RESUMEN
Our previous research identified interleukin-4 (IL-4) as a key regulator of glucose/lipid metabolism, circulatory leptin levels, and insulin action, suggesting its potential as a therapeutic target for obesity and related complications. This study aimed to further elucidate the role of IL-4 in regulating hypothalamic appetite-controlling neuropeptides using leptin dysfunctional Leptin145E/145E mice as the experimental model. IL-4 significantly reduces body weight, food intake, and serum glucose levels. Our data demonstrated that IL-4 exhibits multiple functions in regulating hypothalamic appetite control, including downregulating orexigenic agouti-related peptide and neuropeptide Y levels, promoting expression of anorexigenic proopiomelanocortin, alleviating microenvironmental hypothalamic inflammation, enhancing leptin and insulin pathway, and attenuating insulin resistance. Furthermore, IL-4 promotes uncoupling protein 1 expression of white adipose tissue (WAT), suggesting its role in triggering WAT-beige switch. In summary, this study uncovers novel function of IL-4 in mediating food-intake behaviors and metabolic efficiency by regulating hypothalamic appetite-control and WAT browning activities. These findings support the therapeutic potential of targeting hypothalamic inflammation and reducing adiposity through IL-4 intervention for tackling the pandemic increasing prevalence of obesity and associated metabolic disorders.
Asunto(s)
Hipotálamo , Insulina , Interleucina-4 , Leptina , Transducción de Señal , Animales , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Interleucina-4/metabolismo , Ratones , Transducción de Señal/efectos de los fármacos , Leptina/metabolismo , Insulina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Masculino , Quinasas Janus/metabolismo , Regulación del Apetito/efectos de los fármacos , Apetito/efectos de los fármacos , Factores de Transcripción STAT/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Tejido Adiposo Blanco/metabolismoRESUMEN
Inhibitory γ-aminobutyric acid (GABA)-ergic interneurons mediate inhibition in neuronal circuitry and support normal brain function. Consequently, dysregulation of inhibition is implicated in various brain disorders. Parvalbumin (PV) and somatostatin (SST) interneurons, the two major types of GABAergic inhibitory interneurons in the hippocampus, exhibit distinct morpho-physiological properties and coordinate information processing and memory formation. However, the molecular mechanisms underlying the specialized properties of PV and SST interneurons remain unclear. This study aimed to compare the transcriptomic differences between these two classes of interneurons in the hippocampus using the ribosome tagging approach. The results revealed distinct expressions of genes such as voltage-gated ion channels and GABAA receptor subunits between PV and SST interneurons. Gabrd and Gabra6 were identified as contributors to the contrasting tonic GABAergic inhibition observed in PV and SST interneurons. Moreover, some of the differentially expressed genes were associated with schizophrenia and epilepsy. In conclusion, our results provide molecular insights into the distinct roles of PV and SST interneurons in health and disease.
RESUMEN
Alzheimer disease (AD), a progressive neurodegenerative disorder, is mainly caused by the interaction of genetic and environmental factors. The impact of environmental factors on the genetic mutation in the amyloid precursor protein (APP) is not well characterized. We hypothesized that endoplasmic reticulum (ER) stress would promote disease for the patient carrying the APP D678H mutation. Therefore, we analyzed the impact of a familial AD mutation on amyloid precursor protein (APP D678H) under ER stress. Induced pluripotent stem cells (iPSCs) from APP D678H mutant carrier was differentiated into neurons, which were then analyzed for AD-like changes. Immunocytochemistry and whole-cell patch-clamp recording revealed that the derived neurons on day 28 after differentiation showed neuronal markers and electrophysiological properties similar to those of mature neurons. However, the APP D678H mutant neurons did not have significant alterations in the levels of amyloid-ß (Aß) and phosphorylated tau (pTau) compared to its isogenic wild-type neurons. Only under ER stress, the neurons with the APP D678H mutation had more Aß and pTau via immune detection assays. The higher level of Aß in the APP D678H mutant neurons was probably due to the increased level of ß-site APP cleaving enzyme (BACE1) and decreased level of Aß-degrading enzymes under ER stress. Increased Aß and pTau under ER stress reduced the N-methyl-D-aspartate receptor (NMDAR) in Western blot analysis and altered electrophysiological properties in the mutant neurons. Our study provides evidence that the interaction between genetic mutation and ER stress would induce AD-like changes. Cover Image for this issue: https://doi.org/10.1111/jnc.15420.
Asunto(s)
Enfermedad de Alzheimer , Células Madre Pluripotentes Inducidas , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Estrés del Retículo Endoplásmico/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Neuronas/metabolismo , Fenotipo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
BACKGROUND: Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via regulating collpasin response mediator protein-2 (CRMP2). Accordingly, roles of CRMP2 in CRC and CRC-DM patients were investigated for elucidating the molecular convergence of CRC and DM. METHODS: CRMP2 profile in tumor tissues from CRC and CRC-DM patients was investigated to explore the link between CRC and DM etiology. Meanwhile, molecular mechanism of glucose to regulate CRMP2 profile and CRC characteristics was examined in vitro and in vivo. RESULTS: CRMP2 was significantly lower in tumor lesions and associated with advanced tumor stage in CRC-DM patients. Physiological hyperglycemia suppressed CRMP2 expression/activity and augmented malignant characteristics of CRC cells. Hyperglycemia promotes actin de-polymerization, cytoskeleton flexibility and cell proliferation/metastasis by downregulating CRMP2 profile and thus contributes to CRC disease progression. CONCLUSIONS: This study uncovers molecular evidence to substantiate and elucidate the link between CRC and T2DM, as well as characterizing the roles of CRMP2 in CRC-DM. Accordingly, altered metabolic adaptations are promising targets for anti-diabetic and cancer strategies.
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Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Hiperglucemia , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Neoplasias Colorrectales/complicaciones , Comorbilidad , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas del Tejido Nervioso/genética , FosforilaciónRESUMEN
The expansion of adipose tissue mass is the primary characteristic of the process of becoming obesity, which causes chronic adipose inflammation and is closely associated with type 2 diabetes mellitus (T2DM). Adipocyte hypertrophy restricts oxygen availability, leading to microenvironmental hypoxia and adipose dysfunction. This study aimed at investigating the effects of oxygenated water (OW) on adipocyte differentiation (adipogenesis) and the metabolic function of mature adipocytes. The effects of OW on adipogenesis and the metabolic function of mature adipocytes were examined. Meanwhile, the in vivo metabolic effects of long-term OW consumption on diet-induced obesity (DIO) mice were investigated. OW inhibited adipogenesis and lipid accumulation through down-regulating critical adipogenic transcription factors and lipogenic enzymes. While body weight, blood and adipose parameters were not significantly improved by long-term OW consumption, transient circulatory triglyceride-lowering and glucose tolerance-improving effects were identified. Notably, hepatic lipid contents were significantly reduced, indicating that the DIO-induced hepatic steatosis was attenuated, despite no improvements in fibrosis and lipid contents in adipose tissue being observed in the OW-drinking DIO mice. The study provides evidence regarding OW's effects on adipogenesis and mature adipocytes, and the corresponding molecular mechanisms. OW exhibits transient triglyceride-lowering and glucose tolerance-improving activity as well as hepatic steatosis-attenuating functions.
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Adipogénesis/efectos de los fármacos , Hígado Graso/tratamiento farmacológico , Lipogénesis/efectos de los fármacos , Agua/metabolismo , Células 3T3-L1 , Adipocitos/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Hígado Graso/metabolismo , Hígado Graso/patología , Humanos , Ratones , Ratones Obesos/genética , Ratones Obesos/metabolismo , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , Obesidad/prevención & control , Oxígeno/metabolismo , Agua/farmacologíaRESUMEN
Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications.
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Dieta Alta en Grasa/efectos adversos , Inflamación/prevención & control , Interleucina-4/farmacología , Leptina/deficiencia , Enfermedades Metabólicas/prevención & control , Obesidad/prevención & control , Adyuvantes Inmunológicos/farmacología , Animales , Inflamación/etiología , Resistencia a la Insulina , Masculino , Enfermedades Metabólicas/etiología , Ratones , Ratones Endogámicos C57BL , Obesidad/etiologíaRESUMEN
As emerging evidence suggesting neurodegenerative diseases and metabolic diseases have common pathogenesis, we hypothesized that the neurite outgrowth-controlling collapsin response mediator protein 2 (CRMP2) was involved in energy homeostasis. Therefore, putative roles of CRMP2 in adipocyte differentiation (adipogenesis) and lipid metabolism were explored and addressed in this study. CRMP2 expression profiles were in vitro and in vivo characterized during adipogenic process of 3T3-L1 pre-adipocytes and diet-induced obese (DIO) mice, respectively. Effects of CRMP2 on lipid metabolism and deposits were also analyzed. Our data revealed that CRMP2 expression pattern was coupled with adipogenic stages. CRMP2 overexpression inhibited cell proliferation at MCE phase, and significantly reduced lipid contents by down-regulating adipogenesis-driving transcription factors and lipid-synthesizing enzymes. Interestingly, GLUT4 translocation and the lipid droplets fusion were disturbed in CRMP2-silencing cells by affecting actin polymerization. Moreover, adipose CRMP2 was significantly increased in DIO mice, indicating CRMP2 is associated with obesity. Accordingly, CRMP2 exerts multiple functions in adipogenesis and lipid deposits through mediating cell proliferation, glucose/lipid metabolism and cytoskeleton dynamics. The present study identifies novel roles of CRMP2 in mediating adipogenesis and possible implication in metabolic disorders, as well as provides molecular evidence supporting the link of pathogenesis between neurodegenerative diseases and metabolic abnormalities.
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Adipocitos/metabolismo , Citoesqueleto/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Metabolismo de los Lípidos/genética , Proteínas del Tejido Nervioso/metabolismo , Obesidad/metabolismo , Células 3T3-L1 , Actinas/metabolismo , Adipocitos/citología , Adipogénesis/genética , Animales , Proliferación Celular/genética , Dieta Alta en Grasa , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Lípidos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Obesidad/genética , ARN Interferente Pequeño , Transducción de Señal/genética , Regulación hacia ArribaRESUMEN
Anti-inflammatory cytokine interleukin-4 (IL-4) promotes glucose tolerance and insulin sensitivity while reduces lipid deposits. However, the effects of IL-4 on energy metabolism in muscle, the largest insulin-targeting organ, remain obscure. The study aimed at addressing the roles of IL-4 in myocyte differentiation (myogenesis) and energy metabolism of muscle cells. Effects of IL-4 on myogenesis, and interaction between IL-4 and insulin on glucose metabolism of C2C12 myoblasts and the terminal differentiated myocytes were analyzed. IL-4 improved GLUT4 translocation and tended to elevate glucose uptake by boosting insulin signaling. In diabetic mice, transient and long-term IL-4 showed differential effects on insulin signaling and efficacy. The study provides evidence to address the roles of IL-4 in mediating whole-body muscle reservoir and glucose metabolism, as well as the interaction between immune responses and energy homeostasis. IL-4 has dual potential to act as an adjuvant therapeutic target for sarcopenia to preserve muscle mass and insulin resistance to improve insulin sensitivity, which implicates the regulation of immune system to the muscle differentiation and exercise performance.
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Interleucina-4/farmacología , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Desarrollo de Músculos/efectos de los fármacos , Animales , Transporte Biológico/efectos de los fármacos , Western Blotting , Diferenciación Celular/efectos de los fármacos , Línea Celular , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Mioblastos/efectos de los fármacos , Mioblastos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Accumulating evidence indicates that inflammation participates in the pathophysiological progress from insulin resistance, obesity, metabolic abnormalities, and type 2 diabetes mellitus. Our previous study reveals that interleukin-4 (IL-4) inhibits adipogenesis and promotes lipolysis to decrease lipid deposits by enhancing the activity of hormone sensitive lipase (HSL). The present study further dissects and characterizes the molecular mechanism of IL-4 in regulating HSL expression and lipolytic activity in the terminal differentiated 3T3-L1 mature adipocytes. Our results showed that IL-4 increased cAMP which then enhanced PKA activity and subsequent phosphorylation of HSL and perilipin. The phosphorylated HSL (p-HSL) translocated from cytoplasm to the surface of lipid droplets and exhibited lipolytic function. After being phosphorylated, p-perilipin also facilitated lipolysis through interacting with p-HSL. The in vitro findings were further verified by in vivo study in which IL-4 exhibited pro-lipolytic activity and enhanced HSL activity. In summary, the net outcome of IL-4 treatment is to reduce lipid storage by promoting lipolysis through enhancing HSL activity via cAMP/PKA pathway, the major route leading to lipolysis.
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Interleucina-4/metabolismo , Metabolismo de los Lípidos , Esterol Esterasa/genética , Esterol Esterasa/metabolismo , Células 3T3-L1 , Adipocitos/metabolismo , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Activación Enzimática/efectos de los fármacos , Estabilidad de Enzimas/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-4/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Lipólisis/efectos de los fármacos , Ratones , Modelos Biológicos , Fosforilación , Proteolisis/efectos de los fármacosRESUMEN
Type 2 diabetes mellitus (T2DM), with dysregulated hepatic gluconeogenesis as the major cause of fasting hyperglycemia, is closely associated with chronic inflammation. We previously demonstrated interleukin-4 (IL-4) improves insulin sensitivity and glucose tolerance while reducing lipid deposits. The present study examined the in vitro effects of IL-4 on insulin signaling molecules, glucose uptake, and lipid metabolism in hepatocytes, as well as in vivo effects on hepatic adiposity, for elucidating the roles of IL-4 in hepatic energy metabolism. Potential interaction between IL-4 and insulin in regulating hepatic metabolism was also investigated. Our results showed that IL-4 enhanced Akt and GSK-3α/ß phosphorylations, which in turn promoted glycogen synthesis. IL-4 not only potentiated basal glucose uptake by upregulating glucose transporter 2 expression but also promoted insulin-induced glucose uptake. Additionally, IL-4 increased triglyceride contents through facilitating free fatty acid uptake and expression/activity of lipogenic enzymes. The major effects of IL-4 on the liver were to promote energy storage by boosting insulin-stimulated glucose uptake and lipid synthesis. This study provides evidence to implicate the novel roles of IL-4 in mediating hepatic glucose and lipid metabolism, interactions between immune responses and metabolic homeostasis, and the involvement of IL-4 in metabolic abnormalities.
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Glucosa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Insulina/farmacología , Interleucina-4/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Western Blotting , Diabetes Mellitus Tipo 2/metabolismo , Células Hep G2 , Humanos , Masculino , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Triglicéridos/metabolismoRESUMEN
Type 2 diabetes mellitus (T2DM) is associated with chronic inflammation, suggesting the metabolic abnormalities are originated from or exacerbated by cytokine overproduction. Cytokines and counter-regulatory molecules are crucial in keeping the balance of immune responses and, therefore, are potential candidates involved in T2DM etiology, development and complications. Our previous reports identify several significant associations between the genotypes of cytokine genes and T2DM and/or the clinical lipid parameters, which strongly suggest the participation of immune-regulatory molecules in lipid metabolism. The aim of this study is to determine the distribution of gene encoding cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), a T-cell negative regulator, in T2DM patients and health subjects. Genomic DNA was extracted from 287 Taiwanese T2DM patients and 278 ethnic- and age- matched healthy subjects, and two CTLA-4 polymorphisms (-318 C/T and +49 A/G) were analyzed by polymerase chain reaction-restriction fragment length polymorphism. Intriguingly, CTLA-4 -318 genotype was associated with circulatory triglycerides in T2DM subjects (P=0.019) although no significant association between CTLA-4 -318 (P=0.119) and +49 (P=0.2) genotypes with T2DM was identified. In addition, CTLA-4 +49 genotype was significantly associated with the ratio between total cholesterol and high-density lipoprotein (P=0.004) in control subjects. Our results suggest that CTLA-4 may be involved in lipid metabolism and affect T2DM disease progression and/or the development of diabetic complications although this gene does not represent a major risk factor for T2DM.
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Antígeno CTLA-4/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Regiones Promotoras Genéticas , Adulto , Anciano , Pueblo Asiatico , Diabetes Mellitus Tipo 2/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/patologíaRESUMEN
OBJECTIVE: Adipogenesis determines the number of adipocytes which is increased when individuals become obese. Mitochondria undergo remarkable morphological and functional changes during adipogenesis. PTEN-induced kinase 1 (PINK1) is pivotal to maintain mitochondrial homeostasis in neural cells. The present study aimed at investigating effects of PINK1 on adipogenesis and energy metabolism. METHODS: Expression of presenilin associated rhomboid-like protein (PARL), PINK1 and Parkin, as well as the interaction among these proteins was temporally examined during adipogenesis. In addition, the alterations of mitochondrial mass and the energy metabolism were also analyzed. RESULTS: Adipogenic process can be dissected into 3 stages according to the participation of PARL-PINK1-Parkin system. (1) When pre-adipocytes are switched to differentiation, f-PINK1 is subjected to PARL cleavage to generate s-PINK1 at the early stage of differentiation (0-4day). Mitochondrial mass is increased for generating ambient energy to meet the demands for cellular remodeling. (2) At the second stage (5-6day), s-PINK1 persistently accumulates in mitochondria and translocates into cytoplasm to mediate Parkin degradation. Mitochondria are fragmented to reduce their mass. (3) At the late stage (7-8day), only residual autophagy activity is remained when excess mitochondria have been eliminated. This mitochondria clearance maintains energy consumption of mature adipocytes at the minimal levels for storing energy. PARL silencing aborts adipogenesis by inhibiting PPARγ expression and the finely-orchestrated events. CONCLUSIONS: Our findings reveal the sequential adipogenic events directed by PARL-PINK1-Parkin system, add more evidence supporting the convergence of pathogenesis leading to neurodegenerative and metabolic diseases, and provide substantial information for developing novel therapeutic strategies by manipulating adipogenesis.