[Show abstract][Hide abstract] ABSTRACT: Objective The gut–brain axis is considered as a major regulatory checkpoint in the control of glucose homeostasis. The detection of nutrients and/or hormones in the duodenum informs the hypothalamus of the host's nutritional state. This process may occur via hypothalamic neurons modulating central release of nitric oxide (NO), which in turn controls glucose entry into tissues. The enteric nervous system (ENS) modulates intestinal contractions in response to various stimuli, but the importance of this interaction in the control of glucose homeostasis via the brain is unknown. We studied whether apelin, a bioactive peptide present in the gut, regulates ENS-evoked contractions, thereby identifying a new physiological partner in the control of glucose utilisation via the hypothalamus.
Design We measured the effect of apelin on electrical and mechanical duodenal responses via telemetry probes and isotonic sensors in normal and obese/diabetic mice. Changes in hypothalamic NO release, in response to duodenal contraction modulated by apelin, were evaluated in real time with specific amperometric probes. Glucose utilisation in tissues was measured with orally administrated radiolabeled glucose.
Results In normal and obese/diabetic mice, glucose utilisation is improved by the decrease of ENS/contraction activities in response to apelin, which generates an increase in hypothalamic NO release. As a consequence, glucose entry is significantly increased in the muscle.
Conclusions Here, we identify a novel mode of communication between the intestine and the hypothalamus that controls glucose utilisation. Moreover, our data identified oral apelin administration as a novel potential target to treat metabolic disorders.
Gut 11/2015; DOI:10.1136/gutjnl-2015-310230 · 14.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sterol response element binding protein (SREBP) is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM) were related to peroxisome proliferator-activated receptor-γ (PPARγ), which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARγ/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths) or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK) but not JNK or p38 mitogen-activated protein kinase (MAPK). Ras/Raf-1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down-regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM-unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1-propanol (PPMP), where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM-enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARγ, reversed the effects of SM on SREBP-1, PPARγ and CREB. Taken together, these findings provide novel insights indicating that excess membrane SM might be critical for regulating SREBPs in adipocytes via a MAPK-dependent pathway.
PLoS ONE 08/2015; 10(7):e0133181. DOI:10.1371/journal.pone.0133181 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Frontiers in Physiology 04/2015; 6:115. DOI:10.3389/fphys.2015.00115 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hypothalamus is a key area involved in the control of metabolism and food intake via the integrations of numerous signals (hormones, neurotransmitters, metabolites) from various origins. These factors modify hypothalamic neurons activity and generate adequate molecular and behavioral responses to control energy balance. In this complex integrative system, a new concept has been developed in recent years, that includes reactive oxygen species (ROS) as a critical player in energy balance. ROS are known to act in many signaling pathways in different peripheral organs, but also in hypothalamus where they regulate food intake and metabolism by acting on different types of neurons, including proopiomelanocortin (POMC) and agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons. Hypothalamic ROS release is under the influence of different factors such as pancreatic and gut hormones, adipokines (leptin, apelin,…), neurotransmitters and nutrients (glucose, lipids,…). The sources of ROS production are multiple including NADPH oxidase, but also the mitochondria which is considered as the main ROS producer in the brain. ROS are considered as signaling molecules, but conversely impairment of this neuronal signaling ROS pathway contributes to alterations of autonomic nervous system and neuroendocrine function, leading to metabolic diseases such as obesity and type 2 diabetes. In this review we focus our attention on factors that are able to modulate hypothalamic ROS release in order to control food intake and energy metabolism, and whose deregulations could participate to the development of pathological conditions. This novel insight reveals an original mechanism in the hypothalamus that controls energy balance and identify hypothalamic ROS signaling as a potential therapeutic strategy to treat metabolic disorders.
Frontiers in Neuroscience 02/2015; 9:56. DOI:10.3389/fnins.2015.00056 · 3.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During obesity, an hypoxic state develops within the adipose tissue resulting in insulin resistance. In order to understand the underlying mechanism, we analyzed the involvement of caveolae, since they play crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae, and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of Cavin-1 and -2 expression in the epididymal adipose tissue. Downregulation of expression of Cavins in response to hypoxia is dependent upon HIF-1. Indeed, inhibition of HIF-1 restores expression of Cavins and caveolae formation. Expression of Cavins regulates insulin signaling, since silencing of Cavin-1 and Cavin-2 impairs insulin signaling pathway. In human, Cavin-1 and -2 are decreased in the subcutaneous adipose tissue of obese diabetic patients compared to lean subjects. Moreover, the expression of Cavin-2 correlates negatively with HOMA-IR and HbA1c level. In conclusion, we propose a new mechanism where hypoxia inhibits Cavin-1 and Cavin-2 expression resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance.
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Mitochondria-derived oxidative stress is believed to be crucially involved in cardiac ischaemia reperfusion (I/R) injury, although currently no therapies exist that specifically target mitochondrial reactive oxygen species (ROS) production. The present study was designed to evaluate the potential effects of the structural analogues of apelin-12, an adipocyte-derived peptide, on mitochondrial ROS generation, cardiomyocyte apoptosis, and metabolic and functional recovery to myocardial I/R injury.
In cultured H9C2 cardiomyoblasts and adult cardiomyocytes, oxidative stress was induced by hypoxia reoxygenation. Isolated rat hearts were subjected to 35 min of global ischaemia and 30 min of reperfusion. Apelin-12, apelin-13 and structural apelin-12 analogues, AI and AII, were infused during 5 min prior to ischaemia.
In cardiac cells, mitochondrial ROS production was inhibited by the structural analogues of apelin, AI and AII, in comparison with the natural peptides, apelin-12 and apelin-13. Treatment of cardiomyocytes with AI and AII decreased cell apoptosis concentration-dependently. In a rat model of I/R injury, pre-ischaemic infusion of AI and AII markedly reduced ROS formation in the myocardial effluent and attenuated cell membrane damage. Prevention of oxidative damage by AI and AII was associated with the improvement of functional and metabolic recovery after I/R in the heart.
Conclusions and implications:
These data provide the evidence for the potential of the structural apelin analogues in selective reduction of mitochondrial ROS generation and myocardial apoptosis and form the basis for a promising therapeutic strategy in the treatment of oxidative stress-related heart disease.
British Journal of Pharmacology 12/2014; 172(12). DOI:10.1111/bph.13038 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
Proceedings of the National Academy of Sciences 10/2014; 111(42). DOI:10.1073/pnas.1406107111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence supports the critical roles played by adipose tissue in breast cancer progression. Yet, the mediators and mechanisms are poorly understood. Here, we show that breast cancer-associated adipose tissue from freshly isolated tumors promotes F-actin remodelling, cellular scattering, invasiveness and spheroid reorganization of cultured breast cancer cells. A combination of techniques including transcriptomics, proteomics and kinomics enabled us to identify paracrine secretion of oncostatin M (OSM) by cancer-associated adipose tissue. Specifically, OSM, expressed by CD45+ leucocytes in the stromal vascular fraction, induced phosphorylation of STAT3 (pSTAT3-)Y705 and S727 in breast cancer cells and transcription of several STAT3-dependent genes, including S100 family members S100A7, S100A8 and S100A9. Autocrine activation of STAT3 in MCF-7 cells ectopically expressing OSM induced cellular scattering and peritumoral neo-vascularization of orthotopic xenografts. Conversely, selective inhibition of OSM by neutralizing antibody and Jak family kinases by tofacitinib inhibited STAT3 signaling, peritumoral angiogenesis and cellular scattering. Importantly, nuclear staining of pSTAT3-Y705 identified at the tumor invasion front in ductal breast carcinomas correlates with increased lymphovascular invasion. Our work reveals the potential of novel therapeutic strategies targeting the OSM and STAT3 axis in breast cancer patients harboring nuclear pSTAT3-Y705.
Cancer Research 09/2014; 74(23). DOI:10.1158/0008-5472.CAN-14-0160 · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Outre les complications métaboliques, il est maintenant reconnu que l’obésité favorise la survenue et affecte le pronostic de nombreux cancers dont le cancer du sein. De nombreux arguments récents montrent que le cancer doit être considéré comme une maladie tissulaire dans laquelle les cellules cancéreuses interagissent de façon dynamique avec les cellules « normales » environnantes. Cette interaction dynamique repose sur un véritable cercle vicieux dans lequel les cellules cancéreuses vont modifier leur microenvironnement qui, en retour, va favoriser la croissance et la dissémination de la tumeur. Dans de nombreux cancers invasifs et en particuliers le cancer du sein, les cellules tumorales vont se retrouver à proximité du tissu adipeux (TA). Les adipocytes matures de part leur activité sécrétoire et métabolique sont tout à fait susceptibles de modifier le comportement de la tumeur. L’objectif de cette revue est donc de décrire dans un premier temps le rôle du microenvironnement dans la progression tumorale. Dans un second temps, nous verrons que les adipocytes péri-tumoraux acquièrent un phénotype spécifique et les mécanismes qui leur permettent d’amplifier l’agressivité tumorale. Dans l’obésité, le TA présente des modifications morphologiques et fonctionnelles qui pourraient le rendre plus enclin à favoriser localement la progression tumorale et expliquer le pronostic défavorable observé chez ces patients. Nous verrons donc dans une dernière partie les arguments précliniques qui permettent d’impliquer un effet paracrine du TA dans le lien entre obésité et aggravation de la progression tumorale chez les sujets obèses.
[Show abstract][Hide abstract] ABSTRACT: In mammals, birth entails complex metabolic adjustments essential for neonatal survival. Using a mouse knockout model, we identify crucial biological roles for the miR-379/miR-410 cluster within the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 locus, also named C14MC in humans, is the largest known placental mammal-specific miRNA cluster, whose 39 miRNA genes are expressed only from the maternal allele. We found that heterozygote pups with a maternal—but not paternal—deletion of the miRNA cluster display partially penetrant neonatal lethality with defects in the maintenance of energy homeostasis. This maladaptive metabolic response is caused, at least in part, by profound changes in the activation of the neonatal hepatic gene expression program, pointing to as yet unidentified regulatory pathways that govern this crucial metabolic transition in the newborn's liver. Not only does our study highlight the physiological importance of miRNA genes that recently evolved in placental mammal lineages but it also unveils additional layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on metabolic control at birth and have likely contributed to mammal evolution.
The EMBO Journal 08/2014; 33(19). DOI:10.15252/embj.201387038 · 10.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Objectives
Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin plays a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state.Methods
Adult male C57BL/6 J, Apelin KO or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses.ResultsIn HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P<0.05), accelerated glucose oxidation (P<0.05) and mitochondrial damage. Treatment of HFD-fed mice with apelin for 4 weeks prevented pressure overload-induced decline in FA metabolism (P<0.05) and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose (P<0.01), improved glucose tolerance (P<0.05) and preserved cardiac function (P<0.05) in HFD-fed mice subjected to pressure overload. In apelin KO HFD-fed mice, spontaneous cardiac dysfunction is associated with reduced FA oxidation (P<0.001) and increased glucose oxidation (P<0.05). In isolated cardiomyocytes, apelin stimulated FA oxidation in a dose-dependent manner and this effect was prevented by siRNA sirtuin 3 knock-down.Conclusion
These data suggest that obesity-related decline in cardiac function is associated with defective myocardial energy metabolism and mitochondrial abnormalities. Furthermore, our work points for therapeutic potential of apelin to prevent myocardial metabolic abnormalities in heart failure paired with obesity.International Journal of Obesity accepted article preview online, 16 July 2014; doi:10.1038/ijo.2014.122.
International journal of obesity (2005) 07/2014; 39(2). DOI:10.1038/ijo.2014.122 · 5.00 Impact Factor