Tamas L. Horvath

Bio: Tamas L. Horvath is an academic researcher from Yale University. The author has contributed to research in topics: Hypothalamus & Energy homeostasis. The author has an hindex of 107, co-authored 483 publications receiving 42023 citations. Previous affiliations of Tamas L. Horvath include Humboldt State University & University of West Hungary.

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus

Abstract: The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.

Abstract: Various aspects of the complex spatio-temporal patterning of hypothalamic signaling that leads to the development of synchronized nocturnal feeding in the rat are critically examined. Undoubtedly, as depicted in Fig. 7, a distinct ARN in the hypothalamus is involved in the control of nocturnal appetite. At least four basic elements operate within this ARN. These are: 1) A discrete appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and orexin transduces and releases appetite-stimulating signals. 2) Similarly, anorexigenic signal-producing pathways (e.g., CRH, GLP-1, alpha MSH, and CART) orchestrate neural events for dissipation of appetite and to terminate feeding, possibly by interrupting NPY efflux and action at a postsynaptic level within the hypothalamus. It is possible that some of these may represent the physiologically relevant "off" switches under the influence of GABA alone, or AgrP alone, or in combination with NPY released from the NPY-, GABA-, and AgrP-coproducing neurons. 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals. Since interruption of neurotransmission in the VMN resulted in hyperphagia and development of leptin resistance, it seems likely that the VMN is an effector site for the restraint exercised by leptin. The daily rhythms in leptin synthesis and release are temporally dissociable because the onset of daily rise in leptin gene expression in adipocytes precedes that in leptin secretion. Nevertheless, these rhythms are in phase with daily ingestive behavior because the peak in circulating leptin levels occurs during the middle of the feeding period. These observations, coupled with the fact that circulating levels of leptin are directly related to adiposity, pose a new challenge for elucidating the precise role of leptin in daily patterning of feeding in the rat. 4) A neural timing mechanism also operates upstream from the ARN in the daily management of energy homeostasis. Although the precise anatomical boundaries are not clearly defined, this device is likely to be composed of a group of neurons that integrate incoming internal and external information for the timely onset of the drive to eat. Evidently, this network operates independently in primates, but it is entrained to the circadian time keeper in the SCN of rodents. Apart from its role in the onset of drive to eat, the circadian patterns of gene expression of NPY, GAL, and POMC denote independent control of the timing device on the synthesis and availability for release of orexigenic signals. The VMN-DMN-PVN complex is apparently an integrated constituent of the timing mechanism in this context, because lesions in each of these sites result in loss of regulated feeding. The accumulated evidence points to the PVN and surrounding neural sites within this framework as the primary sites of release and action of various orexigenic and anorexigenic signals. A novel finding is the identification of the interconnected wiring of the DMN-mPVN axis that may mediate leptin restraint on NPY-induced feeding. The chemical phenotypes of leptin and NPY target neurons in this axis remain to be identified. These multiple orexigenic and anorexigenic pathways in the hypothalamic ARN appear to represent redundancy, a characteristic of regulated biological systems to provide a "fail-safe" neural mechanism to meet an organism's constant energy needs for growth and maintenance. Within this formulation, the coexisting orexigenic signals (NPY, NE, GAL, GABA, and AgrP) represent either another level of redundancy or it is possible that these signals operate within the ARN as reinforcing agents to varying degrees under different circumstances. (ABSTRACT TRUNCATED)

Obesity is associated with hypothalamic injury in rodents and humans

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.

The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease

Abstract: The ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc) support mammalian survival during states of energy deficit by serving as alternative sources of ATP. BHB levels are elevated by starvation, caloric restriction, high-intensity exercise, or the low-carbohydrate ketogenic diet. Prolonged fasting reduces inflammation; however, the impact that ketones and other alternative metabolic fuels produced during energy deficits have on the innate immune response is unknown. We report that BHB, but neither AcAc nor the structurally related short-chain fatty acids butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to urate crystals, ATP and lipotoxic fatty acids. BHB did not inhibit caspase-1 activation in response to pathogens that activate the NLR family, CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome and did not affect non-canonical caspase-11, inflammasome activation. Mechanistically, BHB inhibits the NLRP3 inflammasome by preventing K(+) efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 are not dependent on chirality or starvation-regulated mechanisms like AMP-activated protein kinase (AMPK), reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocks the NLRP3 inflammasome without undergoing oxidation in the TCA cycle, and independently of uncoupling protein-2 (UCP2), sirtuin-2 (SIRT2), the G protein-coupled receptor GPR109A or hydrocaboxylic acid receptor 2 (HCAR2). BHB reduces NLRP3 inflammasome-mediated interleukin (IL)-1β and IL-18 production in human monocytes. In vivo, BHB or a ketogenic diet attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases such as Muckle-Wells syndrome, familial cold autoinflammatory syndrome and urate crystal-induced peritonitis. Our findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Abstract: Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Cerebral organoids model human brain development and microcephaly

Abstract: The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue

Microglia: active sensor and versatile effector cells in the normal and pathologic brain

Abstract: Microglial cells constitute the resident macrophage population of the CNS. Recent in vivo studies have shown that microglia carry out active tissue scanning, which challenges the traditional notion of 'resting' microglia in the normal brain. Transformation of microglia to reactive states in response to pathology has been known for decades as microglial activation, but seems to be more diverse and dynamic than ever anticipated—in both transcriptional and nontranscriptional features and functional consequences. This may help to explain why engagement of microglia can be either neuroprotective or neurotoxic, resulting in containment or aggravation of disease progression. Moreover, little is known about the heterogeneity of microglial responses in different pathologic contexts that results from regional adaptations or from the progression of a disease. In this review, we focus on several key observations that illustrate the multi-faceted activities of microglia in the normal and pathologic brain.

Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain

Abstract: The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.