Miguel López

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

We investigated a possible role of the central glucagon-like peptide (GLP-1) receptor system as an essential brain circuit regulating adiposity through effects on nutrient partitioning and lipid metabolism independent from feeding behavior. Both lean and diet-induced obesity mice were used for our experiments. GLP-1 (7–36) amide was infused in the brain for 2 or 7 d. The expression of key enzymes involved in lipid metabolism was measured by real-time PCR or Western blot. To test the hypothesis that the sympathetic nervous system may be responsible for informing adipocytes about changes in CNS GLP-1 tone, we have performed direct recording of sympathetic nerve activity combined with experiments in genetically manipulated mice lacking β-adrenergic receptors. Intracerebroventricular infusion of GLP-1 in mice directly and potently decreases lipid storage in white adipose tissue. These effects are independent from nutrient intake. Such CNS control of adipocyte metabolism was found to depend partially on a functional sympathetic nervous system. Furthermore, the effects of CNS GLP-1 on adipocyte metabolism were blunted in diet-induced obese mice. The CNS GLP-1 system decreases fat storage via direct modulation of adipocyte metabolism. This CNS GLP-1 control of adipocyte lipid metabolism appears to be mediated at least in part by the sympathetic nervous system and is independent of parallel changes in food intake and body weight. Importantly, the CNS GLP-1 system loses the capacity to modulate adipocyte metabolism in obese states, suggesting an obesity-induced adipocyte resistance to CNS GLP-1.

The Central Sirtuin 1/p53 Pathway Is Essential for the Orexigenic Action of Ghrelin

OBJECTIVE Ghrelin is a stomach-derived peptide that increases food intake through the activation of hypothalamic AMP-activated protein kinase (AMPK). However, the molecular mechanisms initiated by the activation of the ghrelin receptor, which in turn lead to AMPK activation, remain unclear. Sirtuin 1 (SIRT1) is a deacetylase activated in response to calorie restriction that acts through the tumor suppressor gene p53. We tested the hypothesis that the central SIRT1/p53 pathway might be mediating the orexigenic action of ghrelin. RESEARCH DESIGN AND METHODS SIRT1 inhibitors, such as Ex527 and sirtinol, and AMPK activators, such as AICAR, were administered alongside ghrelin in the brain of rats and mice (wild-type versus p53 knockout [KO]). Their hypothalamic effects on lipid metabolism and changes in transcription factors and neuropeptides were assessed by Western blot and in situ hybridization. RESULTS The central pretreatment with Ex527, a potent SIRT1 inhibitor, blunted the ghrelin-induced food intake in rats. Mice lacking p53, a target of SIRT1 action, failed to respond to ghrelin in feeding behavior. Ghrelin failed to phosphorylate hypothalamic AMPK when rats were pretreated with Ex527, as it did in p53 KO mice. It is noteworthy that the hypothalamic SIRT1/p53 pathway seems to be specific for mediating the orexigenic action of ghrelin, because central administration of AICAR, a potent AMPK activator, increased food intake in p53 KO mice. Finally, blockade of the central SIRT1 pathway did not modify ghrelin-induced growth hormone secretion. CONCLUSIONS Ghrelin specifically triggers a central SIRT1/p53 pathway that is essential for its orexigenic action, but not for the release of growth hormone.

Role of ghrelin in reproduction.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as a pleiotropic modulator of diverse biological functions, including energy homeostasis and, lately reproduction. Here, we review recent reports evaluating the reproductive effects and sites of action of ghrelin, with particular emphasis regarding its role as a molecule integrating reproductive function and energy status. Data gleaned from rodent studies clearly show that besides having direct gonadal effects, ghrelin may participate in the regulation of gonadotropin secretion and it may influence the timing of puberty. In addition, experimental data showing that ghrelin and/or its receptor are expressed in normal human ovary and testis as well as in human ovarian and testicular tumors raise the possibility that the ghrelin system may be involved in the control of cell proliferation in these tumors. We propose that ghrelin either acting as an endocrine and/or paracrine signal may play a major role in the endocrine network that integrates energy balance and reproduction.

Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender

The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid beta oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid beta oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner.

Hypothalamic AMPK: a canonical regulator of whole-body energy balance.

AMP-activated protein kinase (AMPK) has a major role in the modulation of energy balance. AMPK is activated in conditions of low energy, increasing energy production and reducing energy consumption. The AMPK pathway is a canonical route regulating energy homeostasis by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. Current evidence has implicated AMPK in the hypothalamus and hindbrain with feeding, brown adipose tissue thermogenesis and browning of white adipose tissue, through modulation of the sympathetic nervous system, as well as glucose homeostasis. Interestingly, several potential antiobesity and/or antidiabetic agents, some of which are currently in clinical use such as metformin and liraglutide, exert some of their actions by acting on AMPK. Furthermore, the orexigenic and weight-gain effects of commonly used antipsychotic drugs are also mediated by hypothalamic AMPK. Overall, this evidence suggests that hypothalamic AMPK signalling is an interesting target for drug development, but is this approach feasible? In this Review we discuss the current understanding of hypothalamic AMPK and its role in the central regulation of energy balance and metabolism.

Irisin, two years later.

In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisins action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states.

Dynamic Routing and Wavelength Assignment in Optical Networks by Means of Genetic Algorithms

We propose a novel genetic algorithm for solving the dynamic routing and wavelength assignment (DRWA) problem in wavelength-routed optical networks. The algorithm not only obtains low call blocking probability, but it also employs a very short computation time. Moreover, it is capable of providing fairness among connections, that is, to offer approximately the same quality of service (in terms of blocking probability) for all source-destination node pairs. Since requirements on optical network availability are highly severe, we also propose an extension of the algorithm to provide fault-tolerance capability at the optical layer. It is achieved by means of protection, where each optical connection request is provided with a pair of lightpaths (a primary and a backup lightpath). Again, the genetic algorithm proves to be highly efficient, in this case, at performing routing and wavelength assignment of pairs of lightpaths.

The cellular and molecular bases of leptin and ghrelin resistance in obesity

Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.

Ghrelin and lipid metabolism: key partners in energy balance

Ghrelin, the endogenous ligand of the GH secretagogue receptor, has a pleiotropic role in the modulation of energy balance. Recent evidence has demonstrated that besides its orexigenic role, ghrelin regulates central and peripheral lipid metabolism through specific control of hypothalamic AMP-activated protein kinase (AMPK), a critical metabolic gauge regulating both cellular and whole-body energy homeostasis. In this review, we summarize the new milestones of ghrelins actions on energy balance, with particular focus on its molecular interaction with hypothalamic AMPK and fatty acid metabolism. Understanding this new metabolic pathway can provide new therapeutic targets for the treatment of obesity and the metabolic syndrome.

Radial basis function classifiers to help in the diagnosis of the obstructive sleep apnoea syndrome from nocturnal oximetry

The aim of this study is to assess the ability of radial basis function (RBF) classifiers as an assistant tool for the diagnosis of the obstructive sleep apnoea syndrome (OSAS). A total of 187 subjects suspected of suffering from OSAS were available for our research. The initial population was divided into training, validation and test sets for deriving and testing our neural classifiers. We used nonlinear features from nocturnal oxygen saturation (SaO2) to perform patients’ classification. We evaluated three different RBF construction techniques based on the following algorithms: k-means (KM), fuzzy c-means (FCM) and orthogonal least squares (OLS). A diagnostic accuracy of 86.1, 84.7 and 85.5% was provided by the networks developed with KM, FCM and OLS, respectively. The three proposed networks achieved an area under the receiver operating characteristic (ROC) curve over 0.90. Our results showed that a useful non-invasive method could be applied to diagnose OSAS from nonlinear features of SaO2 with RBF classifiers.