Showing papers by "Tamas L. Horvath published in 2012"
TL;DR: Obesity is associated with neuronal injury in a brain area crucial for body weight control in both humans and rodent models, and evidence of increased gliosis in the mediobasal hypothalamus of obese humans is found.
Abstract: Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.
1,432 citations
Technische Universität München1, Chinese Academy of Sciences2, University of Aberdeen3, University of Buckingham4, École Polytechnique Fédérale de Lausanne5, Max Planck Society6, Baylor College of Medicine7, University of Colorado Denver8, University of California, San Francisco9, University of Chile10, Beth Israel Deaconess Medical Center11, Yale University12, University of Cincinnati Academic Health Center13, Pennington Biomedical Research Center14, Columbia University15, National Institutes of Health16, Roy J. and Lucille A. Carver College of Medicine17, Harvard University18
TL;DR: A consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models is presented, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof.
Abstract: We present a consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof. We hope this guide will facilitate comparisons across studies and minimize spurious interpretations of data. We recommend that division of energy expenditure data by either body weight or lean body weight and that presentation of group effects as histograms should be replaced by plotting individual data and analyzing both group and body-composition effects using analysis of covariance (ANCOVA).
644 citations
TL;DR: The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes as mentioned in this paper.
Abstract: The sirtuins are a family of highly conserved NAD+-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD+ levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.
542 citations
TL;DR: It is shown that hiPSCs grown in suspension in the presence of rostral neuralizing factors can generate 3D structures containing polarized radial glia, intermediate progenitors, and a spectrum of layer-specific cortical neurons reminiscent of their organization in vivo.
Abstract: Human induced pluripotent stem cells (hiPSCs) are emerging as a tool for understanding human brain development at cellular, molecular, and genomic levels. Here we show that hiPSCs grown in suspension in the presence of rostral neuralizing factors can generate 3D structures containing polarized radial glia, intermediate progenitors, and a spectrum of layer-specific cortical neurons reminiscent of their organization in vivo. The hiPSC-derived multilayered structures express a gene expression profile typical of the embryonic telencephalon but not that of other CNS regions. Their transcriptome is highly enriched in transcription factors controlling the specification, growth, and patterning of the dorsal telencephalon and displays highest correlation with that of the early human cerebral cortical wall at 8–10 wk after conception. Thus, hiPSC are capable of enacting a transcriptional program specifying human telencephalic (pallial) development. This model will allow the study of human brain development as well as disorders of the human cerebral cortex.
446 citations
TL;DR: The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis.
Abstract: With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted.
337 citations
TL;DR: This review discusses the latest data on the relationships between UCP2 and glucose and lipid sensing from the perspective of specific hypothalamic neuronal circuits and peripheral tissue functions to provide a framework for discussion of future therapeutic strategies for metabolism-related chronic diseases.
177 citations
TL;DR: It is demonstrated that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function.
Abstract: Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity.
175 citations
TL;DR: Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.
Abstract: Current anti-obesity drugs aim to reduce food intake by either curbing appetite or suppressing the craving for food. However, many of these agents have been associated with severe psychiatric and/or cardiovascular side effects, highlighting the need for alternative therapeutic strategies. Emerging knowledge on the role of the hypothalamus in enabling the central nervous system to adapt to the changing environment — by managing peripheral tissue output and by regulating higher brain functions — may facilitate the discovery of new agents that are more effective and have an acceptable benefit-risk profile. Targeting the molecular pathways that mediate the beneficial effects of calorie restriction and exercise may represent an alternative therapeutic approach for the treatment of chronic metabolic disorders such as obesity.
172 citations
TL;DR: Together, these data provide direct genetic evidence that Atg7 in POMC neurons is required for normal metabolic regulation and neural development, and they implicate hypothalamic autophagy deficiency in the pathogenesis of obesity.
150 citations
TL;DR: In AgRP circuit–impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing–dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain, indicating that AgRP neurons determine the set point of the reward circuitry and associated behaviors.
Abstract: It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit-impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing-dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors.
142 citations
TL;DR: It is demonstrated for the first time that neonatal hypoxia affects the Foxo1/p27Kip1 pathway during white matter development and it is shown that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI.
Abstract: Diffuse white matter injury (DWMI) caused by hypoxia is associated with permanent neurodevelopmental disabilities in preterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Using a mouse model of neonatal hypoxia, we demonstrate a biphasic effect on oligodendrocyte development, resulting in hypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelination, as demonstrated by electron microscopy. Cdk2 activation was essential for the regenerative OPC response after hypoxia and was accompanied by reduced FoxO1-dependent p27(Kip1) expression. p27(Kip1) was also reduced in OPCs in human infant white matter lesions after hypoxia. The negative effects of hypoxia on oligodendrogenesis and myelination were more pronounced in p27(Kip1)-null mice; conversely, overexpression of FoxO1 or p27(Kip1) in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27(Kip1) pathway during white matter development. We also show that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI. Thus, FoxO1 and p27(Kip1) may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI.
TL;DR: A moderate genetic covariance among aortic PWV and central PP, central SBP and brachial SBP was found, and genetic factors explained a moderate phenotypic correlation between central blood pressure, SBP, brachia and central pressure, and aorta pulse wave velocity.
Abstract: Objective:Central blood pressure and aortic stiffness have been consistently reported as strong cardiovascular risk factors. Twin studies by comparing identical with nonidentical twins produce information on the relative contribution of genes and environment.Methods:One hundred and fifty-four monozy
TL;DR: It is shown that natural birth in mice triggers UCP2 expression in hippocampal neurons, revealing a critical role for UCP1 expression in the development of hippocampusal neurons and circuits and hippocampus-related adult behaviors.
Abstract: Mitochondrial uncoupling protein 2 (UCP2) is induced by cellular stress and is involved in regulation of fuel utilization, mitochondrial bioenergetics, cell proliferation, neuroprotection and synaptogenesis in the adult brain. Here we show that natural birth in mice triggers UCP2 expression in hippocampal neurons. Chemical inhibition or genetic ablation of UCP2 lead to diminished neuronal number and size, dendritic growth and synaptogenezis in vitro and impaired complex behaviors in the adult. These data reveal a critical role for Ucp2 expression in the development of hippocampal neurons and circuits and hippocampus-related adult behaviors.
TL;DR: Mechanisms of ghrelin's action that revolve around the central nervous system are reviewed with the goal of highlighting these pathways in integrative physiology of metabolism regulation including ghrelIn's cross-talk with the action of the adipose hormone, leptin.
Abstract: Ghrelin was discovered in 1999 as growth hormone secretagouge released from the gut. Soon after it was recognized that ghrelin is a fundamental driver of appetite in rodents and humans and that its mode of action requires alteration of hypothalamic circuit function. Here we review aspects of ghrelin's action that revolve around the central nervous system with the goal to highlight these pathways in integrative physiology of metabolism regulation including ghrelin's cross-talk with the action of the adipose hormone, leptin.
TL;DR: The heritability of ultrasound characteristics of carotid plaque is high, and the findings should stimulate the search for genes responsible for these traits.
Abstract: Background and Purpose—Few family studies reported moderate genetic impact on the presence and scores of carotid plaques. However, the heritability of carotid plaque characteristics remains still unclear. Twin studies more reliably estimate the relative contribution of genes to these traits in contrast to family study design. Methods—One hundred ninety-two monozygotic and 83 dizygotic adult twin pairs (age 49±15 years) from Italy, Hungary, and the United States underwent B-mode and color Doppler ultrasound of bilateral common, internal, and external carotid arteries. Results—Age-, sex-, and country-adjusted heritability was 78% for the presence of carotid plaque (95% CI, 55%–90%), 74% for plaque echogenicity (hypoechoic, hyperechoic, or mixed; 95% CI, 38%–87%), 69% for plaque size (area in mm2 in longitudinal plane; 50 percentile; 95% CI, 16%–86%), 74% for plaque sidedness (unilateral or bilateral; 95% CI, 25%–90%), 74% for plaque numerosity (95% CI, 26%–86%), 68% (95% CI, 40%–84%), and 66% (95% CI,...
TL;DR: It is demonstrated that vagal heart rate variability indices are related to flow mediated dilation across healthy male subjects, and cannot serve as evidence of a causal relationship, but are of interest and render for further investigation into underlying mechanisms.
Abstract: In various diseased states reduced cardiac vagal activity is accompanied by impaired endothelial function. Evidence from animal studies indicates interaction between the two systems, but such data from human studies is limited. The aim of this study was to test the hypothesis that cardiac vagal activity and endothelial function are related in healthy individuals. 46 young males were studied. From 10 minute long ECG recordings mean RR-interval and time and frequency domain vagal heart rate variability indices (RMSSD; pNN50 and HF, respectively) were determined. Heart rate variability indices were used to define cardiac vagal activity. Endothelial function was assessed by measuring brachial artery flow mediated dilation. Hyperemic, diastolic shear rate was used to normalize flow mediated dilation. All three vagal heart rate variability indices correlated significantly and positively with flow mediated dilation across subjects, with r values within the range of 0.43–0.52, p Our data demonstrate that vagal heart rate variability indices are related to flow mediated dilation across healthy male subjects. The results cannot serve as evidence of a causal relationship, but are of interest and render for further investigation into underlying mechanisms.
TL;DR: It is reported that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of thebrain critical for arousal.
Abstract: Ghrelin, a circulating gut-hormone, has emerged as an important regulator of growth hormone release and appetite. Ghrelin-immunopositive neurons have also been identified in the hypothalamus with a unique anatomical distribution. Here, we report that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of the brain critical for arousal. Hypothalamic ghrelin mRNA oscillates in a circadian pattern peaking in the dark phase prior to the switch from arousal to sleep. Ghrelin inhibits the electrophysiological activity of identified orexin/hypocretin neurons in hypothalamic slices. These observations indicate that the hypothalamic neurons identified by ghrelin immunolabeling may be a key mediator of circadian and visual cues for the hypothalamic arousal system.
TL;DR: An obese phenotype is described in a model of AgRP‐ablated mice, and it is linked to a shift in metabolic profile in efferent tissues such as the liver, muscle and pancreas.
Abstract: AgRP/NPY neurons are critical regulators of body weight and food intake. Concordant with their orexigenic effects, it is expected that AgRP ablation leads to the appearance of a lean phenotype. In the current issue of The EMBO Journal , Joly‐Amado et al (2012) describe an obese phenotype in a model of AgRP‐ablated mice, and link it to a shift in metabolic profile in efferent tissues such as the liver, muscle and pancreas.
TL;DR: The in vitro milieu should be optimized and better defined, so that artifacts due to in vitro culture systems would not pose dangers for the proper interpretation of results.
TL;DR: Carotid artery elasticity in health is not related to conduit artery FMD, suggesting that endothelial influence on baroreceptor activity is not exerted through changes in barosensory wall elasticity.
Abstract: Introduction Carotid artery stiffness, an important determinant of arterial baroreflex sensitivity, varies considerably in healthy individuals, the source of which variability is not known. Tonic relaxant influence of the endothelium on vascular smooth muscle, reducing stiffness of the vessel wall, has been established in muscular conduit arteries. It is not known to what extent stiffness of the elastic carotid artery is under endothelial control. Subjects and methods Seventy-one healthy male volunteers were studied. Endothelial function was assessed by brachial artery flow mediated dilatation (FMD) normalized by diastolic shear rate (SRd). Carotid artery elastic parameters were determined by echo wall-tracking and tonometry. Systemic arterial stiffness was assessed by carotid–femoral pulse wave velocity (PWV). Results In univariate analysis carotid artery elastic parameters were related to BMI and systolic blood pressure, but were not related to any of endothelial function parameters. As expected, PWV was related inversely to nFMD. No relation was found between vascular stiffness parameters and endothelium-independent dilation (EID). Conclusion Carotid artery elasticity in health is not related to conduit artery FMD, suggesting that endothelial influence on baroreceptor activity is not exerted through changes in barosensory wall elasticity.
TL;DR: Tanycytes in the hypothalamic median eminence have now been found to form a metabolically sensitive neurogenic niche in the brain and give rise to hypothalamic regulatory neurons in response to a high-fat diet.
Abstract: Tanycytes in the hypothalamic median eminence have now been found to form a metabolically sensitive neurogenic niche in the brain. In adult mice, tanycytes give rise to hypothalamic regulatory neurons in response to a high-fat diet.
TL;DR: Local problems are formulated for the error and the corresponding Neumann type boundary conditions are approximated using a new family of gradient averaging procedures which define a family of implicit a posteriori error estimators.
Abstract: We develop implicit a posteriori error estimators for elliptic boundary value problems. Local problems are formulated for the error and the corresponding Neumann type boundary conditions are approximated using a new family of gradient averaging procedures. Convergence properties of the implicit error estimator are discussed independently of residual type error estimators, and this gives a freedom in the choice of boundary conditions. General assumptions are elaborated for the gradient averaging which define a family of implicit a posteriori error estimators. We will demonstrate the performance and the favor of the method through numerical experiments.
01 Jan 2012
TL;DR: This work presents a meta-analysis of the literature on circadian clock Genes and Energy Metabolism, which shows clear relationships between sleep loss and obesity, and bariatric surgery for treatment of Obesity.
Abstract: 1 Circadian Clock Genes and the Regulation of Sleep - Thomas Curie and Paul Franken 2 Clock Genes and Energy Metabolism - Hee-Kyung Hong, Wenyu Huang, Kathryn Moynihan Ramsey, Biliana Marcheva, and Joseph Bass 3 Neural Circuitry Underlying Sleep and Waking - Roda Rani Konadhode, Dheeraj Pelluru, and Priyattam J. Shiromani 4 Feeding as a Reward Mechanism- Ralph J. Dileone, Nandakumar S. Narayanan, and Douglas J. Guarnieri 5 Plasticity of Brain Feeding Circuits in Response to Food - Tamas L. Horvath 6 The Neurogenetics of Energy Balance - Martin G. Myers, Jr. 7 Short Sleep and Obesity in Children - Chantelle N. Hart, Elizabeth Kuhl, and Elissa Jelalian 8 Circadian Misalignment and Sleep Disruption in Shift Work: Implications for Fatigue and Risk of Weight Gain and Obesity - Rachel R. Markwald and Kenneth P. Wright 9 Sleep Apnea and Obesity - Vidya Krishnan and Sanjay R. Patel 10 The Connection Between Sleep Loss and Obesity - Eve van Cauter 11 Sleep Disturbances: Impact on Risk and Severity of Diabetes - Kelly Holes-Lewis 12 Insufficient Sleep and Cardiovascular disease - Susan Redline 13 Clinical Guidelines for the Evaluation of Adults with Obstructive Sleep Apnea - Lawrence J. Epstein 14 Pharmacological Treatment of Obesity - Dhiraj Kabra, Uma Kabra, Mathias Tschop, and Susanna Hofmann 15 Bariatric Surgery for Treatment of Obesity - Mark J. Perna, Rana C. Pullattrana, and Thomas Karl Byrne
TL;DR: A new study combines glucagon-like peptide-1 (GLP1) and estrogen in a single molecule, allowing selective targeting of this conjugate to cells that express the GLP1 receptor.
Abstract: Many mechanisms can contribute to complex diseases such as metabolic diseases; thus, combination therapies may be required to target individual underlying pathological mechanisms A new study combines glucagon-like peptide-1 (GLP1) and estrogen in a single molecule, allowing selective targeting of this conjugate to cells that express the GLP1 receptor This strategy improves the metabolic profile of obese mice without the adverse side effects associated with estrogen therapy (pages 1847–1856)
TL;DR: Light is shed on a previously unsuspected neuronal population that appears to be fundamental for the coupling of energy deficit with impaired reproduction and the fine coordination of energy balance and reproduction.
Abstract: Evolutionarily, the ability to regulate energy balance and reproduction in parallel is critical, because reproductive success will only occur when sufficient energy supplies are available. In periods when energy stores are depleted, reproduction is switched off in an attempt to save energy to optimize survival for subsequent reproductive success. The cellular mechanisms involved in the fine coordination of energy balance and reproduction are largely unknown. In PNAS, Wu et al. (1) shed light on a previously unsuspected neuronal population that appears to be fundamental for the coupling of energy deficit with impaired reproduction.
TL;DR: Reduced Gmax/Tmax values indicative of myocardial perfusion abnormalities as measured by densitometry on coronary angiograms could be demonstrated in patients with aortic valve stenosis compared to controls.
Abstract: Az aortabillentyű-szűkulet anginiform panaszokkal jarhat egyutt szignifikans koszoruer-szűkulet hianyaban is, amelynek hattereben microvascularis elteresek allhatnak. Celkitűzes: Jelen tanulmany celja koronarografias felveteleken denzitometrias meresek segitsegevel meghatarozott myocardialis perfuzios parameterek szamitasa volt aortabillentyű-szűkuletben szenvedő betegekben. Modszerek: A vizsgalatba 20, aortabillentyű-szűkuletben szenvedő beteget vontak be (atlagos transaorticus gradiens: 47,4±15,2 Hgmm) es az eredmenyeiket 30 kontrollesethez hasonlitottak. A koronarografia soran a szignifikans coronariaszűkuletet valamennyi esetben kizartak. A koronarografias felveteleken a koszoruereknek megfelelően kijelolt regiokban, az idő-denzitas gorbekből a myocardialis perfuziot jellemző kvantitativ parametert szamitottak a maximalis denzitas (Gmax) es a maximalis denzitas eleresehez szukseges idő (Tmax) hanyadosakent. Eredmenyek: Az aortabillentyű-szűkuletben szenvedők csoportjaban a haromer-atlag Gmax/Tmax erte...
TL;DR: It is shown that the mTOR pathway has a pivotal role in deterioration of POMC neurons during age-dependent obesity.
TL;DR: This review article highlights some of the advance-ments that have led to the current understanding of the brain`s involvement in the acute and chronic regulation of energy homeo-stasis.
Abstract: Significant advancements have been made in the past century regarding the neuronal control of feeding behavior and energy ex-penditure. The effects and mechanisms of action of various peripheral metabolic signals on the brain have become clearer. Molecu-lar and genetic tools for visualizing and manipulating individual components of brain homeostatic systems in combination with neuroanatomical, electrophysiological, behavioral, and pharmacological techniques have begun to elucidate the molecular and neuronal mechanisms of complex feeding behavior and energy expenditure. This review article highlights some of these advance-ments that have led to the current understanding of the brain`s involvement in the acute and chronic regulation of energy homeo-stasis. (Endocrinol Metab 27:268-273, 2012)