RESUMEN
OBJECTIVE: Polyunsaturated fatty acid (PUFA) supplements have been trialled as a treatment for a number of conditions and produced a variety of results. This variety is ascribed to the supplements, that often comprise a mixture of fatty acids, and to different effects in different organs. In this study, we tested the hypothesis that the supplementation of individual PUFAs has system-level effects that are dependent on the molecular structure of the PUFA. METHODS: We undertook a network analysis using Lipid Traffic Analysis to identify both local and system-level changes in lipid metabolism using publicly available lipidomics data from a mouse model of supplementation with FA(20:4n-6), FA(20:5n-3), and FA(22:6n-3); arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, respectively. Lipid Traffic Analysis is a new computational/bioinformatics tool that uses the spatial distribution of lipids to pinpoint changes or differences in control of metabolism, thereby suggesting mechanistic reasons for differences in observed lipid metabolism. RESULTS: There was strong evidence for changes to lipid metabolism driven by and dependent on the structure of the supplemented PUFA. Phosphatidylcholine and triglycerides showed a change in the variety more than the total number of variables, whereas phosphatidylethanolamine and phosphatidylinositol showed considerable change in both which variables and the number of them, in a highly PUFA-dependent manner. There was also evidence for changes to the endogenous biosynthesis of fatty acids and to both the elongation and desaturation of fatty acids. CONCLUSIONS: These results show that the full biological impact of PUFA supplementation is far wider than any single-organ effect and implies that supplementation and dosing with PUFAs require a system-level assessment.
Asunto(s)
Ácidos Grasos Insaturados , Metabolismo de los Lípidos , Animales , Ácidos Docosahexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos , Ácidos Grasos Insaturados/metabolismo , RatonesRESUMEN
Phosphorylation of the translation initiation factor eIF2α within the mediobasal hypothalamus is known to suppress food intake, but the role of the eIF2α phosphatases in regulating body weight is poorly understood. Mice deficient in active PPP1R15A, a stress-inducible eIF2α phosphatase, are healthy and more resistant to endoplasmic reticulum stress than wild type controls. We report that when female Ppp1r15a mutant mice are fed a high fat diet they gain less weight than wild type littermates owing to reduced food intake. This results in healthy leaner Ppp1r15a mutant animals with reduced hepatic steatosis and improved insulin sensitivity, albeit with a possible modest defect in insulin secretion. By contrast, no weight differences are observed between wild type and Ppp1r15a deficient mice fed a standard diet. We conclude that female mice lacking the C-terminal PP1-binding domain of PPP1R15A show reduced dietary intake and preserved glucose tolerance. Our data indicate that this results in reduced weight gain and protection from diet-induced obesity.
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Hipotálamo/metabolismo , Obesidad/prevención & control , Proteína Fosfatasa 1/genética , Proteína Fosfatasa 1/metabolismo , Aumento de Peso/fisiología , Animales , Dieta Alta en Grasa , Ingestión de Alimentos , Estrés del Retículo Endoplásmico , Femenino , Humanos , Resistencia a la Insulina , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FosforilaciónRESUMEN
Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes.
Asunto(s)
Canales de Calcio Tipo R/metabolismo , Calcio/metabolismo , Proteínas de Transporte de Catión/metabolismo , Glucosa/metabolismo , Leptina/farmacología , Hígado/metabolismo , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Animales , Canales de Calcio Tipo R/genética , Proteínas de Transporte de Catión/genética , Células Cultivadas , Homeostasis , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacosRESUMEN
The incidence of overweight and obesity has reached epidemic proportions, making the control of body weight and its complications a primary health problem. Diet has long played a first-line role in preventing and managing obesity. However, beyond the obvious strategy of restricting caloric intake, growing evidence supports the specific antiobesity effects of some food-derived components, particularly (poly)phenolic compounds. The relatively new rediscovery of active brown adipose tissue in adult humans has generated interest in this tissue as a novel and viable target for stimulating energy expenditure and controlling body weight by promoting energy dissipation. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to (poly)phenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Although discrepancies exist in the literature, most in vivo studies with rodents strongly support the role of some (poly)phenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents. Further investigation of effects in humans is warranted.
Asunto(s)
Tejido Adiposo Pardo/fisiología , Metabolismo Energético , Polifenoles/farmacología , Agonistas Adrenérgicos/farmacología , Animales , Fármacos Antiobesidad/farmacología , Peso Corporal , Dieta , Modelos Animales de Enfermedad , Flavonoides/farmacología , Humanos , Obesidad/tratamiento farmacológico , Resveratrol , Estilbenos/farmacología , Té/química , Termogénesis/efectos de los fármacos , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid metabolism. Of note, ablation of AMPKα1 in steroidogenic factor 1 (SF1) neurons of the VMH fully recapitulated the effect of central T3, pointing to this population in mediating the effect of central THs on metabolism. Overall, these findings uncover the underlying pathways through which central T3 modulates peripheral metabolism.
Asunto(s)
Metabolismo Energético , Hipotálamo/metabolismo , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Transducción de Señal , Hormonas Tiroideas/metabolismo , Tejido Adiposo Pardo/metabolismo , Animales , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Termogénesis , Triyodotironina/metabolismoRESUMEN
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/fisiologíaRESUMEN
Thermogenesis in brown adipose tissue (BAT) is fundamental to energy balance and is also relevant for humans. Bone morphogenetic proteins (BMPs) regulate adipogenesis, and, here, we describe a role for BMP8B in the direct regulation of thermogenesis. BMP8B is induced by nutritional and thermogenic factors in mature BAT, increasing the response to noradrenaline through enhanced p38MAPK/CREB signaling and increased lipase activity. Bmp8b(-/-) mice exhibit impaired thermogenesis and reduced metabolic rate, causing weight gain despite hypophagia. BMP8B is also expressed in the hypothalamus, and Bmp8b(-/-) mice display altered neuropeptide levels and reduced phosphorylation of AMP-activated protein kinase (AMPK), indicating an anorexigenic state. Central BMP8B treatment increased sympathetic activation of BAT, dependent on the status of AMPK in key hypothalamic nuclei. Our results indicate that BMP8B is a thermogenic protein that regulates energy balance in partnership with hypothalamic AMPK. BMP8B may offer a mechanism to specifically increase energy dissipation by BAT.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Dieta , Obesidad/metabolismo , Termogénesis , Proteínas Quinasas Activadas por AMP/metabolismo , Adipogénesis , Animales , Proteínas Morfogenéticas Óseas/genética , Metabolismo Energético , Femenino , Hipotálamo/metabolismo , Ratones , Ratones Endogámicos C57BL , Norepinefrina/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Smokers around the world commonly report increased body weight after smoking cessation as a major factor that interferes with their attempts to quit. Numerous controlled studies in both humans and rodents have reported that nicotine exerts a marked anorectic action. The effects of nicotine on energy homeostasis have been mostly pinpointed in the central nervous system, but the molecular mechanisms controlling its action are still not fully understood. The aim of this study was to investigate the effect of nicotine on hypothalamic AMP-activated protein kinase (AMPK) and its effect on energy balance. Here we demonstrate that nicotine-induced weight loss is associated with inactivation of hypothalamic AMPK, decreased orexigenic signaling in the hypothalamus, increased energy expenditure as a result of increased locomotor activity, increased thermogenesis in brown adipose tissue (BAT), and alterations in fuel substrate utilization. Conversely, nicotine withdrawal or genetic activation of hypothalamic AMPK in the ventromedial nucleus of the hypothalamus reversed nicotine-induced negative energy balance. Overall these data demonstrate that the effects of nicotine on energy balance involve specific modulation of the hypothalamic AMPK-BAT axis. These targets may be relevant for the development of new therapies for human obesity.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Nicotina/farmacología , Proteínas Quinasas Activadas por AMP/genética , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Apetito/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Neuropéptido Y/metabolismo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Temazepam , Termogénesis/efectos de los fármacosRESUMEN
SCOPE: Dysfunctional adipose tissue may be an important trigger of molecular inflammatory pathways that cause cardiovascular diseases. Our aim was to determine whether the specific quality and quantity of dietary fat produce differential postprandial inflammatory responses in adipose tissue from metabolic syndrome (MetS) patients. METHODS AND RESULTS: A randomized, controlled trial conducted within the LIPGENE study assigned MetS patients to 1 of 4 diets: (i) high-saturated fatty acid (HSFA), (ii) high-monounsaturated fatty acid (HMUFA), (iii) low-fat, high-complex carbohydrate diet supplemented with n-3 polyunsaturated fatty acids (PUFA) (LFHCC n-3), and (iv) low-fat, high-complex carbohydrate diet supplemented with placebo (LFHCC), for 12 wk each. A fat challenge reflecting the fatty acid composition as the original diets was conducted post-intervention. We found that p65 gene expression is induced in adipose tissue (p=0.003) at the postprandial state. In addition, IκBα (p<0.001), MCP-1 (p<0.001) and IL-1ß (p<0.001) gene expression was equally induced in the postprandial state, regardless of the quality and quantity of the dietary fat. Notably, IL-6 transcripts were only detected in the postprandial state. CONCLUSIONS: Our results indicate that individuals with MetS typically exhibit exacerbated adipose tissue postprandial inflammatory responses, which seem to be independent of the quality and quantity of dietary fat.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Ácidos Grasos Monoinsaturados/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Inflamación/fisiopatología , Síndrome Metabólico/fisiopatología , Periodo Posprandial/efectos de los fármacos , Tejido Adiposo/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Dieta , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Inhibidor NF-kappaB alfaRESUMEN
Two crucial biological processes are (1) the sensing and coordination of responses to low oxygen levels and (2) the control of food intake and energy expenditure. The hypoxia-inducible factor (HIF) family of proteins is known to regulate responses to low oxygen, whereas neuropeptides derived from proopiomelanocortin (POMC) are implicated in the control of food intake and energy expenditure. It is now becoming apparent that these two apparently disparate processes may be linked, with the exciting discovery that HIF proteins can act in the brain to regulate food intake and energy expenditure as reported in the current issue of PLoS Biology. This primer discusses the traditional role of HIF proteins in terms of responding to oxygen levels in the periphery and also their new role in coordinating responses to nutrients in the brain through regulation of POMC.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Metabolismo Energético , Glucosa/farmacología , Hipotálamo/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proopiomelanocortina/genética , Animales , Femenino , MasculinoRESUMEN
The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Benzodiazepinas/farmacología , Hiperfagia/inducido químicamente , Hipotálamo/enzimología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neuropéptidos/metabolismo , Transducción de Señal/efectos de los fármacos , Aumento de Peso/efectos de los fármacos , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Aminoimidazol Carboxamida/administración & dosificación , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Animales , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Núcleo Arqueado del Hipotálamo/metabolismo , Benzodiazepinas/administración & dosificación , Clozapina/administración & dosificación , Clozapina/farmacología , Conducta Alimentaria/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hiperfagia/sangre , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Insulina/sangre , Leptina/sangre , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Olanzapina , Orexinas , Fosforilación/efectos de los fármacos , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Ratas , Ratas Sprague-Dawley , Ribonucleótidos/administración & dosificación , Ribonucleótidos/farmacologíaRESUMEN
The AMP-activated protein kinase (AMPK) is the downstream constituent of a kinase cascade that acts as a sensor of cellular energy levels. Current data unequivocally indicate that hypothalamic AMPK plays a key role in the control of the whole body energy balance, by integrating peripheral signals, such as hormones and metabolites, with central signals, such as neuropeptides, and eliciting allostatic changes in energy homeostasis. Although the molecular details of these interactions are not fully understood, recent evidence has suggested that the interaction between AMPK with hypothalamic lipid metabolism and other metabolic sensors, such as the uncoupling protein 2 (UCP-2), the mammalian target of rapamycin (mTOR) and the deacetylase sirtuin 1 (SIRT1), may play a main role in the hypothalamic control of feeding and energy expenditure. Here, we summarize the role of hypothalamic AMPK as whole body energy gauge. Understanding this key molecule and especially its functions at central level may provide new therapeutic targets for the treatment of metabolic alterations and obesity.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Metabolismo Energético/fisiología , Hipotálamo/metabolismo , Animales , Ingestión de Alimentos/fisiología , Humanos , Metabolismo de los Lípidos/fisiología , Obesidad/metabolismo , Obesidad/fisiopatologíaRESUMEN
Ghrelin, the endogenous ligand of the GH secretagogue receptor, has a pleiotropic role in the modulation of energy balance. Recent evidence has demonstrated that besides its orexigenic role, ghrelin regulates central and peripheral lipid metabolism through specific control of hypothalamic AMP-activated protein kinase (AMPK), a critical metabolic gauge regulating both cellular and whole-body energy homeostasis. In this review, we summarize the new milestones of ghrelin's actions on energy balance, with particular focus on its molecular interaction with hypothalamic AMPK and fatty acid metabolism. Understanding this new metabolic pathway can provide new therapeutic targets for the treatment of obesity and the metabolic syndrome.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Ghrelina/metabolismo , Metabolismo de los Lípidos/fisiología , Receptores de Ghrelina/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Peso Corporal , Metabolismo Energético/fisiología , Femenino , Expresión Génica , Ghrelina/genética , Hormona del Crecimiento/metabolismo , Homeostasis , Humanos , Hipotálamo/metabolismo , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Ratones , Ratones Transgénicos , Obesidad/metabolismo , Obesidad/fisiopatología , Receptores de Ghrelina/genética , Roedores , Transducción de SeñalRESUMEN
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/sangreRESUMEN
The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid beta oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid beta oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner.
Asunto(s)
Ácidos Grasos/metabolismo , Ghrelina/farmacología , Proteínas de Homeodominio/genética , Hipotálamo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/efectos de los fármacos , Factores de Transcripción/metabolismo , Proteína Relacionada con Agouti/efectos de los fármacos , Proteína Relacionada con Agouti/genética , Animales , Ingestión de Alimentos , Femenino , Regulación de la Expresión Génica , Masculino , Neuropéptido Y/efectos de los fármacos , Neuropéptido Y/genética , Neuropéptidos/genética , Ratas , Factores Sexuales , Factores de Transcripción/genéticaRESUMEN
AMP-activated protein kinase (AMPK) is the downstream component of a kinase cascade that acts as a gauge of cellular energy levels. Over the last few years, accumulating evidence has demonstrated that AMPK is also involved in the regulation of energy balance at the whole-body level by responding to hormones and nutrient signals, which leads to changes in energy homeostasis. The physiological relevance of this new role of AMPK is demonstrated by the fact that impairment of AMPK function is associated with metabolic alterations, insulin resistance, obesity, hormonal disorders and cardiovascular disease. Here, we summarize the role of AMPK in the regulation of energy homeostasis. Understanding this key enzyme and its tissue-specific regulation will provide new targets for the treatment of metabolic disorders.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Metabolismo Energético/fisiología , Homeostasis/fisiología , Animales , Regulación del Apetito/fisiología , Trastornos de Alimentación y de la Ingestión de Alimentos/etiología , Glucosa/metabolismo , Hormonas/metabolismo , Humanos , Hipotálamo/enzimología , Metabolismo de los Lípidos , Modelos Biológicos , Obesidad/etiología , Transducción de SeñalRESUMEN
PURPOSE OF REVIEW: To revise current available information related to the role of brain lipogenic pathways in the regulation of energy homeostasis. RECENT FINDINGS: The 'classical' hypothalamic neuropeptide view of feeding regulation has been extensively reviewed and revised during the past few years. Accumulating evidence indicates that the modulation of lipogenesis de novo in the hypothalamus, through selective pharmacologic and genetic manipulation of acetyl-CoA carboxylase, AMP-activated protein kinase, carnitine palmitoyltransferase 1, fatty acid synthase and malonyl-CoA decarboxylase enzymes, has a severe impact on food intake and body weight homeostasis. Furthermore, as these manipulations alter the hypothalamic pool of lipids, such as malonyl-CoA or long chain fatty acyl-CoA or both, the concept of lipids as signals of nutrient abundance able to modulate feeding in the hypothalamus has recently re-emerged. SUMMARY: In this review, we summarize what is known about brain lipogenesis and energy balance and propose further avenues of research. Defining these novel mechanisms could offer new targets for the treatment of obesity and metabolic syndrome.
Asunto(s)
Metabolismo Energético/fisiología , Ácidos Grasos/metabolismo , Hipotálamo/metabolismo , Lipogénesis/fisiología , Ingestión de Alimentos , Ácidos Grasos/biosíntesis , Conducta Alimentaria , Humanos , Hipotálamo/enzimologíaRESUMEN
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 fasRESUMEN
Evidence suggests that the adipocyte-derived hormone resistin (RSTN) directly regulates both feeding and peripheral metabolism through, so far, undefined hypothalamic-mediated mechanisms. Here, we demonstrate that the anorectic effect of RSTN is associated with inappropriately decreased mRNA expression of orexigenic (agouti-related protein and neuropeptide Y) and increased mRNA expression of anorexigenic (cocaine and amphetamine-regulated transcript) neuropeptides in the arcuate nucleus of the hypothalamus. Of interest, RSTN also exerts a profound nutrition-dependent inhibitory effect on hypothalamic fatty acid metabolism, as indicated by increased phosphorylation levels of both AMP-activated protein kinase and its downstream target acetyl-coenzyme A carboxylase, associated with decreased expression of fatty acid synthase in the ventromedial nucleus of the hypothalamus. In addition, we also demonstrate that chronic central RSTN infusion results in decreased body weight and major changes in peripheral expression of lipogenic enzymes, in a tissue-specific and nutrition-dependent manner. Thus, in the fed state central RSTN is associated with induced expression of fatty acid synthesis enzymes and proinflammatory cytokines in liver, whereas its administration in the fasted state does so in white adipose tissue. Overall, our results indicate that RSTN controls feeding and peripheral lipid metabolism and suggest that hepatic RSTN-induced insulin resistance may be mediated by central activation of de novo lipogenesis in liver.
Asunto(s)
Fenómenos Fisiológicos Nutricionales de los Animales , Hipotálamo/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Resistina/farmacología , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales/efectos de los fármacos , Animales , Ingestión de Alimentos/efectos de los fármacos , Ayuno/metabolismo , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Resistencia a la Insulina/fisiología , Lipogénesis/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Resistina/administración & dosificación , Proteína 3 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Factores de TiempoRESUMEN
OBJECTIVE: To study the effects of three weight-maintenance diets with different macronutrient composition on carbohydrate, lipid metabolism, insulin and incretin levels in insulin-resistant subjects. METHODS: A prospective study was performed in eleven (7 W, 4 M) offspring of obese and type 2 diabetes patients. Subjects had a BMI > 25 Kg/m2, waist circumference (men/women) > 102/88, HBA1c < 6.5% and were regarded as insulin-resistant after an OGTT (Matsuda ISIm <4). They were randomly divided into three groups and underwent three dietary periods each of 28 days in a crossover design: a) diet high in saturated fat (SAT), b) diet rich in monounsaturated fat (MUFA; Mediterranean diet) and c) diet rich in carbohydrate (CHO). RESULTS: Body weight and resting energy expenditure did not changed during the three dietary periods. Fasting serum glucose concentrations fell during MUFA-rich and CHO-rich diets compared with high-SAT diets (5.02 +/- 0.1, 5.03 +/- 0.1, 5.50 +/- 0.2 mmol/L, respectively. Anova < 0.05). The MUFA-rich diet improved insulin sensitivity, as indicated by lower homeostasis model analysis-insulin resistance (HOMA-ir), compared with CHO-rich and high-SAT diets (2.32 +/- 0.3, 2.52 +/- 0.4, 2.72 +/- 0.4, respectively, Anova < 0.01). After a MUFA-rich and high-SAT breakfasts (443 kcal) the postprandial integrated area under curve (AUC) of glucose and insulin were lowered compared with isocaloric CHO-rich breakfast (7.8 +/- 1.3, 5.84 +/- 1.2, 11.9 +/- 2.7 mmol . 180 min/L, Anova < 0.05; and 1004 +/- 147, 1253 +/- 140, 2667 +/- 329 pmol . 180 min/L, Anova <0.01, respectively); while the integrated glucagon-like peptide-1 response increased with MUFA and SAT breakfasts compared with isocaloric CHO-rich meals (4.22 +/- 0.7, 4.34 +/- 1.1, 1.85 +/- 1.1, respectively, Anova < 0.05). Fasting and postprandial HDL cholesterol concentrations rose with MUFA-rich diets, and the AUCs of triacylglycerol fell with the CHO-rich diet. Similarly fasting proinsulin (PI) concentration fell, while stimulated ratio PI/I was not changed by MUFA-rich diet. CONCLUSIONS: Weight maintenance with a MUFA-rich diet improves HOMA-ir and fasting proinsulin levels in insulin-resistant subjects. Ingestion of a virgin olive oil-based breakfast decreased postprandial glucose and insulin concentrations, and increased HDL-C and GLP-1 concentrations as compared with CHO-rich diet.