RESUMEN
In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs.
Asunto(s)
Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Cristalografía por Rayos X/métodos , Conformación Proteica , Animales , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genética , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de la Hormona Gastrointestinal/química , Receptores de la Hormona Gastrointestinal/genética , Péptido 1 Similar al Glucagón/metabolismo , Modelos Moleculares , Unión Proteica , Transducción de Señal , Receptores de Glucagón/metabolismo , Receptores de Glucagón/genética , Receptores de Glucagón/químicaRESUMEN
Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.
Asunto(s)
Hepatocitos , Células Madre Pluripotentes Inducidas , Inflamación , Resistencia a la Insulina , Hígado , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Inflamación/metabolismo , Inflamación/patología , Adipocitos/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Hígado Graso/metabolismo , Hígado Graso/patología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/genética , Tejido Adiposo/metabolismo , Sistemas MicrofisiológicosRESUMEN
OBJECTIVE: Glucagon-like peptide-1 (GLP1) and leptin (Lep) are afferent signals that regulate energy metabolism. Lactational hypernutrition results in hyperphagia and adiposity in adult life, and these events can be prevented by exercise. We evaluated the effects of swimming training on hypothalamic (GLP1-R) and Lep receptor (Lep-R) gene expressions in lactational hypernutrition-induced obesity. METHODS: On the 3rd postnatal day, the litter sizes of lactating dams were adjusted to small litters (SL; 3 pups/dams) or normal litters (NL; 9 pups/dams). After weaning (21 days), NL and SL male rats were randomly distributed to sedentary (Sed) and exercised (Exe) groups. Exercised mice swam (30 min/3 times/week) for 68 days. Food intake and body weight gain were registered. At 92 days, intraperitoneal glucose and insulin tolerance tests were performed and rats were euthanized at 93 days; adipose tissue depots were weighed, and blood counts and plasma biochemical analyses performed. Hypothalamus were isolated to evaluate Lep-R and GLP1-R gene expressions. RESULTS: Small litters sedentary rats presented increased body weight gain, adiposity, insulin sensibility and higher fasting values of glucose and triglycerides, besides higher hypothalamic gene expressions of Lep-R and GLP1-R, compared to NLSed animals. SLExe rats did not develop obesity or metabolic abnormalities and Lep-R and GLP1-R hypothalamic gene expressions were normalized. CONCLUSION: Lactational hypernutrition induces obesity and metabolic dysfunction in adult life, in association with higher hypothalamic expressions of the Lep-R and GLP1-R genes. Exercise prevented obesity and improved metabolic state in SL overnourished rats, and normalized their hypothalamic Lep-R and GLP1-R gene expressions.
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Hipotálamo , Obesidad , Condicionamiento Físico Animal , Ratas Wistar , Receptores de Leptina , Natación , Animales , Hipotálamo/metabolismo , Obesidad/metabolismo , Obesidad/genética , Obesidad/prevención & control , Condicionamiento Físico Animal/fisiología , Condicionamiento Físico Animal/métodos , Masculino , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Femenino , Natación/fisiología , Tamaño de la Camada , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genética , Ratas , Lactancia/metabolismo , Lactancia/fisiología , Péptido 1 Similar al Glucagón/metabolismo , Leptina/sangre , Leptina/metabolismo , Distribución Aleatoria , Expresión Génica , Ingestión de Alimentos/fisiología , Adiposidad/fisiologíaRESUMEN
Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Liraglutida , Neuronas , Liraglutida/farmacología , Animales , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/genética , Ratones , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Núcleos Septales/metabolismo , Núcleos Septales/efectos de los fármacos , Masculino , Pérdida de Peso/efectos de los fármacos , Depresores del Apetito/farmacologíaRESUMEN
BACKGROUND: The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans. METHODS: In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests. FINDINGS: 24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred. INTERPRETATION: In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters. FUNDING: Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.
Asunto(s)
Estudios Cruzados , Receptor del Péptido 1 Similar al Glucagón , Péptidos Similares al Glucagón , Fragmentos Fc de Inmunoglobulinas , Proteínas Recombinantes de Fusión , Humanos , Masculino , Fragmentos Fc de Inmunoglobulinas/farmacología , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/farmacología , Péptidos Similares al Glucagón/uso terapéutico , Adulto , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Persona de Mediana Edad , Adulto Joven , Método Doble Ciego , Adolescente , Testosterona/análogos & derivados , Hormona Luteinizante/sangreRESUMEN
Crotamine (Ctm) is a peptide isolated from Crotalus durissus terrificus venom. This molecule has been demonstrated to diminish body weight gain and enhance browning in adipose tissue, glucose tolerance, and insulin sensitivity; hence, it has been postulated as an anti-obesogenic peptide. However, the mechanism to elicit the anti-obesogenic effects has yet to be elucidated. Thus, we investigated the possible interaction of Ctm with receptors involved in obesity-related metabolic pathways through protein-protein docking and molecular dynamics refinement. To test the anti-obesogenic mechanism of Ctm, we selected and retrieved 18 targets involved in obesity-related drug discovery from Protein Data Bank. Then, we performed protein-protein dockings. The best three Ctm-target models were selected and refined by molecular dynamics simulations. Molecular docking demonstrated that Ctm was able to interact with 13 of the 18 targets tested. Having a better docking score with glucagon-like peptide-1 receptor (GLP-1R) (-1430.2 kcal/mol), DPP-IV (dipeptidyl peptidase-IV) (-1781.7 kcal/mol) and α-glucosidase (-1232.3 kcal/mol). These three models were refined by molecular dynamics. Ctm demonstrated a higher affinity for GLP-1R (ΔG: -41.886 ± 2.289 kcal/mol). However, Ctm interaction was more stable with DPP-IV (RMSD: 0.360 ± 0.015 nm, Radius of gyration: 2.781 ± 0.009 nm). Moreover, the number of interactions and the molecular mechanics energies of Ctm residues suggest that the interaction of Ctm with these receptors is mainly mediated by basic-hydrophobic dyads Y1-K2, W31-R32, and W33-R34. Together, all these results allow elucidating a possible molecular mechanism behind the previously described anti-obesogenic effects.
Asunto(s)
Venenos de Crotálidos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Obesidad , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Venenos de Crotálidos/química , Venenos de Crotálidos/metabolismo , Animales , Humanos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/química , Dipeptidil Peptidasa 4/metabolismo , Dipeptidil Peptidasa 4/química , Redes y Vías Metabólicas , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/químicaRESUMEN
BACKGROUND: Epilepsy is a prevalent disorder of the central nervous system. Approximately, one-third of patients show resistance to pharmacological interventions. The pathogenesis of epilepsy is complex, and neuronal apoptosis plays a critical role. Aberrantly reactive astrocytes, induced by cytokine release from activated microglia, may lead to neuronal apoptosis. This study investigated the role of glucagon-like peptide 1 receptor (GLP1R) in microglial activation in epilepsy and its impact on astrocyte-mediated neurotoxicity. METHODS: We used human hippocampal tissue from patients with temporal lobe epilepsy and a pilocarpine-induced epileptic mouse model to assess neurobiological changes in epilepsy. BV2 microglial cells and primary astrocytes were used to evaluate cytokine release and astrocyte activation in vitro. The involvement of GLP1R was explored using the GLP1R agonist, Exendin-4 (Ex-4). RESULTS: Our findings indicated that reduced GLP1R expression in hippocampal microglia in both epileptic mouse models and human patients, correlated with increased cytokine release and astrocyte activation. Ex-4 treatment restored microglial homeostasis, decreased cytokine secretion, and reduced astrocyte activation, particularly of the A1 phenotype. These changes were associated with a reduction in neuronal apoptosis. In addition, Ex-4 treatment significantly decreased the frequency and duration of seizures in epileptic mice. CONCLUSIONS: This study highlights the crucial role of microglial GLP1R in epilepsy pathophysiology. GLP1R downregulation contributes to microglial- and astrocyte-mediated neurotoxicity, exacerbating neuronal death and seizures. Activation of GLP1R with Ex-4 has emerged as a promising therapeutic strategy to reduce neuroinflammation, protect neuronal cells, and control seizures in epilepsy. This study provides a foundation for developing novel antiepileptic therapies targeting microglial GLP1R, with the potential to improve outcomes in patients with epilepsy.
Asunto(s)
Apoptosis , Receptor del Péptido 1 Similar al Glucagón , Hipocampo , Microglía , Neuronas , Animales , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Apoptosis/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Exenatida/farmacología , Exenatida/uso terapéutico , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Epilepsia/inducido químicamente , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Femenino , Adulto , Pilocarpina , Modelos Animales de Enfermedad , Citocinas/metabolismo , Ratones Endogámicos C57BL , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/patología , Persona de Mediana EdadRESUMEN
We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by -1.5 ± 0.6, -1.3 ± 0.4 and -1.9 ± 0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.
Asunto(s)
Peso Corporal , Dieta Alta en Grasa , Ingestión de Energía , Receptor del Péptido 1 Similar al Glucagón , Ratones Obesos , Obesidad , Animales , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Femenino , Masculino , Ratones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ratones Noqueados , Ratones Endogámicos C57BLRESUMEN
As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 µM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.
Asunto(s)
Receptor del Péptido 1 Similar al Glucagón , Tiofenos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Animales , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Regulación Alostérica/efectos de los fármacos , Ratones , Humanos , Relación Estructura-Actividad , Estructura Molecular , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Insulina/metabolismo , Fosfato de Sitagliptina/farmacología , Fosfato de Sitagliptina/síntesis química , Fosfato de Sitagliptina/químicaRESUMEN
Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain-gut-microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials.
Asunto(s)
Fármacos Antiobesidad , Obesidad , Humanos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/farmacología , Animales , Metabolismo Energético/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal/efectos de los fármacosRESUMEN
OBJECTIVES: Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment. METHODS: We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period. RESULTS: AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects. CONCLUSIONS: This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.
Asunto(s)
Liraglutida , Macaca fascicularis , Obesidad , Receptores de la Hormona Gastrointestinal , Pérdida de Peso , Animales , Humanos , Liraglutida/farmacología , Liraglutida/administración & dosificación , Pérdida de Peso/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Masculino , Receptores de la Hormona Gastrointestinal/antagonistas & inhibidores , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Células HEK293 , Dieta Alta en Grasa/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Péptido 1 Similar al Glucagón , Glucemia/efectos de los fármacos , Glucemia/metabolismoRESUMEN
Various small molecule GLP1R agonists have been developed and tested for treating type 2 diabetes (T2DM) and obesity. However, many of these new compounds have drawbacks, such as potential hERG inhibition, lower activity compared to natural GLP-1, limited oral bioavailability in cynomolgus monkeys, and short duration of action. Recently, a new category of 3-phenyloxetane derivative GLP1R agonists with enhanced hERG inhibition has been discovered. Using an AIDD/CADD method, compound 14 (DD202-114) was identified as a potent and selective GLP1R agonist, which was chosen as a preclinical candidate (PCC). Compound 14 demonstrates full agonistic efficacy in promoting cAMP accumulation and possesses favorable drug-like characteristics compared to the clinical drug candidate Danuglipron. Additionally, in hGLP-1R knock-in mice, compound 14 displayed a sustained pharmacological effect, effectively reducing blood glucose levels and food intake. These findings suggest that compound 14 holds promise as a future treatment option for T2DM and obesity, offering improved properties.
Asunto(s)
Diseño de Fármacos , Receptor del Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Animales , Humanos , Ratones , Relación Estructura-Actividad , Masculino , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Receptores de Glucagón/agonistas , Receptores de Glucagón/metabolismoRESUMEN
GLP-1 (Glucagon-like peptide 1) serves as both a peptide hormone and a growth factor, is released upon nutrient intake and contributes to insulin secretion stimulated by glucose levels. Also, GLP-1 is synthesized within several brain areas and plays a vital function in providing neuroprotection and reducing inflammation through the activation of the GLP-1 receptor. Parkinson's Disease (PD) is a neurodegenerative illness that worsens with time and is defined by considerable morbidity. Presently, there are few pharmaceutical choices available, and none of the existing therapies are capable of modifying the course of the disease. There is a suggestion that type 2 diabetes mellitus (T2DM) could increase the risk of PD, and the presence of both conditions concurrently might exacerbate PD symptoms and hasten neurodegeneration. GLP-1 receptor (GLP-1R) agonists exhibit numerous implications like enhancement of glucose-dependent insulin release and biosynthesis, suppression of glucagon secretion and gastric emptying. Also, some GLP-1R agonists have received clinical approval for the management of T2DM. Moreover, the use of GLP-1R agonists has demonstrated counter-inflammatory, neurotrophic, and neuroprotective actions in various preclinical models of neurodegenerative disorders. Considering the significant amount of evidence backing the potential of GLP-1R agonists to protect the nervous system across different research settings, this article delves into examining the hopeful prospect of GLP-1R agonists as a treatment option for PD. This review sheds light on combined neuroprotective benefits of GLP-1R agonists and the possible mechanisms driving the protective effects on the PD brain, through the collection of data from various preclinical and clinical investigations.
Asunto(s)
Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Insulina , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Insulina/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacologíaRESUMEN
OBJECTIVE: To investigate the impact of the glucagon-like peptide-1 (GLP-1) receptor agonist Exendin-4 on the proportion of myeloid-derived suppressor cells (MDSCs) in male ApoE-/- mice, and investigate alterations in the concentrations of inflammatory factors in plasma and spleen tissues and assess their correlation with MDSCs. METHODS: Thirty male ApoE-/- mice were randomly divided into five groups (n = 6 per group): control group (CON), model group (MOD), Exendin-4 intervention group (MOD/Ex-4), Exendin-9-39 intervention group (MOD/Ex-9-39), and Exendin-4 + Exendin-9-39 combined intervention group (MOD/Ex-4 + Ex-9-39). After 4 weeks of drug intervention, changes in aortic plaque were observed using Oil Red O staining and H&E staining. Flow cytometry was employed to detect the content of myeloid-derived suppressor cells (MDSCs) in bone marrow and peripheral blood. ELISA was utilized to measure the concentrations of inflammatory factors in mouse peripheral blood plasma, while RT-qPCR was employed to quantify the expression levels of inflammatory factors in the spleen. Pearson correlation analysis was conducted to assess the relationship between MDSCs and inflammatory factors. RESULTS: Mice in the MOD group had significantly higher body weight compared to the CON group, with a statistically significant difference (P<0.05). Following Exendin-4 intervention, body weight was reduced compared to the MOD group (P<0.05). Additionally, Exendin-4 treatment led to a significant reduction in atherosclerotic plaque compared to the MOD group (P<0.001). After Exendin-4 intervention, the proportion of MDSCs in the bone marrow was higher than in the MOD group (P<0.001), and the proportion of MDSCs in peripheral blood was significantly higher than in the MOD group (P<0.05). Further investigation revealed that Exendin-4 could regulate lipid levels in mice, decreasing concentrations of TG (P<0.01), TC (P<0.0001), and LDL-C (P<0.0001), while increasing HDL-C concentrations (P<0.01). Moreover, after Exendin-4 treatment, the level of the cytokine IL-6 in peripheral plasma was significantly lower compared to the MOD group (P<0.0001), while levels of IL-10 and TGF-ß were significantly higher compared to the MOD group (P<0.0001). In the spleen, levels of the cytokines IL-10 (P<0.0001) and TGF-ß (P<0.001) were significantly increased compared to the MOD group. Pearson correlation analysis showed that the proportion of MDSCs in peripheral blood was positively correlated with IL-10 and TGF-ß levels in both the spleen and peripheral blood. Additionally, the proportion of MDSCs in the bone marrow was positively correlated with IL-10 and TGF-ß levels in the spleen and peripheral blood. CONCLUSION: Exendin-4 alleviates the severity of atherosclerosis. This process may be achieved by promoting the secretion of myeloid-derived suppressor cells (MDSCs) in the bone marrow and peripheral blood of atherosclerotic ApoE-/- mice, regulating the ratio of inflammatory factors in the body, reducing mouse body weight, and lowering blood lipids.
Asunto(s)
Apolipoproteínas E , Aterosclerosis , Citocinas , Exenatida , Células Supresoras de Origen Mieloide , Animales , Exenatida/farmacología , Exenatida/uso terapéutico , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/metabolismo , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/inmunología , Masculino , Citocinas/metabolismo , Citocinas/sangre , Ratones , Apolipoproteínas E/genética , Bazo/inmunología , Bazo/efectos de los fármacos , Placa Aterosclerótica/tratamiento farmacológico , Ratones Endogámicos C57BL , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Ratones Noqueados , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Fragmentos de PéptidosRESUMEN
Aim: The purpose of this work was to determine the feasibility of supporting a clinical microdose study for PF-06882961 (danuglipron), an oral small molecule agonist of the GLP-1 receptor, by LC-MS/MS. Methodology: Statistical instrument parameter optimization using response surface methodology was employed to develop a LC-MS/MS method for the analyte, PF-06882961. Results: An LC-MS/MS method was developed and validated to support a proof of concept microdose pharmacokinetics preclinical study in monkeys, administered PF-06882961 (0.005 mg total, average dose = 0.0007 mg/kg) via intravenous bolus injection. Conclusion: The present study demonstrated the feasibility of analyzing human microdose plasma samples for PF-06882961 by LC-MS/MS, instead of accelerator mass spectrometry, thereby reducing cost and eliminating synthesis and exposure to 14C labeled material.
[Box: see text].
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Receptor del Péptido 1 Similar al Glucagón , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Cromatografía Liquida/métodos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Cromatografía Líquida con Espectrometría de MasasRESUMEN
Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α2-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABAA receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.
Asunto(s)
Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Secreción de Insulina , Ratones Endogámicos C57BL , Bulbo Olfatorio , Núcleo Hipotalámico Paraventricular , Animales , Péptido 1 Similar al Glucagón/metabolismo , Masculino , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Secreción de Insulina/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones , Núcleo Hipotalámico Paraventricular/metabolismo , Insulina/metabolismo , Obesidad/metabolismo , Sistema Nervioso Simpático/metabolismo , Neuronas/metabolismo , Transducción de Señal , Norepinefrina/metabolismo , Glucosa/metabolismoRESUMEN
The newfound knowledge in type 2 diabetes (T2D) during the past decade for the sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) is wealthy in favorable results for key patient-important outcomes including morbidity, mortality and health-related quality of life (HRQoL). The SGLT-2i and GLP-1RA offer cardiovascular and renal protection beyond their glucose lowering effect, reduce body weight and hypoglycemia and improve diabetes-related distress, physical function and HRQoL. Along with the fixed-ratio combinations of basal insulin/GLP-1RA, they make feasible a regimen simplification and de-escalation from high dose and multiple injections of insulin reducing treatment burden. Besides cardiorenal risk reduction, the SGLT-2i and GLP-1RA reduce the incidence of depression, cognitive decline, respiratory disease, gout, arrhythmias and other co-occurring conditions of T2D, namely multimorbidity, which frequently complicates T2D and adversely affects HRQoL. The alleviation of multimorbidity by the pleiotropic effects of the SGLT-2i and GLP-1RA, could improve patients' HRQoL. The use of the SGLT-2i and GLP-1RA should be increased within a shared decision-making in which they are reframed as cardiorenal risk-reducing medications with the potential to lower blood glucose. By improving outcomes that patients may highly perceive and value, the SGLT-2i and GLP-1RA may facilitate the contemporary person-centered management of T2D.
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Glucemia , Diabetes Mellitus Tipo 2 , Receptor del Péptido 1 Similar al Glucagón , Hipoglucemiantes , Calidad de Vida , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Resultado del Tratamiento , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Factores de Riesgo , Control Glucémico/efectos adversos , Incretinas/uso terapéutico , Incretinas/efectos adversos , Biomarcadores/sangre , Medición de Resultados Informados por el Paciente , Medición de Riesgo , Estado de Salud , Agonistas Receptor de Péptidos Similares al GlucagónAsunto(s)
Receptor del Péptido 1 Similar al Glucagón , Regeneración , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Animales , Humanos , Regeneración/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Transducción de SeñalRESUMEN
The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.
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Fármacos Antiobesidad , Reacción de Prevención , Receptor del Péptido 1 Similar al Glucagón , Vías Nerviosas , Rombencéfalo , Respuesta de Saciedad , Animales , Femenino , Masculino , Ratones , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/farmacología , Área Postrema/metabolismo , Área Postrema/efectos de los fármacos , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Ratones Endogámicos C57BL , Vías Nerviosas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/efectos de los fármacos , Obesidad/metabolismo , Rombencéfalo/citología , Rombencéfalo/efectos de los fármacos , Rombencéfalo/metabolismo , Rombencéfalo/fisiología , Respuesta de Saciedad/efectos de los fármacos , Respuesta de Saciedad/fisiología , Núcleo Solitario/citología , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiología , AlimentosRESUMEN
GLP-1 receptor agonists (GLP-1RAs) are an innovative class of drugs with significant therapeutic value for type 2 diabetes mellitus (T2DM). The GLP-1RAs currently available on the market are biologic macromolecular peptide agents that are expensive to treat and not easy to take orally. Therefore, the development of small molecule GLP-1RAs is becoming one of the most sought-after research targets for hypoglycemic drugs. In this study, we sought to find a potential oral small molecule GLP-1RA and to evaluate its effect on insulin secretion in rat pancreatic ß cells and on blood glucose in mice. We downloaded the mRNA expression profiles of GSE102194 and GSE37936 from the Gene Expression Omnibus database. Subsequently, the small molecule compound idebenone was screened through the connectivity map database. The results of molecular docking, biolayer interferometry, and cellular thermal shift assay indicated that idebenone could bind potently with GLP-1R. Furthermore, ibebenone elevated intracellular cAMP levels. The radioimmunoassay data showed that idebenone enhanced glucose-stimulated insulin secretion via agonism of GLP-1R. Moreover, the results of oral glucose tolerance tests in C57BL/6, Glp-1r-/-, and hGlp-1r mice demonstrated that the glucose-lowering effects of idebenone were mediated by GLP-1R and that there were no species differences in the agonistic effect of idebenone on GLP-1R. In summary, idebenone reduces blood glucose in mice by promoting insulin release through agonism of GLP-1R, suggesting that idebenone is probably a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of metabolic diseases such as T2DM.