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1.
Cell Rep Med ; 3(11): 100810, 2022 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-36384093

RESUMEN

Glucagon analogs show promise as components of next-generation, multi-target, anti-obesity therapeutics. The biology of chronic glucagon treatment, in particular, its ability to induce energy expenditure and weight loss, remains poorly understood. Using a long-acting glucagon analog, G108, we demonstrate that glucagon-mediated body weight loss is intrinsically linked to the hypoaminoacidemia associated with its known amino acid catabolic action. Mechanistic studies reveal an energy-consuming response to low plasma amino acids in G108-treated mice, prevented by dietary amino acid supplementation and mimicked by a rationally designed low amino acid diet. Therefore, low plasma amino acids are a pre-requisite for G108-mediated energy expenditure and weight loss. However, preventing hypoaminoacidemia with additional dietary protein does not affect the ability of G108 to improve glycemia or hepatic steatosis in obese mice. These studies provide a mechanism for glucagon-mediated weight loss and confirm the hepatic glucagon receptor as an attractive molecular target for metabolic disease therapeutics.


Asunto(s)
Glucagón , Pérdida de Peso , Ratones , Animales , Glucagón/metabolismo , Metabolismo Energético/fisiología , Receptores de Glucagón/metabolismo , Ratones Obesos , Aminoácidos/farmacología
2.
Cell Metab ; 23(5): 821-36, 2016 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-27133129

RESUMEN

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Células Secretoras de Insulina/enzimología , Células Secretoras de Insulina/patología , Obesidad/enzimología , Adiposidad/genética , Adulto , Envejecimiento/patología , Proteína Relacionada con Agouti/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Metabolismo Energético/genética , Activación Enzimática , Conducta Alimentaria , Femenino , Heterocigoto , Humanos , Hiperfagia/complicaciones , Hiperfagia/enzimología , Hiperfagia/genética , Hiperfagia/patología , Hipotálamo/metabolismo , Insulina/metabolismo , Masculino , Ratones , Mitocondrias/metabolismo , Mutación/genética , Neuronas/metabolismo , Obesidad/sangre , Obesidad/complicaciones , Obesidad/patología , Fosforilación Oxidativa , Receptores de Ghrelina/metabolismo , Ribosomas/metabolismo , Transducción de Señal/genética , Transcriptoma/genética , Regulación hacia Arriba/genética
3.
Cell Rep ; 11(3): 335-43, 2015 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-25865886

RESUMEN

Hypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons.


Asunto(s)
Metabolismo Energético/fisiología , Conducta Alimentaria/fisiología , Glucosa/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Peso Corporal/fisiología , Homeostasis/fisiología , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proopiomelanocortina/metabolismo , Transducción de Señal/fisiología
4.
Nat Commun ; 5: 3611, 2014 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-24781306

RESUMEN

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo(11)C-acetate and PET-CT scanning to show that colonic acetate crosses the blood-brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through (13)C high-resolution magic-angle-spinning that (13)C acetate from fermentation of (13)C-labelled carbohydrate in the colon increases hypothalamic (13)C acetate above baseline levels. Hypothalamic (13)C acetate regionally increases the (13)C labelling of the glutamate-glutamine and GABA neuroglial cycles, with hypothalamic (13)C lactate reaching higher levels than the 'remaining brain'. These observations suggest that acetate has a direct role in central appetite regulation.


Asunto(s)
Acetatos/metabolismo , Animales , Apetito , Encéfalo/metabolismo , Isótopos de Carbono/metabolismo , Catálisis , Ingestión de Alimentos/fisiología , Homeostasis/fisiología , Hipotálamo/metabolismo , Ácido Láctico/metabolismo , Ratones , Ratones Endogámicos C57BL
5.
Diabetes ; 60(3): 735-45, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21266325

RESUMEN

OBJECTIVE: AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase ß (CaMKKß) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation. RESEARCH DESIGN AND METHODS: Mice lacking either Camkkß or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed. RESULTS: Deletion of Camkkß in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice. CONCLUSIONS: Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.


Asunto(s)
Glucosa/metabolismo , Homeostasis/genética , Hipotálamo/metabolismo , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Análisis de Varianza , Animales , Área Bajo la Curva , Peso Corporal/genética , Recuento de Células , Ingestión de Alimentos/genética , Electrofisiología , Metabolismo Energético/genética , Femenino , Glucosa/genética , Técnica de Clampeo de la Glucosa , Inmunohistoquímica , Resistencia a la Insulina/genética , Masculino , Ratones , Ratones Transgénicos , Proopiomelanocortina/genética , Proteínas Serina-Treonina Quinasas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Estadísticas no Paramétricas
6.
Nat Med ; 16(9): 1001-8, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20802499

RESUMEN

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Metabolismo Energético/fisiología , Ácidos Grasos/metabolismo , Hipotálamo/enzimología , Glándula Tiroides/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/fisiología , Proteína Relacionada con Agouti/genética , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Cerulenina/farmacología , Inhibidores de la Síntesis de Ácidos Grasos/farmacología , Hiperfagia/etiología , Hipertiroidismo/complicaciones , Hipertiroidismo/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismo , Proopiomelanocortina/metabolismo , ARN Mensajero/genética , Ratas , Termogénesis/fisiología , Hormona Liberadora de Tirotropina/genética , Tiroxina/sangre , Tiroxina/farmacología , Triyodotironina/sangre
7.
Biochem J ; 429(2): 323-33, 2010 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-20465544

RESUMEN

AMPK (AMP-activated protein kinase) signalling plays a key role in whole-body energy homoeostasis, although its precise role in pancreatic beta-cell function remains unclear. In the present study, we therefore investigated whether AMPK plays a critical function in beta-cell glucose sensing and is required for the maintenance of normal glucose homoeostasis. Mice lacking AMPK alpha2 in beta-cells and a population of hypothalamic neurons (RIPCre alpha2KO mice) and RIPCre alpha2KO mice lacking AMPK alpha1 (alpha1KORIPCre alpha2KO) globally were assessed for whole-body glucose homoeostasis and insulin secretion. Isolated pancreatic islets from these mice were assessed for glucose-stimulated insulin secretion and gene expression changes. Cultured beta-cells were examined electrophysiologically for their electrical responsiveness to hypoglycaemia. RIPCre alpha2KO mice exhibited glucose intolerance and impaired GSIS (glucose-stimulated insulin secretion) and this was exacerbated in alpha1KORIPCre alpha2KO mice. Reduced glucose concentrations failed to completely suppress insulin secretion in islets from RIPCre alpha2KO and alpha1KORIPCre alpha2KO mice, and conversely GSIS was impaired. Beta-cells lacking AMPK alpha2 or expressing a kinase-dead AMPK alpha2 failed to hyperpolarize in response to low glucose, although KATP (ATP-sensitive potassium) channel function was intact. We could detect no alteration of GLUT2 (glucose transporter 2), glucose uptake or glucokinase that could explain this glucose insensitivity. UCP2 (uncoupling protein 2) expression was reduced in RIPCre alpha2KO islets and the UCP2 inhibitor genipin suppressed low-glucose-mediated wild-type mouse beta-cell hyperpolarization, mimicking the effect of AMPK alpha2 loss. These results show that AMPK alpha2 activity is necessary to maintain normal pancreatic beta-cell glucose sensing, possibly by maintaining high beta-cell levels of UCP2.


Asunto(s)
Proteínas Quinasas Activadas por AMP/deficiencia , Células Secretoras de Insulina/fisiología , Insulina/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Glucoquinasa/metabolismo , Glucosa/metabolismo , Glucosa/farmacología , Transportador de Glucosa de Tipo 2/metabolismo , Homeostasis , Hipoglucemia/fisiopatología , Hipotálamo/fisiología , Técnicas In Vitro , Secreción de Insulina , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Canales Iónicos/antagonistas & inhibidores , Canales Iónicos/metabolismo , Potenciales de la Membrana , Ratones , Ratones Noqueados , Proteínas Mitocondriales/antagonistas & inhibidores , Proteínas Mitocondriales/metabolismo , Ratas , Transducción de Señal , Proteína Desacopladora 2
8.
Cell Metab ; 7(5): 389-99, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18460330

RESUMEN

Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelin's effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.


Asunto(s)
Ácidos Grasos/metabolismo , Ghrelina/fisiología , Hipotálamo/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Western Blotting , Carnitina O-Palmitoiltransferasa/metabolismo , Ayuno/fisiología , Ácido Graso Sintasas/antagonistas & inhibidores , Ácido Graso Sintasas/metabolismo , Conducta Alimentaria , Hipotálamo/patología , Hibridación in Situ , Leptina/metabolismo , Masculino , Malonil Coenzima A/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Fosforilación , Proteínas Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor fas
9.
J Clin Invest ; 117(8): 2325-36, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17671657

RESUMEN

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP alpha 2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.


Asunto(s)
Metabolismo Energético/fisiología , Homeostasis/fisiología , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Complejos Multienzimáticos/metabolismo , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Proteína Relacionada con Agouti , Animales , Ingestión de Alimentos/fisiología , Glucosa/metabolismo , Insulina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/deficiencia , Leptina/metabolismo , Ratones , Ratones Noqueados , Complejos Multienzimáticos/deficiencia , Proopiomelanocortina/deficiencia , Proteínas Serina-Treonina Quinasas/deficiencia , Transducción de Señal/fisiología
10.
Biochimie ; 87(1): 87-91, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15733742

RESUMEN

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that plays a key role in the regulation of energy control. AMPK is activated in response to an increase in the ratio of AMP:ATP within the cell. Activation requires phosphorylation of threonine 172 within the catalytic subunit of AMPK by an upstream kinase. The identity of the upstream kinase in the cascade remained frustratingly elusive for many years, but was recently identified as LKB1, a kinase that is inactivated in a rare hereditary form of cancer called Peutz-Jeghers syndrome. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance within the cell. ATP-consuming, anabolic pathways, such as fatty acid synthesis and protein synthesis are switched-off, whereas ATP-generating, catabolic pathways, such as fatty acid oxidation and glycolysis, are switched-on. More recent studies have indicated, that AMPK plays an important role in the regulation of whole body energy metabolism. The adipocyte-derived hormones, leptin and adiponectin, activate AMPK in peripheral tissues, including skeletal muscle and liver, increasing energy expenditure. In the hypothalamus, AMPK is inhibited by leptin and insulin, hormones which suppress feeding, whilst ghrelin, a hormone that increases food intake, activates AMPK. Furthermore, direct pharmacological activation of AMPK in the hypothalamus by 5-aminoimidazole-4-carboxamide ribose increases food intake in rats, demonstrating that AMPK plays a direct role in the regulation of feeding. Taken together these findings indicate that AMPK has a pivotal role in regulating pathways that control both energy expenditure and energy intake.


Asunto(s)
Complejos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Regulación Alostérica , Animales , Ingestión de Alimentos/fisiología , Metabolismo Energético , Activación Enzimática , Humanos , Hipotálamo/enzimología , Complejos Multienzimáticos/antagonistas & inhibidores , Complejos Multienzimáticos/química , Fosforilación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/química
11.
Biochem Biophys Res Commun ; 329(2): 719-25, 2005 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-15737645

RESUMEN

Recent studies have demonstrated that AMP-activated protein kinase (AMPK) in the hypothalamus is involved in the regulation of food intake. Because exercise is known to influence appetite and cause substrate depletion, it may also influence AMPK in the hypothalamus. Male rats that either rested or ran for 30 or 60 min on a treadmill (22 m/min, 10% slope) were sacrificed immediately after exercise or after 60 min recovery either in the fasted state or after oral gavage with glucose (3g/kg body weight). Exercise decreased muscle and liver glycogen substantially. Hypothalamic total or alpha2-associated AMPK activity and phosphorylation state of the AMPK substrate acetyl-CoA carboxylase were not changed significantly immediately following treadmill running or during fed or fasted recovery. Plasma ghrelin increased (P<0.05) by 40% during exercise whereas the concentration of PYY was unchanged. In recovery, glucose feeding increased plasma glucose and insulin concentrations whereas ghrelin and PYY decreased to (ghrelin) or below (PPY) resting levels. It is concluded that 1h of strenuous exercise in rats does not elicit significant changes in hypothalamic AMPK activity despite an increase in plasma ghrelin. Thus, changes in energy metabolism during or after exercise are likely not coordinated by changes in hypothalamic AMPK activity.


Asunto(s)
Glucosa/metabolismo , Hipotálamo/enzimología , Complejos Multienzimáticos/metabolismo , Estado Nutricional/fisiología , Condicionamiento Físico Animal/fisiología , Esfuerzo Físico/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Adaptación Fisiológica/fisiología , Animales , Prueba de Esfuerzo , Masculino , Ratas , Ratas Wistar
13.
J Biol Chem ; 279(13): 12005-8, 2004 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-14742438

RESUMEN

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that acts as an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs.


Asunto(s)
Aminoimidazol Carboxamida/análogos & derivados , Ingestión de Alimentos , Péptidos y Proteínas de Señalización Intercelular , Complejos Multienzimáticos/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Quinasas Activadas por AMP , Adiponectina , Aminoimidazol Carboxamida/farmacología , Animales , Regulación del Apetito , Western Blotting , Encéfalo/metabolismo , Ghrelina , Hipotálamo/metabolismo , Leptina/metabolismo , Hígado/metabolismo , Músculos/metabolismo , Hormonas Peptídicas/metabolismo , Péptido YY/farmacología , Proteínas/metabolismo , Ratas , Ratas Wistar , Ribonucleósidos/farmacología , Factores de Tiempo
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