RESUMEN
It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKß) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor α (TNF-α) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKß-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKß phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKß activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKß-mediated hepatic inflammation in glucose homeostasis.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Estrés del Retículo Endoplásmico , Glucosa/metabolismo , Quinasa I-kappa B/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Línea Celular Tumoral , Homeostasis , Humanos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/metabolismo , Fosforilación , Estabilidad ProteicaRESUMEN
Despite all modern advances in medicine, an effective drug treatment of obesity has not been found yet. Discovery of leptin two decades ago created hopes for treatment of obesity. However, development of leptin resistance has been a big obstacle, mitigating a leptin-centric treatment of obesity. Here, by using in silico drug-screening methods, we discovered that Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, is a powerful anti-obesity agent. Celastrol suppresses food intake, blocks reduction of energy expenditure, and leads to up to 45% weight loss in hyperleptinemic diet-induced obese (DIO) mice by increasing leptin sensitivity, but it is ineffective in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mouse models. These results indicate that Celastrol is a leptin sensitizer and a promising agent for the pharmacological treatment of obesity.
Asunto(s)
Fármacos Antiobesidad/administración & dosificación , Obesidad/tratamiento farmacológico , Animales , Fármacos Antiobesidad/metabolismo , Metabolismo Energético , Perfilación de la Expresión Génica , Glucosa/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Ratones , Triterpenos Pentacíclicos , Extractos Vegetales/administración & dosificación , Tripterygium/química , Triterpenos/administración & dosificaciónRESUMEN
Endoplasmic reticulum (ER) stress has been shown to contribute to various metabolic diseases, including non-alcoholic fatty liver disease and type 2 diabetes. Reduction of ER stress by treatment with chemical chaperones or overexpression of ER chaperone proteins alleviates hepatic steatosis. Nonetheless, X-box binding protein 1s (XBP1s), a key transcription factor that reduces ER stress, has been proposed as a lipogenic transcription factor. In this report, we document that XBP1s leads to suppression of lipogenic gene expression and reduction of hepatic triglyceride and diacylglycerol content in livers of diet-induced obese and genetically obese and insulin-resistant ob/ob mice. Furthermore, we also show that PKCϵ activity, which correlates with fatty liver and which causes insulin resistance, was significantly reduced in diet-induced obese mice. Finally, we have shown that XBP1s reduces the hepatic fatty acid synthesis rate and enhances macrolipophagy, an initiating step in lipolysis. Our results reveal that XBP1s reduces hepatic lipogenic gene expression and improves hepatosteatosis in mouse models of obesity and insulin resistance, which leads us to conclude that XBP1s has anti-lipogenic properties in the liver.
Asunto(s)
Estrés del Retículo Endoplásmico , Ácidos Grasos/biosíntesis , Hígado Graso/metabolismo , Regulación de la Expresión Génica , Resistencia a la Insulina , Lipogénesis , Obesidad/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Modelos Animales de Enfermedad , Ácidos Grasos/genética , Hígado Graso/genética , Hígado Graso/patología , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Obesos , Obesidad/genética , Obesidad/patología , Proteína Quinasa C-epsilon/genética , Proteína Quinasa C-epsilon/metabolismo , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.
Asunto(s)
Diabetes Mellitus Tipo 2 , Glucosa , Obesidad , Proteínas de Unión a Tacrolimus , Respuesta de Proteína Desplegada , Animales , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Homeostasis , Ratones , Ratones Obesos , Obesidad/metabolismo , Transducción de Señal , Proteínas de Unión a Tacrolimus/metabolismoRESUMEN
Obesity is a debilitating disease that has become a global epidemic. Although progress is being made, the underlying molecular mechanism by which obesity develops still remains elusive. Recently, we reported that the expression levels of bromodomain-containing protein 7 (BRD7) are significantly reduced in the liver of obese mice. However, it is not clear whether decreased levels of hepatic BRD7 are directly associated with the development of obesity and disturbance in glucose homeostasis. Here, using heterozygous BRD7 knockout and liver-specific BRD7 knockout mouse models, we report that reduced BRD7 levels lead to increased weight gain with little effect on glucose metabolism. On the other hand, upregulating BRD7 in the liver starting at an early age protects mice from gaining excessive weight and developing glucose intolerance and insulin resistance when challenged with a high-fat diet.
Asunto(s)
Proteínas Cromosómicas no Histona/deficiencia , Predisposición Genética a la Enfermedad , Hiperglucemia/sangre , Hiperglucemia/genética , Obesidad/sangre , Obesidad/genética , Animales , Biomarcadores , Glucemia , Peso Corporal , Modelos Animales de Enfermedad , Estudios de Asociación Genética , Genotipo , Homeostasis , Hiperglucemia/diagnóstico , Insulina/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Ratones , Ratones Noqueados , Obesidad/diagnósticoRESUMEN
Celastrol is a leptin-sensitizing agent with profound anti-obesity effects in diet-induced obese (DIO) mice. However, the genes and pathways that mediate celastrol-induced leptin sensitization have not been fully understood. By comparing the hypothalamic transcriptomes of celastrol and vehicle-treated DIO mice, we identified lipocalin-2 (Lcn2) as the gene most strongly upregulated by celastrol. LCN2 was previously suggested as an anorexigenic and anti-obesity agent. Celastrol increased LCN2 protein levels in hypothalamus, liver, fat, muscle, and bone marrow, as well as in the plasma. However, genetic deficiency of LCN2 altered neither the development of diet-induced obesity, nor the ability of celastrol to promote weight loss and improve obesity-associated dyshomeostasis. We conclude that LCN2 is dispensable for both high fat diet-induced obesity and its therapeutic reduction by celastrol.
Asunto(s)
Fármacos Antiobesidad/farmacología , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Lipocalina 2/fisiología , Triterpenos/farmacología , Pérdida de Peso/efectos de los fármacos , Animales , Femenino , Expresión Génica/efectos de los fármacos , Lipocalina 2/deficiencia , Lipocalina 2/metabolismo , Masculino , Ratones Endogámicos C57BL , Obesidad/metabolismo , Triterpenos PentacíclicosRESUMEN
Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far1. The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Leptina/farmacología , Obesidad/tratamiento farmacológico , Receptores Tipo I de Interleucina-1/metabolismo , Triterpenos/uso terapéutico , Animales , Fármacos Antiobesidad/farmacología , Dieta , Células HEK293 , Humanos , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Triterpenos Pentacíclicos , Triterpenos/farmacologíaRESUMEN
OBJECTIVE: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism. METHODS: We investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. RESULTS: We show that PGC-1α interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction. CONCLUSIONS: Our findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s.
Asunto(s)
Gluconeogénesis , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Animales , Línea Celular , Células Cultivadas , Proteína Forkhead Box O1/metabolismo , Homeostasis , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Unión Proteica , Proteína 1 de Unión a la X-Box/genéticaRESUMEN
The increasing global prevalence of obesity and its associated disorders points to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules that have mRNA expression profiles similar to that of celastrol, a naturally occurring compound that we previously identified as a leptin sensitizer. Through this process, we identified another naturally occurring compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin-A treatment of mice with diet-induced obesity (DIO) resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities, including hepatic steatosis. Withaferin-A treatment marginally affected the body weight of ob/ob and db/db mice, both of which are deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism that occur independently of its leptin-sensitizing effect. Our results show that the metabolic abnormalities of DIO can be mitigated by sensitizing animals to endogenous leptin, and they indicate that withaferin A is a potential leptin sensitizer with additional antidiabetic actions.