expenditure was measured using an indirect calorimetry system. RESULTS: The astrocyte-specific Myd88 KO mice displayed ameliorated hypothalamic reactive gliosis and inflammation induced by injections of saturated free fatty acids and a long-term HFD. Accordingly, the KO mice were resistant to long-term HFD-induced obesity and showed an improvement in HFD-induced leptin resistance. CONCLUSIONS: These results suggest that MyD88 in hypothalamic astrocytes is a critical molecular unit for obesity pathogenesis that acts by mediating HFD signals for reactive gliosis and inflammation.
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Astrocitos/metabolismo , Metabolismo Energético/fisiología , Hipotálamo/metabolismo , Inflamación/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Animales , Glucemia/metabolismo , Dieta Alta en Grasa , Gliosis/genética , Gliosis/metabolismo , Gliosis/patología , Hipotálamo/patología , Inflamación/genética , Inflamación/patología , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Transducción de Señal/fisiologíaRESUMEN
PURPOSE: Hospital bed utility and length of stay affect the healthcare budget and quality of patient care. Prior studies already show admission and operation on weekends have higher mortality rates compared with weekdays, which has been identified as the 'weekend effect.' However, discharges on weekends are also linked with quality of care, and have been evaluated in the recent decade with different dimensions. This meta-analysis aims to discuss weekend discharges associated with 30-day readmission, 30-day mortality, 30-day emergency department visits and 14-day follow-up visits compared with weekday discharges. DATA SOURCES: PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov were searched from January 2000 to November 2019. STUDY SELECTION: Preferred reporting items for systematic reviews and meta-analyses guidelines were followed. Only studies published in English were reviewed. The random-effects model was applied to assess the effects of heterogeneity among the selected studies. DATA EXTRACTION: Year of publication, country, sample size, number of weekday/weekend discharges, 30-day readmission, 30-day mortality, 30-day ED visits and 14-day appointment follow-up rate. RESULTS OF DATA SYNTHESIS: There are 20 studies from seven countries, including 13 articles from America, in the present meta-analysis. There was no significant difference in odds ratio (OR) in 30-day readmission, 30-day mortality, 30-day ED visit, and 14-day follow-up between weekday and weekend. However, the OR for 30-day readmission was significantly higher among patients in the USA, including studies with high heterogeneity. CONCLUSION: In the USA, the 30-day readmission rate was higher in patients who had been discharged on the weekend compared with the weekday. However, interpretation should be cautious because of data limitation and high heterogeneity. Further intervention should be conducted to eliminate any healthcare inequality within the healthcare system and to improve the quality of patient care.
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Alta del Paciente/estadística & datos numéricos , Alta del Paciente/normas , Garantía de la Calidad de Atención de Salud , Cuidados Posteriores/legislación & jurisprudencia , Cuidados Posteriores/estadística & datos numéricos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Humanos , Tiempo de Internación , Mortalidad , Evaluación de Resultado en la Atención de Salud , Readmisión del Paciente/estadística & datos numéricos , Factores de TiempoRESUMEN
The cytokine-like protein FAM19A5 is highly expressed in the brain, but little is known about its functions there. Here, we found that FAM19A5 was expressed in mouse hypothalamic cells expressing proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related peptide (AgRP), and in the microglia. Tumor necrosis factor-α (TNF-α), which induces inflammatory sickness responses, greatly increased hypothalamic expression of FAM19A5. Knockdown of FAM19A5 expression resulted in decreased TNF-α-induced anorexia, body weight loss and TNF-α-induced expression of inflammatory factors. In contrast, intracerebroventricular administration of FAM19A5 induced anorexia, body weight loss and hyperthermia, together with increased expression of inflammatory factors. FAM19A5 injection also induced increases in c-fos activation and POMC mRNA level in hypothalamic POMC neurons. Together, these results suggest that FAM19A5 plays an important role in hypothalamic inflammatory responses.
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Citocinas/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patología , Inflamación/metabolismo , Animales , Citocinas/administración & dosificación , Citocinas/farmacología , Humanos , Hipotálamo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Especificidad de Órganos/efectos de los fármacos , Proopiomelanocortina/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Factor de Necrosis Tumoral alfa/administración & dosificaciónRESUMEN
Tonicity-responsive enhancer binding protein (TonEBP) is a widely expressed transcription factor and is important in the regulation of inflammatory cytokines. Here, we have identified TonEBP expression in the hypothalamus, which is particularly high in proopiomelanocortin (POMC) neurons. TonEBP overexpression stimulates POMC transcription, and TonEBP haploinsufficiency in TonEBP (+/-) mice results in a decrease in hypothalamic POMC expression. TonEBP (+/-) mice show reduced sickness responses, which include anorexia and hyperthermia, that are initially induced by tumor necrosis factor (TNF)-α. TonEBP (+/-) mice also show lower levels of TNF-α-induced hypothalamic expression of POMC and pro-inflammatory cytokines. These results suggest that TonEBP is an important molecular regulator in the development of inflammatory sickness responses through the control of POMC and pro-inflammatory cytokine expression in the hypothalamus.