RESUMEN
Platelets are key contributors to allergic asthma and aspirin-exacerbated respiratory disease (AERD), an asthma phenotype involving platelet activation and IL-33-dependent mast cell activation. Human platelets express the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists decrease lung IL-33 release and airway hyperresponsiveness in mouse asthma models. We hypothesized that GLP-1R agonists reduce platelet activation and downstream platelet-mediated airway inflammation in AERD. GLP-1R expression on murine platelets was assessed using flow cytometry. We tested the effect of the GLP-1R agonist liraglutide on lysine-aspirin (Lys-ASA)-induced changes in airway resistance, and platelet-derived mediator release in a murine AERD model. We conducted a prospective cohort study comparing the effect of pretreatment with liraglutide or vehicle on thromboxane receptor agonist-induced in vitro activation of platelets from patients with AERD and nonasthmatic controls. GLP-1R expression was higher on murine platelets than on leukocytes. A single dose of liraglutide inhibited Lys-ASA-induced increases in airway resistance and decreased markers of platelet activation and recruitment to the lung in AERD-like mice. Liraglutide attenuated thromboxane receptor agonist-induced activation as measured by CXCL7 release in plasma from patients with AERD and CD62P expression in platelets from both patients with AERD (n = 31) and nonasthmatic, healthy controls (n = 11). Liraglutide, a Food and Drug Administration-approved GLP-1R agonist for treatment of type 2 diabetes and obesity, attenuates in vivo platelet activation in an AERD murine model and in vitro activation in human platelets in patients with and without AERD. These data advance the GLP-1R axis as a new target for platelet-mediated inflammation warranting further study in asthma.
Asunto(s)
Asma Inducida por Aspirina , Asma , Diabetes Mellitus Tipo 2 , Humanos , Ratones , Animales , Liraglutida/farmacología , Liraglutida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/uso terapéutico , Interleucina-33 , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios Prospectivos , Activación Plaquetaria , Aspirina/farmacología , Inflamación , Receptores de Tromboxanos/uso terapéuticoRESUMEN
AIM: To compare the incidence of adverse events (AEs) related to antiobesity medications (AOMs; glucagon-like peptide-1 receptor agonists [GLP-1RAs] vs. non-GLP-1RAs) after bariatric surgery. METHODS: This single-centre retrospective cohort included patients (aged 16-65 years) who had undergone laparoscopic Roux-en-Y gastric bypass or sleeve gastrectomy (cohort entry date) and initiated AOMs. Participants were categorized as users of US Food and Drug Administration (FDA)-approved, off-label, or GLP-1RA AOMs if documented as receiving the medication on or after cohort entry date. Non-GLP-1RA AOMs were phentermine, orlistat, topiramate, canagliflozin, dapagliflozin, empagliflozin, naltrexone, bupropion/naltrexone and phentermine/topiramate. GLP-1RA AOMs included: semaglutide, dulaglutide, exenatide and liraglutide. The primary outcome was AE incidence. Logistic regression was used to determine the association of AOM exposure with AEs. RESULTS: We identified 599 patients meeting our inclusion criteria, 83% of whom were female. Their median (interquartile range [IQR]) age was 47.8 (40.9-55.4) years. The median duration of surgery to AOM exposure was 30 months. GLP-1RAs use was not associated with higher odds of AEs: adjusted odds ratio (aOR) 1.1 (95% confidence interval [CI] 0.5-2.6) and aOR 1.1 (95% CI 0.6-2.3) for GLP-1RA versus FDA-approved and off-label AOM use, respectively. AOM initiation ≥12 months after surgery was associated with lower risk of AEs compared to <12 months (aOR 0.01 [95% CI 0.0-0.01]; p < 0.001). CONCLUSION: Our results showed that GLP-1RA AOMs were not associated with an increased risk of AEs compared to non-GLP-1RA AOMs in patients who had previously undergone bariatric surgery. Prospective studies are needed to identify the optimal timeframe for GLP-1RA initiation.
Asunto(s)
Fármacos Antiobesidad , Cirugía Bariátrica , Receptor del Péptido 1 Similar al Glucagón , Humanos , Femenino , Persona de Mediana Edad , Adulto , Masculino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Estudios Retrospectivos , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/efectos adversos , Adulto Joven , Adolescente , Cirugía Bariátrica/efectos adversos , Anciano , Liraglutida/uso terapéutico , Exenatida/uso terapéutico , Obesidad Mórbida/cirugía , Péptidos Similares al Glucagón/uso terapéutico , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/efectos adversos , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/efectos adversos , Agonistas Receptor de Péptidos Similares al GlucagónRESUMEN
AIMS: To investigate the hypothesis that weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, that also enhances GLP-1 activity - to determine the independent effects of each treatment. METHODS: A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (-390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase-4 inhibitor sitagliptin (100 mg/d) as a weight-neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x-ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal-Wallis test or Pearson's chi-squared test. RESULTS: Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA-IR). CONCLUSIONS: Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors.
Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Inhibidores de la Dipeptidil-Peptidasa IV , Estado Prediabético , Humanos , Adulto , Liraglutida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/complicaciones , Restricción Calórica , Apetito , Diabetes Mellitus Tipo 2/complicaciones , Hipoglucemiantes/efectos adversos , Fosfato de Sitagliptina/uso terapéutico , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/inducido químicamente , Inhibidores de la Dipeptidil-Peptidasa IV/efectos adversos , Peso Corporal , Ingestión de Alimentos , Distribución de la Grasa Corporal , Pérdida de Peso , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas , Enfermedades Cardiovasculares/complicacionesRESUMEN
INTRODUCTION: This is the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic gastroesophageal reflux disease (GERD). METHODS: Ninety-eight veterans with symptomatic GERD were randomly assigned to high total/high simple, high total/low simple, low total/high simple, or low total/low simple carbohydrate diet for 9 weeks. The primary outcomes were esophageal acid exposure time (AET) and total number of reflux episodes derived from 24-hour ambulatory pH monitoring. Secondary outcomes were esophageal reflux symptoms rated using the Gastroesophageal Reflux Disease Questionnaire (GERDQ) and GERD Symptom Assessment Scale (GSAS). RESULTS: Half of the subjects were White and half African American (mean age, 60.0 ± 12.5 years; mean body mass index, 32.7 ± 5.4 kg/m 2 ). There was a significant main effect of diet treatment on AET ( P = 0.001) and on the total number of reflux episodes ( P = 0.003). The change in AET in the high total/low simple group (-4.3% ± 3.8%) differed significantly from the high total/high simple control group (+3.1% ± 3.7%), (P = 0.04). The reduction in simple sugar intake averaged 62 g less per day. Subjects' ratings of symptoms improved in all carbohydrate modification groups, including significant reductions in heartburn frequency, heartburn severity, acid taste in the mouth, lump/pain in the throat or chest, and sleep disturbance. DISCUSSION: A modification of dietary carbohydrate intake that targeted a substantial reduction in the intakes of simple sugars improved pH monitoring outcomes and symptoms of GERD that profoundly affect daily life. These findings provide a feasible and clinically applicable contribution to the limited objective data existing for efficacious dietary recommendations in the routine treatment and management of GERD.
Asunto(s)
Esofagitis Péptica , Reflujo Gastroesofágico , Anciano , Humanos , Persona de Mediana Edad , Carbohidratos de la Dieta , Monitorización del pH Esofágico , Reflujo Gastroesofágico/diagnóstico , Pirosis/etiología , MonosacáridosRESUMEN
OBJECTIVE: Despite enthusiasm for low carbohydrate diets (LCDs) among patients with type 1 diabetes (T1DM), no prospective study has investigated outcomes in adolescent T1DM. We aimed to quantify a pragmatic LCD intervention's impact on glycemia, lipidemia, and quality of life (QOL) in adolescents with T1DM. RESEARCH DESIGN AND METHODS: At an academic center, we randomized 39 patients with T1DM aged 13-21 years to one of three 12-week interventions: an LCD, an isocaloric standard carbohydrate diet (SCD), or general diabetes education without a prescriptive diet. Glycemic outcomes included glycosylated hemoglobin (HbA1c) and continuous glucose monitoring. RESULTS: There were no significant differences in glycemic, lipidemic, or QOL parameters between groups at any timepoint. Median HbA1c was similar at baseline between groups and did not change appreciably (7.9%-8.4% in LCDs, 7.9%-7.9% in SCDs, and 8.2%-7.8% in controls). Change in carbohydrate consumption was minimal with only one participant reaching target carbohydrate intake. CONCLUSIONS: This pragmatic LCD intervention did not alter carbohydrate consumption or glycemia. Although this study was unable to evaluate a highly controlled LCD, it indicates that adolescents are unlikely to implement an educational LCD intervention in routine clinic settings. Thus, this approach is unlikely to effectively mitigate hyperglycemia in adolescents.
Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adolescente , Glucemia , Automonitorización de la Glucosa Sanguínea , Diabetes Mellitus Tipo 1/terapia , Dieta Baja en Carbohidratos , Hemoglobina Glucada/análisis , Humanos , Calidad de Vida , Adulto JovenRESUMEN
BACKGROUND: Obesity is a risk factor for the development of asthma. However, pharmacologic therapeutic strategies that specifically target obese asthmatics have not been identified. We hypothesize that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment inhibits aeroallergen-induced early innate airway inflammation in a mouse model of asthma in the setting of obesity. METHODS: SWR (lean) and TALLYHO (obese) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or PBS for 4 consecutive days concurrent with GLP-1RA or vehicle treatment. RESULTS: TALLYHO mice had greater Alt-Ext-induced airway neutrophilia and lung protein expression of IL-5, IL-13, CCL11, CXCL1, and CXCL5, in addition to ICAM-1 expression on lung epithelial cells compared with SWR mice, and all endpoints were reduced by GLP-1RA treatment. Alt-Ext significantly increased BALF IL-33 in both TALLYHO and SWR mice compared to PBS challenge, but there was no difference in the BALF IL-33 levels between these two strains. However, TALLYHO, but not SWR, mice had significantly higher airway TSLP in BALF following Alt-Ext challenge compared to PBS, and BALF TSLP was significantly greater in TALLYHO mice compared to SWR mice following airway Alt-Ext challenge. GLP-1RA treatment significantly decreased the Alt-Ext-induced TSLP and IL-33 release in TALLYHO mice. While TSLP or ST2 inhibition with a neutralizing antibody decreased airway eosinophils, they did not reduce airway neutrophils in TALLYHO mice. CONCLUSIONS: These results suggest that GLP-1RA treatment may be a novel pharmacologic therapeutic strategy for obese persons with asthma by inhibiting aeroallergen-induced neutrophilia, a feature not seen with either TSLP or ST2 inhibition.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Inmunidad Innata , Alternaria , Animales , Inflamación , Pulmón , Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones ObesosRESUMEN
The Medtronic MiniMed 670G system delivers insulin to patients with type 1 diabetes mellitus (T1DM) using either its hybrid closed-loop (HCL) "Auto Mode" feature or an open-loop mode. In this retrospective, cross-sectional analysis, we quantified the association between time in Auto Mode and both haemoglobin A1c (HbA1c) and time in range (TIR, sensor glucose 70-180 mg/dL) among 96 paediatric and young adult patients with T1DM. The median percentage time in Auto Mode was 38.5% (interquartile range 0%-64%). The percentage time in Auto Mode significantly correlated with HbA1c after adjustment for covariables (ß = -0.008, P = 0.014). Each daily 3.4-h increase in Auto Mode time was associated with a 0.1% decrease in HbA1c. Auto Mode time was also correlated with TIR after adjustment for covariables (ß = 0.14, P = 0.02): for each daily 8.6-h increase in Auto Mode time, TIR increased by 5%. While Auto Mode use was low, increased time in Auto Mode was associated with a significantly lower HbA1c and increased TIR. These findings emphasize the importance of identifying strategies to improve the ease of use of HCL systems.
Asunto(s)
Diabetes Mellitus Tipo 1 , Adolescente , Glucemia , Automonitorización de la Glucosa Sanguínea , Niño , Estudios Transversales , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Control Glucémico , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Sistemas de Infusión de Insulina , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: IL-33 is one of the most consistently associated gene candidates for asthma identified by using a genome-wide association study. Studies in mice and in human cells have confirmed the importance of IL-33 in inducing type 2 cytokine production from both group 2 innate lymphoid cells (ILC2s) and TH2 cells. However, there are no pharmacologic agents known to inhibit IL-33 release from airway cells. OBJECTIVE: We sought to determine the effect of glucagon-like peptide 1 receptor (GLP-1R) signaling on aeroallergen-induced airway IL-33 production and release and on innate type 2 airway inflammation. METHODS: BALB/c mice were challenged intranasally with Alternaria extract for 4 consecutive days. GLP-1R agonist or vehicle was administered starting either 2 days before the first Alternaria extract challenge or 1 day after the first Alternaria extract challenge. RESULTS: GLP-1R agonist treatment starting 2 days before the first Alternaria extract challenge decreased IL-33 release in the bronchoalveolar lavage fluid and dual oxidase 1 (Duox1) mRNA expression 1 hour after the first Alternaria extract challenge and IL-33 expression in lung epithelial cells 24 hours after the last Alternaria extract challenge. Furthermore, GLP-1R agonist significantly decreased the number of ILC2s expressing IL-5 and IL-13, lung protein expression of type 2 cytokines and chemokines, the number of perivascular eosinophils, mucus production, and airway responsiveness compared with vehicle treatment. GLP-1R agonist treatment starting 1 day after the first Alternaria extract challenge also significantly decreased eosinophilia and type 2 cytokine and chemokine expression in the airway after 4 days of Alternaria extract challenge. CONCLUSION: These results reveal that GLP-1R signaling might be a therapy to reduce IL-33 release and inhibit the ILC2 response to protease-containing aeroallergens, such as Alternaria.
Asunto(s)
Asma/inmunología , Péptido 1 Similar al Glucagón/inmunología , Receptor del Péptido 1 Similar al Glucagón/inmunología , Interleucina-33/inmunología , Alérgenos/inmunología , Alternaria/inmunología , Animales , Citocinas/inmunología , Dermatophagoides pteronyssinus/inmunología , Eosinofilia/inmunología , Femenino , Receptor del Péptido 1 Similar al Glucagón/agonistas , Inmunidad Innata , Pulmón/citología , Pulmón/inmunología , Linfocitos/inmunología , Ratones Endogámicos BALB C , Ratones Transgénicos , Moco/inmunología , Transducción de SeñalRESUMEN
Food intake induces synthesis of N-acylphosphatidylethanolamines (NAPEs) in the intestinal tract. While NAPEs exert leptin-like (leptogenic) effects, including reduced weight gain and food intake, the mechanisms by which NAPEs induce these leptogenic effects remain unclear. One key question is whether intestinal NAPEs act directly on cognate receptors or first require conversion to N-acylethanolamides (NAEs) by NAPE-hydrolyzing phospholipase D (NAPE-PLD). Previous studies using Nape-pld-/- mice were equivocal because intraperitoneal injection of NAPEs led to nonspecific aversive effects. To avoid the aversive effects of injection, we delivered NAPEs and NAEs intestinally using gut bacteria synthesizing these compounds. Unlike in wild-type mice, increasing intestinal levels of NAPE using NAPE-synthesizing bacteria in Nape-pld-/- mice failed to reduce food intake and weight gain or alter gene expression. In contrast, increasing intestinal NAE levels in Nape-pld-/- mice using NAE-synthesizing bacteria induced all of these effects. These NAE-synthesizing bacteria also markedly increased NAE levels and decreased inflammatory gene expression in omental adipose tissue. These results demonstrate that intestinal NAPEs require conversion to NAEs by the action of NAPE-PLD to exert their various leptogenic effects, so that the reduced intestinal NAPE-PLD activity found in obese subjects may directly contribute to excess food intake and obesity.
Asunto(s)
Leptina/metabolismo , Fosfatidiletanolaminas/metabolismo , Fosfolipasa D/metabolismo , Animales , Arabidopsis/enzimología , Hidrólisis , RatonesRESUMEN
Daily rhythmic processes are coordinated by circadian clocks, which are present in numerous central and peripheral tissues. In mammals, two circadian clocks, the food-entrainable oscillator (FEO) and methamphetamine-sensitive circadian oscillator (MASCO), are "black box" mysteries because their anatomical loci are unknown and their outputs are not expressed under normal physiological conditions. In the current study, the investigation of the timekeeping mechanisms of the FEO and MASCO in mice with disruption of all three paralogs of the canonical clock gene, Period, revealed unique and convergent findings. We found that both the MASCO and FEO in Per1(-/-)/Per2(-/-)/Per3(-/-) mice are circadian oscillators with unusually short (â¼21 h) periods. These data demonstrate that the canonical Period genes are involved in period determination in the FEO and MASCO, and computational modeling supports the hypothesis that the FEO and MASCO use the same timekeeping mechanism or are the same circadian oscillator. Finally, these studies identify Per1(-/-)/Per2(-/-)/Per3(-/-) mice as a unique tool critical to the search for the elusive anatomical location(s) of the FEO and MASCO.
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Ritmo Circadiano/fisiología , Conducta Alimentaria/fisiología , Metanfetamina/farmacología , Proteínas Circadianas Period/fisiología , Núcleo Supraquiasmático/fisiología , Animales , Anticipación Psicológica/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Ritmo Circadiano/efectos de los fármacos , Femenino , Privación de Alimentos/fisiología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/fisiología , Proteínas Circadianas Period/genética , FotoperiodoAsunto(s)
Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/uso terapéutico , Liraglutida/uso terapéutico , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/fisiología , Células Th2/inmunología , Animales , Células Cultivadas , Receptor del Péptido 1 Similar al Glucagón/agonistas , Humanos , Hipoglucemiantes/farmacología , Inmunidad Innata , Lactante , Interleucina-13/metabolismo , Liraglutida/farmacología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Transducción de Señal , Carga ViralRESUMEN
OBJECTIVE: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. METHODS: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. RESULTS: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. CONCLUSIONS: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and is shared with VAT, nuancing the current VAT-centric concept of IR in humans.
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Resistencia a la Insulina , Grasa Intraabdominal , Obesidad , Grasa Subcutánea , Transcriptoma , Humanos , Grasa Intraabdominal/metabolismo , Masculino , Grasa Subcutánea/metabolismo , Femenino , Persona de Mediana Edad , Adulto , Obesidad/genética , Obesidad/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Índice de Masa Corporal , Adipocitos/metabolismo , Sitios de Carácter CuantitativoRESUMEN
The methamphetamine-sensitive circadian oscillator (MASCO) is an enigmatic circadian clock whose output is observed during continuous consumption of low-dose methamphetamine. The MASCO rhythm persists when the light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) is lesioned, but the anatomical location of MASCO is unknown. We recently found that the period of the MASCO rhythm is unusually short (21 h) in mice with disruption of all three paralogs of the canonical clock gene, Period. In this study, we investigated the contribution of each Period paralog to timekeeping in MASCO. We measured wheel-running activity rhythms in intact and SCN-lesioned Per1-, 2- and 3-mutant mice administered methamphetamine, and found that none of the mice displayed a short (21-h) period, demonstrating that no single Period gene is responsible for the short-period MASCO rhythm of Per1(-/-) /Per2(-/-) /Per3(-/-) mice. We also found that the periods of activity rhythms in constant darkness were lengthened by methamphetamine treatment in intact wild-type, Per1(-/-) and Per3(-/-) mice but not Per2(-/-) mice, and Per2(-/-) mice had two distinct activity rhythms upon release to constant light. These data suggest that the SCN and MASCO are not coupled in Per2(-/-) mice. The MASCO rhythm in Per1(-/-) /Per2(-/-) mice in constant darkness alternated between a short (22-h) and a long (27-h) period. This pattern could result from two coupled oscillators that are not synchronised to each other, or from a single oscillator displaying birhythmicity. Finally, we propose a working model of the in vivo relationship between MASCO and the SCN that poses testable hypotheses for future studies.
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Estimulantes del Sistema Nervioso Central/farmacología , Ritmo Circadiano/fisiología , Metanfetamina/farmacología , Proteínas Circadianas Period/metabolismo , Animales , Ritmo Circadiano/efectos de los fármacos , Femenino , Luz , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Proteínas Circadianas Period/genética , Núcleo Supraquiasmático/efectos de los fármacos , Núcleo Supraquiasmático/lesiones , Núcleo Supraquiasmático/fisiologíaRESUMEN
The organisation of timing in mammalian circadian clocks optimally coordinates behavior and physiology with daily environmental cycles. Chronic consumption of a high-fat diet alters circadian rhythms, but the acute effects on circadian organisation are unknown. To investigate the proximate effects of a high-fat diet on circadian physiology, we examined the phase relationship between central and peripheral clocks in mice fed a high-fat diet for 1 week. By 7 days, the phase of the liver rhythm was markedly advanced (by 5 h), whereas rhythms in other tissues were not affected. In addition, immediately upon consumption of a high-fat diet, the daily rhythm of eating behavior was altered. As the tissue rhythm of the suprachiasmatic nucleus was not affected by 1 week of high-fat diet consumption, the brain nuclei mediating the effect of a high-fat diet on eating behavior are likely to be downstream of the suprachiasmatic nucleus.
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Ritmo Circadiano/fisiología , Dieta Alta en Grasa/efectos adversos , Conducta Alimentaria/fisiología , Actividad Motora/fisiología , Animales , Mediciones Luminiscentes , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2(R899X) was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2(R899X) mice treated with dexamethasone. Compared to controls, Bmpr2(R899X) mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0 ± 0.4 versus 2.2 ± 1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2(R899X) mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.
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Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Hipertensión Pulmonar/tratamiento farmacológico , Resistencia a la Insulina , Animales , Composición Corporal , Línea Celular , Dexametasona/farmacología , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Metabolismo Energético , Humanos , Hipertensión Pulmonar/metabolismo , Masculino , Ratones , Ratones Transgénicos , Mutación , Fenotipo , Transporte de Proteínas , Ratas , Receptores de Glucocorticoides/metabolismoRESUMEN
The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multimeric signaling unit that phosphorylates protein kinase B/Akt following hormonal and growth factor stimulation. Defective Akt phosphorylation at the mTORC2-catalyzed Ser473 site has been linked to schizophrenia. While human imaging and animal studies implicate a fundamental role for Akt signaling in prefrontal dopaminergic networks, the molecular mechanisms linking Akt phosphorylation to specific schizophrenia-related neurotransmission abnormalities have not yet been described. Importantly, current understanding of schizophrenia suggests that cortical decreases in DA neurotransmission and content, defined here as cortical hypodopaminergia, contribute to both the cognitive deficits and the negative symptoms characteristic of this disorder. We sought to identify a mechanism linking aberrant Akt signaling to these hallmarks of schizophrenia. We used conditional gene targeting in mice to eliminate the mTORC2 regulatory protein rictor in neurons, leading to impairments in neuronal Akt Ser473 phosphorylation. Rictor-null (KO) mice exhibit prepulse inhibition (PPI) deficits, a schizophrenia-associated behavior. In addition, they show reduced prefrontal dopamine (DA) content, elevated cortical norepinephrine (NE), unaltered cortical serotonin (5-HT), and enhanced expression of the NE transporter (NET). In the cortex, NET takes up both extracellular NE and DA. Thus, we propose that amplified NET function in rictor KO mice enhances accumulation of both NE and DA within the noradrenergic neuron. This phenomenon leads to conversion of DA to NE and ultimately supports both increased NE tissue content as well as a decrease in DA. In support of this hypothesis, NET blockade in rictor KO mice reversed cortical deficits in DA content and PPI, suggesting that dysregulation of DA homeostasis is driven by alteration in NET expression, which we show is ultimately influenced by Akt phosphorylation status. These data illuminate a molecular link, Akt regulation of NET, between the recognized association of Akt signaling deficits in schizophrenia with a specific mechanism for cortical hypodopaminergia and hypofunction. Additionally, our findings identify Akt as a novel modulator of monoamine homeostasis in the cortex.
Asunto(s)
Proteínas Portadoras/fisiología , Dopamina/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/fisiología , Corteza Prefrontal/metabolismo , Esquizofrenia/fisiopatología , Animales , Proteínas Portadoras/genética , Ratones , Ratones Noqueados , Fosforilación , Proteínas Proto-Oncogénicas c-akt/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina , Serina/metabolismo , Transducción de Señal , Transactivadores/metabolismo , Factores de TranscripciónRESUMEN
As the worldwide prevalence of overweight and obesity continues to rise, so too does the urgency to fully understand mediating mechanisms, to discover new targets for safe and effective therapeutic intervention, and to identify biomarkers to track obesity and the success of weight loss interventions. In 2016, the American Heart Association sought applications for a Strategically Focused Research Network (SFRN) on Obesity. In 2017, 4 centers were named, including Johns Hopkins University School of Medicine, New York University Grossman School of Medicine, University of Alabama at Birmingham, and Vanderbilt University Medical Center. These 4 centers were convened to study mechanisms and therapeutic targets in obesity, to train a talented cadre of American Heart Association SFRN-designated fellows, and to initiate and sustain effective and enduring collaborations within the individual centers and throughout the SFRN networks. This review summarizes the central themes, major findings, successful training of highly motivated and productive fellows, and the innovative collaborations and studies forged through this SFRN on Obesity. Leveraging expertise in in vitro and cellular model assays, animal models, and humans, the work of these 4 centers has made a significant impact in the field of obesity, opening doors to important discoveries, and the identification of a future generation of obesity-focused investigators and next-step clinical trials. The creation of the SFRN on Obesity for these 4 centers is but the beginning of innovative science and, importantly, the birth of new collaborations and research partnerships to propel the field forward.
Asunto(s)
American Heart Association , Sobrepeso , Animales , Humanos , Sobrepeso/epidemiología , Sobrepeso/terapia , Obesidad/epidemiología , Obesidad/terapia , Causalidad , New YorkRESUMEN
Elevated plasma triglyceride (TG) levels contribute to an atherogenic dyslipidemia that is associated with obesity, diabetes, and metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone that contributes to excess food intake and obesity. Previously, we demonstrated that intracerebroventricular (icv) administration of NPY in lean fasted rats also elevates hepatic production of very low-density lipoprotein (VLDL)-TG. Thus, we hypothesize that elevated CNS NPY action contributes to not only the pathogenesis of obesity but also dyslipidemia. Here, we sought to determine whether the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. Pair-fed, icv NPY-treated, chow-fed Long-Evans rats develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation compared with vehicle-treated controls. We then modulated CNS NPY signaling by icv injection of selective NPY receptor agonists and found that Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean, ad libitum chow-fed Long-Evans rats, with the Y2 receptor agonist having the most pronounced effect. Next, we found that at equipotent doses for food intake NPY Y1 receptor agonist had the most robust effect on VLDL-TG secretion, a Y2 receptor agonist had a modest effect, and no effect was observed for Y4 and Y5 receptor agonists. These findings, using selective agonists, suggest the possibility that the effect of CNS NPY signaling on hepatic VLDL-TG secretion may be relatively dissociable from effects on feeding behavior via the Y1 receptor.
Asunto(s)
Sistema Nervioso Central/metabolismo , Hiperfagia/metabolismo , Lipoproteínas VLDL/metabolismo , Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/metabolismo , Transducción de Señal , Animales , Regulación del Apetito/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Humanos , Hiperfagia/sangre , Hiperfagia/inducido químicamente , Hiperfagia/fisiopatología , Infusiones Intraventriculares , Lipoproteínas VLDL/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Proteínas del Tejido Nervioso/administración & dosificación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptido Y/administración & dosificación , Neuropéptido Y/análogos & derivados , Neuropéptido Y/genética , Obesidad/etiología , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratas , Ratas Long-Evans , Receptores de Neuropéptido Y/agonistas , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Despite a global obesity epidemic suggesting that human physiology is unable to prevent unhealthy gains in body weight, ample evidence indicates that weight can be tightly regulated. Food intake regulation is complex and in this article we will present a basic endocrine feedback loop model of energy homeostasis. Next, integration of long-term regulation with short-term, meal specific regulation and satiety will be discussed. Finally, the role of adiposity signals in modulation of food reward will be highlighted. A basic understanding of the structure-function of these systems will inform the challenges of clinical care for those with disorders of energy balance.