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AIMS: Apelin is a recently identified adipokine known to improve glucose tolerance and insulin sensitivity in murine models. This study was dedicated to the proof of concept that apelin administration also enhances insulin sensitivity in humans. MATERIALS AND METHODS: Healthy overweight men were enrolled in this randomized, double-blind, placebo-controlled, cross-over study that successively considered the efficacy and the tolerance of 2 doses of (pyr1)-Apelin-13. A first group of subjects received 9 nmol/kg (n = 8) of (pyr1)-Apelin-13 and, after examination of safety data, a second group received 30 nmol/kg (n = 8). Each volunteer underwent 2 hyperinsulinaemic-euglycaemic clamps where the basal level of glucose infusion rate (GIR) was measured from the 90th to the 120th minute (level 1). Continuous intravenous administration of apelin or placebo was ongoing for 2 hours and GIR was finally evaluated from the 210th to the 240th minute (level 2). Primary evaluation endpoint was the difference in GIR between level 2 and level 1 (ΔGIR). RESULTS: A slight increase in ΔGIR was observed with the low apelin dose (0.65 ± 0.71 mg/kg/min, P = .055) whereas the highest dose significantly improved insulin sensitivity (0.82 ± 0.71 mg/kg/min, P = .033). Cardiovascular monitoring and safety reports did not reveal any side effect of apelin administration. CONCLUSION: As the first demonstration of the insulin-sensitizing action of apelin in humans, alongside numerous studies in rodents, this trial confirms that the apelin/APJ pathway should be considered as a new target to design alternative therapeutic strategies to control insulin resistance in type 2 diabetic patients.
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Fármacos Antiobesidad/uso terapéutico , Receptores de Apelina/agonistas , Apelina/análogos & derivados , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Sobrepeso/tratamiento farmacológico , Adolescente , Adulto , Fármacos Antiobesidad/administración & dosificación , Fármacos Antiobesidad/efectos adversos , Apelina/efectos adversos , Apelina/sangre , Apelina/uso terapéutico , Receptores de Apelina/metabolismo , Índice de Masa Corporal , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Técnica de Clampeo de la Glucosa , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Infusiones Intravenosas , Péptidos y Proteínas de Señalización Intercelular/administración & dosificación , Péptidos y Proteínas de Señalización Intercelular/efectos adversos , Péptidos y Proteínas de Señalización Intercelular/farmacocinética , Masculino , Sobrepeso/sangre , Sobrepeso/metabolismo , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/efectos adversos , Fragmentos de Péptidos/farmacocinética , Fragmentos de Péptidos/uso terapéutico , Prueba de Estudio Conceptual , Adulto JovenRESUMEN
The APJ receptor cloned in 1993 found its ligand in 1998 with the discovery of apelin. The presence of APJ in the central nervous system (more particularly in the hypothalamus) and in various tissues (heart, blood vessels, stomach, etc.) makes it a potential pharmacological target. Interest in APJ has allowed the development of peptidic molecules able to stimulate and/or inhibit the receptor and, more recently, to discover another endogenous ligand: apela. Among the functions regulated by the APJ/apelin system, the control of energy metabolism appears today in the forefront. A better understanding of the pharmacology of APJ receptor should allow innovative therapeutic approaches in the treatment of metabolic diseases.
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Diabetes Mellitus/terapia , Terapia Molecular Dirigida , Receptores Acoplados a Proteínas G/fisiología , Animales , Apelina , Receptores de Apelina , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Ratones , Obesidad/genética , Obesidad/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND & AIMS: Glucose is absorbed into intestine cells via the sodium glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT2); various peptides and hormones control this process. Apelin is a peptide that regulates glucose homeostasis and is produced by proximal digestive cells; we studied whether glucose modulates apelin secretion by enterocytes and the effects of apelin on intestinal glucose absorption. METHODS: We characterized glucose-related luminal apelin secretion in vivo and ex vivo by mass spectroscopy and immunologic techniques. The effects of apelin on (14)C-labeled glucose transport were determined in jejunal loops and in mice following apelin gavage. We determined levels of GLUT2 and SGLT-1 proteins and phosphorylation of AMPKα2 by immunoblotting. The net effect of apelin on intestinal glucose transepithelial transport was determined in mice. RESULTS: Glucose stimulated luminal secretion of the pyroglutaminated apelin-13 isoform ([Pyr-1]-apelin-13) in the small intestine of mice. Apelin increased specific glucose flux through the gastric epithelial barrier in jejunal loops and in vivo following oral glucose administration. Conversely, pharmacologic apelin blockade in the intestine reduced the increased glycemia that occurs following oral glucose administration. Apelin activity was associated with phosphorylation of AMPKα2 and a rapid increase of the GLUT2/SGLT-1 protein ratio in the brush border membrane. CONCLUSIONS: Glucose amplifies its own transport from the intestinal lumen to the bloodstream by increasing luminal apelin secretion. In the lumen, active apelin regulates carbohydrate flux through enterocytes by promoting AMPKα2 phosphorylation and modifying the ratio of SGLT-1:GLUT2. The glucose-apelin cycle might be pharmacologically handled to regulate glucose absorption and assess better control of glucose homeostasis.
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Carbohidratos/farmacocinética , Glucosa/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Análisis de Varianza , Animales , Transporte Biológico/efectos de los fármacos , Transporte Biológico/fisiología , Western Blotting , Cromatografía Liquida/métodos , Modelos Animales de Enfermedad , Glucosa/farmacología , Transportador de Glucosa de Tipo 2/metabolismo , Inmunohistoquímica , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Distribución Aleatoria , Valores de Referencia , Transportador 1 de Sodio-Glucosa/metabolismoRESUMEN
The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose homeostasis, pointing out a relationship between its dysfunction and insulin resistance, and the therapeutic potential of its targeting. While studies from cellular or tissue-specific models concluded on both pros-and-cons effects of SHP2 on insulin resistance, recent data from integrated systems argued for an insulin resistance promoting role for SHP2, and therefore a therapeutic benefit of its inhibition. In this review, we will summarize the general knowledge of SHP2's molecular, cellular, and physiological functions, explaining the pathophysiological impact of its dysfunctions, then discuss its protective or promoting roles in insulin resistance as well as the potency and limitations of its pharmacological modulation.
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Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD.
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Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.
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Tejido Adiposo/fisiología , Proteínas Portadoras/biosíntesis , Diabetes Mellitus Tipo 2/metabolismo , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Músculo Esquelético/fisiología , Receptores Acoplados a Proteínas G/biosíntesis , Adipoquinas , Tejido Adiposo/metabolismo , Adulto , Animales , Apelina , Receptores de Apelina , Proteínas Portadoras/genética , Diabetes Mellitus Tipo 2/genética , Femenino , Regulación de la Expresión Génica , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Resistencia a la Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular/genética , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Músculo Esquelético/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores Acoplados a Proteínas G/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
INTRODUCTION: Apelin, a bioactive peptide, is the endogenous ligand of APJ, a G protein-coupled receptor which is widely expressed in peripheral tissues and in the central nervous system. The apelin/APJ system is involved in the regulation of various physiological functions and is a therapeutic target in different pathologies; the development of APJ agonists and antagonists has thus increased. Area covered: This review focuses on the in vitro and in vivo metabolic effects of apelin in physiological conditions and in the context of metabolic diseases. Expert opinion: In experimental models, novel APJ agonists are efficient in vivo, to treat metabolic diseases and associated complications. However, more clinical trials are necessary to determine whether molecules that target APJ could become an alternative therapeutic strategy in the treatment of metabolic diseases and associated complications.
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Receptores de Apelina/efectos de los fármacos , Apelina/metabolismo , Enfermedades Metabólicas/tratamiento farmacológico , Animales , Receptores de Apelina/metabolismo , Desarrollo de Medicamentos , Humanos , Enfermedades Metabólicas/fisiopatología , Terapia Molecular DirigidaRESUMEN
By using pangenomic microarray, we identified apelin as a unique adipokine up regulated by the transcriptional co-activator peroxisome proliferator-activated receptor gamma (PPARgamma) co-activator 1alpha (PGC-1alpha) in human white adipocytes. We investigated its regulation in vitro and in vivo. Overexpression of PGC-1alpha by adenovirus in human adipocytes induces apelin expression and secretion. Pharmacological induction of cAMP, an upstream regulator of endogenous PGC-1alpha expression, up regulates apelin gene expression and also apelin secretion in human and mice adipocytes. Moreover, during cold exposure in mice, a physiological situation known to induce both cAMP and PGC-1alpha, apelin expression in adipocytes and plasma levels were increased. This is the first demonstration that PGC-1alpha is involved in the regulation of an adipokine gene expression and release.
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Adipocitos/fisiología , Proteínas Portadoras/fisiología , Proteínas de Choque Térmico/fisiología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Transactivadores/fisiología , Factores de Transcripción/fisiología , Adipocitos/metabolismo , Adipoquinas , Tejido Adiposo Blanco/citología , Animales , Apelina , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
PURPOSE: Apelin treatment has been shown to improve insulin sensitivity in insulin resistant mice by acting in skeletal muscles. However, the effects of systemic apelin on the hepatic energy metabolism have not been addressed. We thus aimed to determine the effect of chronic apelin treatment on the hepatic lipid metabolism in insulin resistant mice. The apelin receptor (APJ) expression was also studied in this context since its regulation has only been reported in severe liver pathologies. METHODS: Mice were fed a high-fat diet (HFD) in order to become obese and insulin resistant compared to chow fed mice (CD). HFD mice then received a daily intraperitoneal injection of apelin (0.1 µmol/kg) or PBS during 28 days. RESULTS: Triglycerides content and the expression of different lipogenesis-related genes were significantly decreased in the liver of HFD apelin-treated compared to PBS-treated mice. Moreover, at this stage of insulin resistance, the beta-oxidation was increased in liver homogenates of HFD PBS-treated mice compared to CD mice and reduced in HFD apelin-treated mice. Finally, APJ expression was not up-regulated in the liver of insulin resistant mice. In isolated hepatocytes from chow and HFD fed mice, apelin did not induce significant effect. CONCLUSIONS: Altogether, these results suggest that systemic apelin treatment decreases steatosis in insulin resistant mice without directly targeting hepatocytes.
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Apelina/farmacología , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Obesidad/metabolismo , Animales , Metabolismo Energético/efectos de los fármacos , Hígado Graso/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hígado/metabolismo , Masculino , Ratones , Triglicéridos/metabolismoRESUMEN
Non-conventional major histocompatibility complex class I molecules are involved in a variety of physiological functions, most at the periphery of the immune system per se. Zinc-alpha(2)-glycoprotein (ZAG), the sole soluble member of this superfamily has been implicated in cachexia, a poorly understood yet life-threatening, severe wasting syndrome. To further ascertain the role of ZAG in lipid metabolism and perhaps the immune system, we inactivated both ZAG alleles by gene targeting in mice. Subjecting these ZAG deficient animals to standard or lipid rich food regimens led to increased body weight in comparison to identically treated wild-type mice. This phenotype appeared to correlate with a significant decrease in adipocytic lipolysis that could not be rescued by several pharmacological agents including beta(3)-adrenoreceptor agonists. Furthermore, in contrast to previously reported data, ZAG was found to be ubiquitously and constitutively expressed, with an especially high level in the mouse liver. No overt immunological phenotype was identified in these animals.
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Antígenos de Histocompatibilidad Clase I/metabolismo , Lipólisis/fisiología , Proteínas de Plasma Seminal/metabolismo , Adipocitos/metabolismo , Agonistas de Receptores Adrenérgicos beta 3 , Alelos , Animales , Secuencia de Bases , Células CHO , Cricetinae , Cricetulus , ADN/genética , Grasas de la Dieta/administración & dosificación , Expresión Génica , Marcación de Gen , Células HeLa , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Técnicas In Vitro , Hígado/inmunología , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas de Plasma Seminal/genética , Distribución Tisular , Transfección , Aumento de Peso , Zn-alfa-2-GlicoproteínaRESUMEN
We have recently identified apelin as a novel adipokine up-regulated by insulin and obesity. Since obesity and insulin resistance are associated with chronically elevated levels of both insulin and TNFalpha, the present study was performed to investigate a putative regulation of apelin expression in adipocytes by TNFalpha. Herein, we report a tight correlation between apelin and TNFalpha expression in adipose tissue of lean and obese humans. Apelin regulation by TNFalpha was further studied in cultured explants of human adipose tissue. The endogenous expression of TNFalpha in adipocytes isolated from the explants was accompanied by a 6-9 h subsequent increase of apelin expression in adipocytes. This increase was reversed by inhibiting TNFalpha expression with 100 microM isobutylmethylxanthine. In different mouse models of obesity, expression of both TNFalpha and apelin was also significantly increased in adipocytes of obese mice. Furthermore, short-term exposure to an i.p. injection of TNFalpha in C57Bl6/J mice induced an increase of apelin expression in adipose tissue as well as apelin plasma levels. Finally, a direct positive effect of TNFalpha has been shown in differentiated 3T3F442A adipocytes on apelin expression and secretion. The signaling pathways of TNFalpha for the induction of apelin were dependent of PI3-kinase, c-Jun NH2-terminal kinase (JNK), and MAPK but not PKC activation. All together, these findings suggest that apelin might be a candidate to better understand potential links between obesity and associated disorders such as inflammation and insulin resistance.
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Tejido Adiposo/fisiología , Factor de Necrosis Tumoral alfa/farmacología , Células 3T3 , Abdomen , Adipocitos/citología , Adipocitos/fisiología , Adipoquinas , Tejido Adiposo/efectos de los fármacos , Adulto , Animales , Apelina , Proteínas Portadoras , Diferenciación Celular , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inflamación/fisiopatología , Resistencia a la Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular , Ratones , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/fisiopatologíaRESUMEN
The results presented herein demonstrate that apelin is expressed and secreted by both human and mouse adipocytes. Apelin mRNA levels in isolated adipocytes are close to other cell types present in white adipose tissue or other organs known to express apelin such as kidney, heart, and to a lesser extent brown adipose tissue. Apelin expression is increased during adipocyte differentiation stage. A comparison of four different models of obesity in mice showed a large increase in both apelin expression in fat cells and apelin plasma levels in all the hyperinsulinemia-associated obesities and clearly demonstrated that obesity or high-fat feeding are not the main determinants of the rise of apelin expression. The lack of insulin in streptozotocin-treated mice is associated with a decreased expression of apelin in adipocytes. Furthermore, apelin expression in fat cells is strongly inhibited by fasting and recovered after refeeding, in a similar way to insulin. A direct regulation of apelin expression by insulin is observed in both human and mouse adipocytes and clearly associated with the stimulation of phosphatidylinositol 3-kinase, protein kinase C, and MAPK. These data provide evidence that insulin exerts a direct control on apelin gene expression in adipocytes. In obese patients, both plasma apelin and insulin levels were significantly higher, suggesting that the regulation of apelin by insulin could influence blood concentrations of apelin. The present work identifies apelin as a novel adipocyte endocrine secretion and focuses on its potential link with obesity-associated variations of insulin sensitivity status.
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Proteínas Portadoras/genética , Insulina/farmacología , Obesidad/metabolismo , Adipocitos/citología , Adipocitos/metabolismo , Adipoquinas , Tejido Adiposo/metabolismo , Animales , Apelina , Proteínas Portadoras/fisiología , Diferenciación Celular , Femenino , Regulación de la Expresión Génica , Humanos , Hiperinsulinismo/metabolismo , Insulina/sangre , Péptidos y Proteínas de Señalización Intercelular , Ratones , Ratones Endogámicos C57BL , Regulación hacia ArribaRESUMEN
A wide range of adipokines identified over the past years has allowed considering the white adipose tissue as a secretory organ closely integrated into overall physiological and metabolic control. Apelin, a ubiquitously expressed peptide was known to exert different physiological effects mainly on the cardiovascular system and the regulation of fluid homeostasis prior to its characterization as an adipokine. This has broadened its range of action and apelin now appears clearly as a new player in energy metabolism in addition to leptin and adiponectin. Apelin has been shown to act on glucose and lipid metabolism but also to modulate insulin secretion. Moreover, different studies in both animals and humans have shown that plasma apelin concentrations are usually increased during obesity and type 2 diabetes. This mini-review will focus on the various systemic apelin effects on energy metabolism by addressing its mechanisms of action. The advances concerning the role of apelin in metabolic diseases in relation with the recent reports on apelin concentrations in obese and/or diabetic subjects will also be discussed.
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AIMS: Adipose tissue secretes various proteins referred to as adipokines, being involved in inflammation. It was recognized that mesenteric adipose tissue (MAT) is altered by inflammation, and pathologies such as inflammatory bowel disease (IBD). The aim of this study was to investigate the alterations of the mesenteric adipose tissue in two experimental colitis models in mice adapted to obtain moderate colonic inflammation. MAIN METHODS: Colonic inflammation was obtained using two models, either DSS dissolved in drinking water or intra-colonic instillation of DNBS. The expression of adipokines (leptin and adiponectin) and inflammatory markers (IL-6, MCP-1, F4/80) was studied by qRT-PCR in the MAT of treated and control mice. KEY FINDINGS: Observations of the colon and IL-6 plasma level determination demonstrated that DNBS treatment led to stronger inflammation. Colitis induced a decrease of mRNA encoding to leptin and adiponectin in MAT. In contrast, colonic inflammation led to an increase of mRNA encoding to IL-6, MCP-1 and F4/80, a specific marker of macrophages. SIGNIFICANCE: The mesenteric adipose tissue, in two models of moderate colitis, shows a loss of adipose profile and a strong increase of inflammatory pattern, close to the observations made in MAT of IBD patients. These data suggest that these pro-inflammatory modifications of MAT have to be taken into account in the pathophysiology of IBD.
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Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Colitis/fisiopatología , Inflamación/fisiopatología , Leptina/metabolismo , Animales , Sulfato de Dextran/toxicidad , Dinitrofluorobenceno/análogos & derivados , Dinitrofluorobenceno/toxicidad , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/fisiopatología , Masculino , Ratones , Ratones Endogámicos BALB C , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Various studies have shown that eicosapentaenoic acid (EPA) has beneficial effects on obesity and associated disorders. Apelin, the ligand of APJ receptor also exerts insulin-sensitizing effects especially by improving muscle metabolism. EPA has been shown to increase apelin production in adipose tissue but its effects in muscle have not been addressed. Thus, the effects of EPA supplementation (36 g/kg EPA) in high-fat diet (HFD) (45% fat, 20% protein, 35% carbohydrate) were studied in mice with focus on muscle lipid metabolism and apelin/APJ expression. Compared with HFD mice, HFD+EPA mice had significantly less weight gain, fat mass, lower blood glucose, insulinemia and hepatic steatosis after 10 weeks of diet. In addition, EPA prevented muscle metabolism alterations since intramuscular triglycerides were decreased and ß-oxidation increased. In soleus muscles of HFD+EPA mice, apelin and APJ expression were significantly increased compared to HFD mice. However, plasma apelin concentrations in HFD and HFD+EPA mice were similar. EPA-induced apelin expression was confirmed in differentiated C2C12 myocytes but in this model, apelin secretion was also increased in response to EPA treatment. In conclusion, EPA supplementation in HFD prevents obesity and metabolic alterations in mice, especially in skeletal muscle. Since EPA increases apelin/APJ expression in muscle, apelin may act in a paracrine/autocrine manner to contribute to these benefical effects.
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Grasas de la Dieta/farmacología , Suplementos Dietéticos , Ácido Eicosapentaenoico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Proteínas Musculares/biosíntesis , Músculo Esquelético/metabolismo , Adipoquinas , Animales , Apelina , Glucemia/metabolismo , Línea Celular , Grasas de la Dieta/efectos adversos , Masculino , Ratones , Músculo Esquelético/patología , Obesidad/metabolismo , Obesidad/patología , Obesidad/prevención & controlRESUMEN
Insulin resistance is a main feature of obesity and type 2 diabetes mellitus (T2DM). Several mechanisms linking obesity to insulin resistance have been proposed. Adipose tissue modulates metabolism by secreting a variety of factors, which exhibit altered production during obesity. Apelin, a small peptide present in a number of tissues and also produced and secreted by adipocytes, has emerged as a new player with potent functions in energy metabolism, and in insulin sensitivity improvement. In this review, we describe the various metabolic functions that are affected by apelin and we present an integrated overview of recent findings that collectively propose apelin as a promising target for the treatment of T2DM.
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Diabetes Mellitus Tipo 2/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Tejido Adiposo/metabolismo , Apelina , Diabetes Mellitus Tipo 2/genética , Humanos , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Péptidos y Proteínas de Señalización Intercelular/genética , Modelos BiológicosRESUMEN
Both acute and chronic apelin treatment have been shown to improve insulin sensitivity in mice. However, the effects of apelin on fatty acid oxidation (FAO) during obesity-related insulin resistance have not yet been addressed. Thus, the aim of the current study was to determine the impact of chronic treatment on lipid use, especially in skeletal muscles. High-fat diet (HFD)-induced obese and insulin-resistant mice treated by an apelin injection (0.1 µmol/kg/day i.p.) during 4 weeks had decreased fat mass, glycemia, and plasma levels of triglycerides and were protected from hyperinsulinemia compared with HFD PBS-treated mice. Indirect calorimetry experiments showed that apelin-treated mice had a better use of lipids. The complete FAO, the oxidative capacity, and mitochondrial biogenesis were increased in soleus of apelin-treated mice. The action of apelin was AMP-activated protein kinase (AMPK) dependent since all the effects studied were abrogated in HFD apelin-treated mice with muscle-specific inactive AMPK. Finally, the apelin-stimulated improvement of oxidative capacity led to decreased levels of acylcarnitines and enhanced insulin-stimulated glucose uptake in soleus. Thus, by promoting complete lipid use in muscle of insulin-resistant mice through mitochondrial biogenesis and tighter matching between FAO and the tricarboxylic acid cycle, apelin treatment could contribute to insulin sensitivity improvement.
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Ácidos Grasos/metabolismo , Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intercelular/farmacología , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteínas Quinasas Activadas por AMP/fisiología , Adipoquinas , Animales , Apelina , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Dieta Alta en Grasa , Metabolismo Energético/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Oxidación-ReducciónRESUMEN
Apelin is a peptide known as the ligand of the G-protein-coupled receptor APJ. Several active apelin forms exist such as apelin-36, apelin-17, apelin-13, and the pyroglutamated form of apelin-13. Apelin and APJ are expressed in the central nervous system, particularly in the hypothalamus and in many peripheral tissues. Apelin has been shown to be involved in the regulation of cardiovascular and fluid homeostasis, food intake, cell proliferation, and angiogenesis. In addition to be an ubiquitous peptide, apelin is also produced and secreted by adipocytes and thus considered as an adipokine. This has opened a new field of investigation establishing a link between apelin and metabolic disorders (obesity, type 2 diabetes, etc.) which is the focus of the present review. Several studies, but not all, have reported an increase of plasma apelin concentrations in humans and in animal models with different metabolic pathologies. Moreover, important roles for apelin both in glucose and lipid metabolism have been highlighted as well as the associated signaling pathways. Apelin appears as a beneficial adipokine with anti-obesity and anti-diabetic properties and thus as a promising therapeutic target in metabolic disorders.
Asunto(s)
Diabetes Mellitus Tipo 2/fisiopatología , Péptidos y Proteínas de Señalización Intercelular/fisiología , Obesidad/fisiopatología , Adipoquinas/fisiología , Animales , Apelina , Modelos Animales de Enfermedad , Metabolismo Energético/fisiología , Glucosa/metabolismo , Humanos , Metabolismo de los Lípidos/fisiología , RatonesRESUMEN
BACKGROUND: In human pathology, the "creeping fat" (CF) of the mesentery is unique to Crohn's disease (CD). CF is usually referred to as an ectopic extension of mesenteric adipose tissue (MAT). However, since no animal model developing CF has ever been established, very little is known about this type of fat-depot expansion and its role in the development of the disease. METHODS: We developed and standardized an experimental protocol in mice that reproducibly induces CF development when a severe colonic inflammation is obtained by intracolonic instillation of DNBS. RESULTS: Macro-microscopic observations revealed a fatty appearance of CF. Yet when compared to MAT from the same animals, CF contains very little triglycerides, few adipocytes, and we observed a very low expression and protein levels of both adipose markers (hormone-sensitive lipase, perilipin) and adipocytokines (leptin, adiponectin). The decreased expression of perilipin in CF was also observed by immunohistochemistry. Conversely, the expression of proinflammatory and fibrous markers (Pref-1) was much higher in CF than in MAT. These observations were fully consistent with those made on CF recovered from five CD patients and compared with subcutaneous and mesenteric fat from the same patients. CONCLUSIONS: Altogether, this work reports an original experimental mice model of CF. In this model we establish for the first time that CF only occurs in severe colonic inflammation and shows an inflammatory, fibrous but not an adipose pattern.