RESUMEN
Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obscure. Herein, we report that temporary fasting drastically reduces the number of lymphocytes by â¼50% in Peyer's patches (PPs), the inductive site of the gut immune response. Subsequent refeeding seemingly restored the number of lymphocytes, but whose cellular composition was conspicuously altered. A large portion of germinal center and IgA+ B cells were lost via apoptosis during fasting. Meanwhile, naive B cells migrated from PPs to the bone marrow during fasting and then back to PPs during refeeding when stromal cells sensed nutritional signals and upregulated CXCL13 expression to recruit naive B cells. Furthermore, temporal fasting before oral immunization with ovalbumin abolished the induction of antigen-specific IgA, failed to induce oral tolerance, and eventually exacerbated food antigen-induced diarrhea. Thus, nutritional signals are critical in maintaining gut immune homeostasis.
Asunto(s)
Linfocitos B/fisiología , Inmunidad Mucosa , Animales , Antígenos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Ayuno , Regulación de la Expresión Génica , Glucólisis , Inmunoglobulina A/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Estado Nutricional , Ovalbúmina/inmunología , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/patología , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Transducción de Señal , Células del Estroma/citología , Células del Estroma/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion. Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.
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Aterosclerosis/metabolismo , Hipercolesterolemia/metabolismo , Receptores Acoplados a Proteínas G/deficiencia , Animales , Aterosclerosis/sangre , Secuencia de Bases , Colesterol/sangre , Dependovirus/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Ayuno , Femenino , Hepatocitos/metabolismo , Humanos , Hipercolesterolemia/sangre , Lipoproteínas VLDL/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , ARN Interferente Pequeño/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de LDL/metabolismo , Transducción de Señal , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/sangre , Regulación hacia ArribaRESUMEN
Cycles of fasting reduce autoimmunity and activate lymphocyte-dependent killing of cancer cells, but the mechanisms remain poorly understood. Three studies in this issue of Cell begin to reveal the drastic and complex effects of fasting and severe calorie restriction on the levels and localization of different immune cells and the mechanisms responsible for them.
Asunto(s)
Ayuno , Inmunidad MucosaRESUMEN
Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.
Asunto(s)
Ayuno , Células Asesinas Naturales , Ratones Endogámicos C57BL , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Humanos , Neoplasias/inmunología , Médula Ósea/inmunología , Médula Ósea/metabolismo , Ratones Noqueados , Interferón gamma/metabolismo , Interferón gamma/inmunología , Bazo/inmunología , Bazo/metabolismo , Inmunidad Innata/inmunología , Interleucina-12/metabolismo , Interleucina-12/inmunología , Receptores CXCR4/metabolismoRESUMEN
We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knockout of caveolin 1 (cav1) protein. Although we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist among adipocytes, stromal vascular cells, and, potentially, distal organs.
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Adipocitos/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Ayuno/metabolismo , Transducción de Señal , Animales , Caveolina 1/genética , Caveolina 1/metabolismo , Línea Celular , Células Cultivadas , Endotelio Vascular/citología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Diet profoundly influences physiology. Whereas over-nutrition elevates risk for disease via its influence on immunity and metabolism, caloric restriction and fasting appear to be salutogenic. Despite multiple correlations observed between diet and health, the underlying biology remains unclear. Here, we identified a fasting-induced switch in leukocyte migration that prolongs monocyte lifespan and alters susceptibility to disease in mice. We show that fasting during the active phase induced the rapid return of monocytes from the blood to the bone marrow. Monocyte re-entry was orchestrated by hypothalamic-pituitary-adrenal (HPA) axis-dependent release of corticosterone, which augmented the CXCR4 chemokine receptor. Although the marrow is a safe haven for monocytes during nutrient scarcity, re-feeding prompted mobilization culminating in monocytosis of chronologically older and transcriptionally distinct monocytes. These shifts altered response to infection. Our study shows that diet-in particular, a diet's temporal dynamic balance-modulates monocyte lifespan with consequences for adaptation to external stressors.
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Médula Ósea , Monocitos , Ratones , Animales , Células de la Médula Ósea , Ayuno , Quimiocinas/metabolismoRESUMEN
Hunger, driven by negative energy balance, elicits the search for and consumption of food. While this response is in part mediated by neurons in the hypothalamus, the role of specific cell types in other brain regions is less well defined. Here, we show that neurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter, DRNVgat and DRNVGLUT3 neurons), are reciprocally activated by changes in energy balance and that modulating their activity has opposite effects on feeding-DRNVgat neurons increase, whereas DRNVGLUT3 neurons suppress, food intake. Furthermore, modulation of these neurons in obese (ob/ob) mice suppresses food intake and body weight and normalizes locomotor activity. Finally, using molecular profiling, we identify druggable targets in these neurons and show that local infusion of agonists for specific receptors on these neurons has potent effects on feeding. These data establish the DRN as an important node controlling energy balance. PAPERCLIP.
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Regulación del Apetito , Núcleo Dorsal del Rafe/metabolismo , Neuronas/metabolismo , Animales , Peso Corporal , Encéfalo/fisiología , Núcleo Dorsal del Rafe/citología , Electrofisiología , Ayuno , Hambre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , OptogenéticaRESUMEN
Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing ß cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models. PAPERCLIP.
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Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Ayuno , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Dieta , Prueba de Tolerancia a la Glucosa , Humanos , Técnicas In Vitro , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos , Ratones , Proteínas del Tejido Nervioso/genética , Páncreas/citología , Páncreas/metabolismo , Transducción de Señal , TranscriptomaRESUMEN
Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.
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Ayuno/metabolismo , Proteínas de Microfilamentos/metabolismo , Fragmentos de Péptidos/metabolismo , Hormonas Peptídicas/metabolismo , Tejido Adiposo Blanco/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos/administración & dosificación , Ritmo Circadiano , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Ayuno/sangre , Femenino , Retardo del Crecimiento Fetal/metabolismo , Fibrilina-1 , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Proteínas de Microfilamentos/sangre , Proteínas de Microfilamentos/química , Proteínas de Microfilamentos/genética , Datos de Secuencia Molecular , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Hormonas Peptídicas/sangre , Hormonas Peptídicas/química , Hormonas Peptídicas/genética , Progeria/metabolismo , Proteínas Recombinantes/administración & dosificación , Alineación de SecuenciaRESUMEN
Control of plasma glucose level is essential to organismal survival. Sustained inflammation has been implicated in control of glucose homeostasis in cases of infection, obesity, and type 2 diabetes; however, the precise role of inflammation in these complex disease states remains poorly understood. Here, we find that sustained inflammation results in elevated plasma glucose due to increased hepatic glucose production. We find that sustained inflammation suppresses CYP7A1, leading to accumulation of intermediate metabolites at the branch point of the mevalonate pathway. This results in prenylation of RHOC, which is concomitantly induced by inflammatory cytokines. Subsequent activation of RHO-associated protein kinase results in elevated plasma glucose. These findings uncover an unexpected mechanism by which sustained inflammation alters glucose homeostasis.
Asunto(s)
Vías Biosintéticas , Hepatitis/metabolismo , Hiperglucemia/metabolismo , Ácido Mevalónico/metabolismo , Animales , Glucemia/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Colesterol 7-alfa-Hidroxilasa/metabolismo , Ayuno/sangre , Lipopolisacáridos , Ratones , Ratones Obesos , Prenilación de Proteína , Transcripción Genética , Triglicéridos/sangre , Proteínas ras/metabolismo , Quinasas Asociadas a rho/metabolismo , Proteína rhoC de Unión a GTPRESUMEN
Acute infections are associated with a set of stereotypic behavioral responses, including anorexia, lethargy, and social withdrawal. Although these so-called sickness behaviors are the most common and familiar symptoms of infections, their roles in host defense are largely unknown. Here, we investigated the role of anorexia in models of bacterial and viral infections. We found that anorexia was protective while nutritional supplementation was detrimental in bacterial sepsis. Furthermore, glucose was necessary and sufficient for these effects. In contrast, nutritional supplementation protected against mortality from influenza infection and viral sepsis, whereas blocking glucose utilization was lethal. In both bacterial and viral models, these effects were largely independent of pathogen load and magnitude of inflammation. Instead, we identify opposing metabolic requirements tied to cellular stress adaptations critical for tolerance of differential inflammatory states. VIDEO ABSTRACT.
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Manejo de la Enfermedad , Ayuno , Glucosa/metabolismo , Conducta de Enfermedad/fisiología , Gripe Humana/metabolismo , Listeriosis/metabolismo , Apoyo Nutricional/efectos adversos , Animales , Antimetabolitos/uso terapéutico , Células Cultivadas , Desoxiglucosa/uso terapéutico , Glucosa/administración & dosificación , Humanos , Inflamación , Gripe Humana/fisiopatología , Gripe Humana/terapia , Lipopolisacáridos , Listeriosis/mortalidad , Listeriosis/fisiopatología , Listeriosis/terapia , Masculino , Ratones , Ratones Endogámicos C57BL , Poli I-C , Sepsis/inducido químicamente , Sepsis/prevención & control , Factor de Transcripción CHOP/metabolismoRESUMEN
The glucagon-PKA signal is generally believed to control hepatic gluconeogenesis via the CREB transcription factor. Here we uncovered a distinct function of this signal in directly stimulating histone phosphorylation for gluconeogenic gene regulation in mice. In the fasting state, CREB recruited activated PKA to regions near gluconeogenic genes, where PKA phosphorylated histone H3 serine 28 (H3S28ph). H3S28ph, recognized by 14-3-3ζ, promoted recruitment of RNA polymerase II and transcriptional stimulation of gluconeogenic genes. In contrast, in the fed state, more PP2A was found near gluconeogenic genes, which counteracted PKA by dephosphorylating H3S28ph and repressing transcription. Importantly, ectopic expression of phosphomimic H3S28 efficiently restored gluconeogenic gene expression when liver PKA or CREB was depleted. These results together highlight a different functional scheme in regulating gluconeogenesis by the glucagon-PKA-CREB-H3S28ph cascade, in which the hormone signal is transmitted to chromatin for rapid and efficient gluconeogenic gene activation.
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Glucagón , Gluconeogénesis , Animales , Ratones , Gluconeogénesis/genética , Glucagón/metabolismo , Histonas/metabolismo , Fosforilación , Proteínas 14-3-3/metabolismo , Hígado/metabolismo , Ayuno/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismoRESUMEN
The kynurenine pathway of tryptophan metabolism is involved in the pathogenesis of several brain diseases, but its physiological functions remain unclear. We report that kynurenic acid, a metabolite in this pathway, functions as a regulator of food-dependent behavioral plasticity in C. elegans. The experience of fasting in C. elegans alters a variety of behaviors, including feeding rate, when food is encountered post-fast. Levels of neurally produced kynurenic acid are depleted by fasting, leading to activation of NMDA-receptor-expressing interneurons and initiation of a neuropeptide-y-like signaling axis that promotes elevated feeding through enhanced serotonin release when animals re-encounter food. Upon refeeding, kynurenic acid levels are eventually replenished, ending the elevated feeding period. Because tryptophan is an essential amino acid, these findings suggest that a physiological role of kynurenic acid is in directly linking metabolism to activity of NMDA and serotonergic circuits, which regulate a broad range of behaviors and physiologies.
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Conducta Animal , Caenorhabditis elegans/metabolismo , Conducta Alimentaria , Ácido Quinurénico/metabolismo , Animales , Señales (Psicología) , Ayuno , Interneuronas/metabolismo , Quinurenina/metabolismo , Neuronas/metabolismo , Neuropéptidos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Serotonina , Transducción de Señal , Transaminasas/metabolismo , Triptófano/metabolismoRESUMEN
Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology, and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we 1) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; 2) discuss the interaction between circadian molecular metabolism and TRE; 3) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; 4) summarize other time-related dietary interventions that have been studied in people; and 4) identify current gaps in knowledge and provide a framework for future research directions.
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Ritmo Circadiano , Ayuno , Peso Corporal , Ritmo Circadiano/fisiología , Ingestión de Alimentos , Ayuno/fisiología , HumanosRESUMEN
Induction of beige cells causes the browning of white fat and improves energy metabolism. However, the central mechanism that controls adipose tissue browning and its physiological relevance are largely unknown. Here, we demonstrate that fasting and chemical-genetic activation of orexigenic AgRP neurons in the hypothalamus suppress the browning of white fat. O-linked ß-N-acetylglucosamine (O-GlcNAc) modification of cytoplasmic and nuclear proteins regulates fundamental cellular processes. The levels of O-GlcNAc transferase (OGT) and O-GlcNAc modification are enriched in AgRP neurons and are elevated by fasting. Genetic ablation of OGT in AgRP neurons inhibits neuronal excitability through the voltage-dependent potassium channel, promotes white adipose tissue browning, and protects mice against diet-induced obesity and insulin resistance. These data reveal adipose tissue browning as a highly dynamic physiological process under central control, in which O-GlcNAc signaling in AgRP neurons is essential for suppressing thermogenesis to conserve energy in response to fasting.
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Tejido Adiposo Pardo/metabolismo , Dieta , N-Acetilglucosaminiltransferasas/metabolismo , Neuronas/metabolismo , Tejido Adiposo Blanco/metabolismo , Proteína Relacionada con Agouti/metabolismo , Animales , Ayuno , Femenino , Ghrelina/metabolismo , Hipotálamo/citología , Hipotálamo/metabolismo , Resistencia a la Insulina , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , N-Acetilglucosaminiltransferasas/genética , Obesidad/metabolismo , Obesidad/prevención & controlRESUMEN
Fasting initiates a multitude of adaptations to allow survival. Activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent release of glucocorticoid hormones is a key response that mobilizes fuel stores to meet energy demands1-5. Despite the importance of the HPA axis response, the neural mechanisms that drive its activation during energy deficit are unknown. Here, we show that fasting-activated hypothalamic agouti-related peptide (AgRP)-expressing neurons trigger and are essential for fasting-induced HPA axis activation. AgRP neurons do so through projections to the paraventricular hypothalamus (PVH), where, in a mechanism not previously described for AgRP neurons, they presynaptically inhibit the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis (BNST) that otherwise restrain activity of corticotrophin-releasing hormone (CRH)-expressing neurons. This disinhibition of PVHCrh neurons requires γ-aminobutyric acid (GABA)/GABA-B receptor signalling and potently activates the HPA axis. Notably, stimulation of the HPA axis by AgRP neurons is independent of their induction of hunger, showing that these canonical 'hunger neurons' drive many distinctly different adaptations to the fasted state. Together, our findings identify the neural basis for fasting-induced HPA axis activation and uncover a unique means by which AgRP neurons activate downstream neurons: through presynaptic inhibition of GABAergic afferents. Given the potency of this disinhibition of tonically active BNST afferents, other activators of the HPA axis, such as psychological stress, may also work by reducing BNST inhibitory tone onto PVHCrh neurons.
Asunto(s)
Ayuno , Sistema Hipotálamo-Hipofisario , Neuronas , Sistema Hipófiso-Suprarrenal , Proteína Relacionada con Agouti/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Ayuno/fisiología , Neuronas GABAérgicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Sistema Hipotálamo-Hipofisario/citología , Sistema Hipotálamo-Hipofisario/metabolismo , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/citología , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/citología , Sistema Hipófiso-Suprarrenal/inervación , Sistema Hipófiso-Suprarrenal/metabolismo , Terminales Presinápticos/metabolismo , Núcleos Septales/citología , Núcleos Septales/metabolismoRESUMEN
Mammals undergo regular cycles of fasting and feeding that engage dynamic transcriptional responses in metabolic tissues. Here we review advances in our understanding of the gene regulatory networks that contribute to hepatic responses to fasting and feeding. The advent of sequencing and -omics techniques have begun to facilitate a holistic understanding of the transcriptional landscape and its plasticity. We highlight transcription factors, their cofactors, and the pathways that they impact. We also discuss physiological factors that impinge on these responses, including circadian rhythms and sex differences. Finally, we review how dietary modifications modulate hepatic gene expression programs.
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Ingestión de Alimentos/genética , Ayuno/fisiología , Regulación de la Expresión Génica/fisiología , Hígado/metabolismo , Animales , Ritmo Circadiano , Redes Reguladoras de Genes/genética , Humanos , Factores Sexuales , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Stem cells maintain tissues by balancing self-renewal with differentiation. A stem cell's local microenvironment, or niche, informs stem cell behavior and receives inputs at multiple levels. Increasingly, it is becoming clear that the overall metabolic status of an organism or metabolites themselves can function as integral members of the niche to alter stem cell fate. Macroscopic dietary interventions such as caloric restriction, the ketogenic diet, and a high-fat diet systemically alter an organism's metabolic state in different ways. Intriguingly, however, they all converge on a propensity to enhance self-renewal. Here, we highlight our current knowledge on how dietary changes feed into stem cell behavior across a wide variety of tissues and illuminate possible explanations for why diverse interventions can result in similar stem cell phenotypes. In so doing, we hope to inspire new avenues of inquiry into the importance of metabolism in stem cell homeostasis and disease.
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Dieta , Células Madre/fisiología , Animales , Dieta Alta en Grasa/efectos adversos , Ayuno/fisiología , Glucosa/metabolismo , Humanos , Metabolismo de los Lípidos/fisiología , Células Madre/microbiología , Células Madre/parasitología , Estrés Fisiológico/fisiologíaRESUMEN
Chronic caloric restriction (CR) has powerful anticarcinogenic actions in both preclinical and clinical studies but may be difficult to sustain. As an alternative to CR, there has been growing interest in intermittent fasting (IF) in both the scientific and lay community as a result of promising study results, mainly in experimental animal models. According to a survey by the International Food Information Council Foundation, IF has become the most popular diet in the last year, and patients with cancer are seeking advice from oncologists about its beneficial effects for cancer prevention and treatment. However, as discussed in this review, results from IF studies in rodents are controversial and suggest potential detrimental effects in certain oncologic conditions. The effects of IF on human cancer incidence and prognosis remain unknown because of a lack of high-quality randomized clinical trials. Preliminary studies suggest that prolonged fasting in some patients who have cancer is safe and potentially capable of decreasing chemotherapy-related toxicity and tumor growth. However, because additional trials are needed to elucidate the risks and benefits of fasting for patients with cancer, the authors would not currently recommend patients undergoing active cancer treatment partake in IF outside the context of a clinical trial. IF may be considered in adults seeking cancer-prevention benefits through means of weight management, but whether IF itself affects cancer-related metabolic and molecular pathways remains unanswered.
Asunto(s)
Ayuno , Neoplasias/terapia , Animales , Restricción Calórica , Ensayos Clínicos como Asunto , Dieta , Humanos , Obesidad/complicaciones , Pronóstico , RiesgoRESUMEN
Survival in the wild requires organismal adaptations to the availability of nutrients. Endosomes and lysosomes are key intracellular organelles that couple nutrition and metabolic status to cellular responses, but how they detect cytosolic ATP levels is not well understood. Here, we identify an endolysosomal ATP-sensitive Na(+) channel (lysoNa(ATP)). The channel is a complex formed by two-pore channels (TPC1 and TPC2), ion channels previously thought to be gated by nicotinic acid adenine dinucleotide phosphate (NAADP), and the mammalian target of rapamycin (mTOR). The channel complex detects nutrient status, becomes constitutively open upon nutrient removal and mTOR translocation off the lysosomal membrane, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis. Mutant mice lacking lysoNa(ATP) have much reduced exercise endurance after fasting. Thus, TPCs make up an ion channel family that couples the cell's metabolic state to endolysosomal function and are crucial for physical endurance during food restriction.