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1.
Am J Physiol Endocrinol Metab ; 324(3): E226-E240, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36724126

RESUMEN

Obesity is one of the leading noncommunicable diseases in the world. Despite intense efforts to develop strategies to prevent and treat obesity, its prevalence continues to rise worldwide. A recent study has shown that the tricarboxylic acid intermediate succinate increases body energy expenditure by promoting brown adipose tissue thermogenesis through the activation of uncoupling protein-1; this has generated interest surrounding its potential usefulness as an approach to treat obesity. It is currently unknown how succinate impacts brown adipose tissue protein expression, and how exogenous succinate impacts body mass reduction promoted by a drug approved to treat human obesity, the glucagon-like-1 receptor agonist, liraglutide. In the first part of this study, we used bottom-up shotgun proteomics to determine the acute impact of exogenous succinate on the brown adipose tissue. We show that succinate rapidly affects the expression of 177 brown adipose tissue proteins, which are mostly associated with mitochondrial structure and function. In the second part of this study, we performed a short-term preclinical pharmacological intervention, treating diet-induced obese mice with a combination of exogenous succinate and liraglutide. We show that the combination was more efficient than liraglutide alone in promoting body mass reduction, food energy efficiency reduction, food intake reduction, and an increase in body temperature. Using serum metabolomics analysis, we showed that succinate, but not liraglutide, promoted a significant increase in the blood levels of several medium and long-chain fatty acids. In conclusion, exogenous succinate promotes rapid changes in brown adipose tissue mitochondrial proteins, and when used in association with liraglutide, increases body mass reduction.NEW & NOTEWORTHY Exogenous succinate induces major changes in brown adipose tissue protein expression affecting particularly mitochondrial respiration and structural proteins. When given exogenously in drinking water, succinate mitigates body mass gain in a rodent model of diet-induced obesity; in addition, when given in association with the glucagon-like peptide-1 receptor agonist, liraglutide, succinate increases body mass reduction promoted by liraglutide alone.


Asunto(s)
Tejido Adiposo Pardo , Liraglutida , Animales , Ratones , Tejido Adiposo Pardo/metabolismo , Metabolismo Energético , Liraglutida/farmacología , Liraglutida/uso terapéutico , Obesidad/metabolismo , Proteoma/metabolismo , Ácido Succínico/farmacología , Ácido Succínico/metabolismo , Ácido Succínico/uso terapéutico , Termogénesis , Proteína Desacopladora 1/metabolismo
2.
Sci Rep ; 10(1): 11047, 2020 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-32632088

RESUMEN

Hypothalamic adult neurogenesis provides the basis for renewal of neurons involved in the regulation of whole-body energy status. In addition to hormones, cytokines and growth factors, components of the diet, particularly fatty acids, have been shown to stimulate hypothalamic neurogenesis; however, the mechanisms behind this action are unknown. Here, we hypothesized that GPR40 (FFAR1), the receptor for medium and long chain unsaturated fatty acids, could mediate at least part of the neurogenic activity in the hypothalamus. We show that a GPR40 ligand increased hypothalamic cell proliferation and survival in adult mice. In postnatal generated neurospheres, acting in synergy with brain-derived neurotrophic factor (BDNF) and interleukin 6, GPR40 activation increased the expression of doublecortin during the early differentiation phase and of the mature neuronal marker, microtubule-associated protein 2 (MAP2), during the late differentiation phase. In Neuro-2a proliferative cell-line GPR40 activation increased BDNF expression and p38 activation. The chemical inhibition of p38 abolished GPR40 effect in inducing neurogenesis markers in neurospheres, whereas BDNF immunoneutralization inhibited GPR40-induced cell proliferation in the hypothalamus of adult mice. Thus, GPR40 acts through p38 and BDNF to induce hypothalamic neurogenesis. This study provides mechanistic advance in the understating of how a fatty acid receptor regulates adult hypothalamic neurogenesis.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/fisiología , Hipotálamo/citología , Hipotálamo/fisiología , Neurogénesis/fisiología , Receptores Acoplados a Proteínas G/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/fisiología , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Hipotálamo/efectos de los fármacos , Imidazoles/farmacología , Interleucina-6/fisiología , Ligandos , Masculino , Metilaminas/farmacología , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Propionatos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores
3.
Amino Acids ; 42(6): 2403-10, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21818562

RESUMEN

Taurine is known to modulate a number of metabolic parameters such as insulin secretion and action and blood cholesterol levels. Recent data have suggested that taurine can also reduce body adiposity in C. elegans and in rodents. Since body adiposity is mostly regulated by insulin-responsive hypothalamic neurons involved in the control of feeding and thermogenesis, we hypothesized that some of the activity of taurine in the control of body fat would be exerted through a direct action in the hypothalamus. Here, we show that the intracerebroventricular injection of an acute dose of taurine reduces food intake and locomotor activity, and activates signal transduction through the Akt/FOXO1, JAK2/STAT3 and mTOR/AMPK/ACC signaling pathways. These effects are accompanied by the modulation of expression of NPY. In addition, taurine can enhance the anorexigenic action of insulin. Thus, the aminoacid, taurine, exerts a potent anorexigenic action in the hypothalamus and enhances the effect of insulin on the control of food intake.


Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Taurina/administración & dosificación , Quinasas de la Proteína-Quinasa Activada por el AMP , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Sinergismo Farmacológico , Ingestión de Alimentos/fisiología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Expresión Génica/fisiología , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Insulina/administración & dosificación , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo
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