scholarly journals Functional Role of c-Jun-N-Terminal Kinase in Feeding Regulation

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 671-682 ◽  
Author(s):  
Elizabeth K. Unger ◽  
Merisa L. Piper ◽  
Louise E. Olofsson ◽  
Allison W. Xu
Keyword(s):  
Functional Role ◽  
Central Administration ◽  
Peripheral Tissues ◽  
Immunological Responses ◽  
Feeding Regulation ◽  
Central Inhibition ◽  
The Brain ◽  
Nuclear Immunoreactivity ◽  
Deficient Mice

c-Jun-N-terminal kinase (JNK) is a signaling molecule that is activated by proinflammatory signals, endoplasmic reticulum (ER) stress, and other environmental stressors. Although JNK has diverse effects on immunological responses and insulin resistance in peripheral tissues, a functional role for JNK in feeding regulation has not been established. In this study, we show that central inhibition of JNK activity potentiates the stimulatory effects of glucocorticoids on food intake and that this effect is abolished in mice whose agouti-related peptide (AgRP) neurons are degenerated. JNK1-deficient mice feed more upon central administration of glucocorticoids, and glucocorticoid receptor nuclear immunoreactivity is enhanced in the AgRP neurons. JNK inhibition in hypothalamic explants stimulates Agrp expression, and JNK1-deficient mice exhibit increased Agrp expression, heightened hyperphagia, and weight gain during refeeding. Our study shows that JNK1 is a novel regulator of feeding by antagonizing glucocorticoid function in AgRP neurons. Paradoxically, JNK1 mutant mice feed less and lose more weight upon central administration of insulin, suggesting that JNK1 antagonizes insulin function in the brain. Thus, JNK may integrate diverse metabolic signals and differentially regulate feeding under distinct physiological conditions.

scholarly journals The Antiobesity Effects of Centrally Administered Neuromedin U and Neuromedin S Are Mediated Predominantly by the Neuromedin U Receptor 2 (NMUR2)

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3101-3109 ◽  
Author(s):  
Andrea Peier ◽  
Jennifer Kosinski ◽  
Kimberly Cox-York ◽  
Ying Qian ◽  
Kunal Desai ◽  
...  
Keyword(s):  
Food Intake ◽  
Energy Homeostasis ◽  
Central Administration ◽  
Diet Induced Obesity ◽  
Inhibit Food Intake ◽  
Selective Agonists ◽  
Treatment Of Obesity ◽  
The Brain ◽  
Deficient Mice

Neuromedin U (NMU) and neuromedin S (NMS) are structurally related neuropeptides that have been reported to modulate energy homeostasis. Pharmacological data have shown that NMU and NMS inhibit food intake when administered centrally and that NMU increases energy expenditure. Additionally, NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU are lean and hypophagic. Two high-affinity NMU/NMS receptors, NMUR1 and NMUR2, have been identified. NMUR1 is predominantly expressed in the periphery, whereas NMUR2 is predominantly expressed in the brain, suggesting that the effects of centrally administered NMU and NMS are mediated by NMUR2. To evaluate the role of NMUR2 in the regulation of energy homeostasis, we characterized NMUR2-deficient (Nmur2−/−) mice. Nmur2−/− mice exhibited a modest resistance to diet-induced obesity that was at least in part due to reduced food intake. Acute central administration of NMU and NMS reduced food intake in wild-type but not in Nmur2−/− mice. The effects on activity and core temperature induced by centrally administered NMU were also absent in Nmur2−/− mice. Moreover, chronic central administration of NMU and NMS evoked significant reductions in body weight and sustained reductions in food intake in mice. In contrast, Nmur2−/− mice were largely resistant to these effects. Collectively, these data demonstrate that the anorectic and weight-reducing actions of centrally administered NMU and NMS are mediated predominantly by NMUR2, suggesting that NMUR2-selective agonists may be useful for the treatment of obesity.

Central administration of alpha-MSH antiserum augments fever in the rabbit

1986 ◽  
Vol 250 (5) ◽  
pp. R803-R806 ◽  
Author(s):  
S. T. Shih ◽  
O. Khorram ◽  
J. M. Lipton ◽  
S. M. McCann
Keyword(s):  
Interleukin 1 ◽  
Rabbit Serum ◽  
Normal Rabbit Serum ◽  
Central Administration ◽  
Normal Body Temperature ◽  
Melanocyte Stimulating Hormone ◽  
Average Rise ◽  
The Brain ◽  
Antipyretic Action

alpha-Melanocyte-stimulating hormone (alpha-MSH) has a marked antipyretic action when given centrally or peripherally, and the concentration of this peptide within the septal region of the brain increases during fever. To assess the significance of endogenous central alpha-MSH in fever, antiserum was given to rabbits via a cannula implanted in the third cerebral ventricle. Each day for 3 days, the animals received 50 microliters of normal rabbit serum (NRS) or an equal volume of antiserum raised against alpha-MSH. Interleukin 1 (IL 1) was then injected intravenously to determine the effect of central immunoneutralization of alpha-MSH on the febrile response. Immunoneutralization markedly prolonged fever. The average rise in temperature and the area under the fever curve after IL 1 injection were also significantly increased. Antiserum treatment did not alter normal body temperature, and NRS had no effect on IL 1-induced fever. These results indicate that endogenous central alpha-MSH contributes to physiological limitation of fever and that the role of this peptide in temperature regulation is relevant to the febrile state but not to normothermia.

The use of siRNA as a pharmacological tool to assess a role for the transcription factor NF-IL6 in the brain under in vitro and in vivo conditions during LPS-induced inflammatory stimulation

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Jelena Damm ◽  
Joachim Roth ◽  
Rüdiger Gerstberger ◽  
Christoph Rummel
Keyword(s):  
Transcription Factor ◽  
Brain Cells ◽  
Nuclear Factor ◽  
Si Rna ◽  
The Brain ◽  
Deficient Mice ◽  
Transcription Factor Nuclear Factor

AbstractBackground:Studies with NF-IL6-deficient mice indicate that this transcription factor plays a dual role during systemic inflammation with pro- and anti-inflammatory capacities. Here, we aimed to characterize the role of NF-IL6 specifically within the brain.Methods:In this study, we tested the capacity of short interfering (si) RNA to silence the inflammatory transcription factor nuclear factor-interleukin 6 (NF-IL6) in brain cells underResults:In cells of a mixed neuronal and glial primary culture from the ratConclusions:This approach was, thus, not suitable to characterize the role NF-IL6 in the brain

Abstract 152: Stat4 Deficiency limits the Development and Progression of Atherosclerosis

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Paresa Taghavie-Moghadam ◽  
Matthew Butcher ◽  
Mark Kaplan ◽  
Jerry Nadler ◽  
Elena Galkina
Keyword(s):  
T Cells ◽  
B Cell ◽  
Plaque Burden ◽  
Chow Diet ◽  
Th1 Cells ◽  
Peripheral Tissues ◽  
The Impact ◽  
Deficient Mice

T helper 1 (Th1) cells constitute the majority of plaque infiltrating IFNγ+ T cells and play a pro-atherogenic role. Th1 cells are induced via IFNγ-dependent activation of T-box expressed in T cells (Tbet) and/or IL-12-dependent activation of signal transducer and activator of transcription 4 (Stat4). While the role of Tbet in atherosclerosis is established, the impact of the IL-12/Stat4-dependent pathway is not well defined. To address the role of Stat4 in atherosclerosis, we bred Stat4-deficient mice with Apolipoprotein E-deficient mice to generate Stat4-/-Apoe-/- mice. Deficiency of Stat4 resulted in approximately a 70% reduction in the plaque burden for 34 week old Stat4-/-Apoe-/- mice fed a chow diet and in 12 week old Stat4-/-Apoe-/- mice fed a western diet there was approximately a 40% reduction in plaque burden, both compared with diet matched Apoe-/- controls females (p<0.001). To assess the effect of Stat4 on Th1 and Treg cell differentiation, we performed an in vitro polarization assay. Deficiency of Stat4 reduced differentiation of IFNγ+ Th1 cells in Th1 conditions, but supported the induction of Tregs in Treg polarizing conditions, confirming the importance of Stat4 in regulating the Th1/Treg balance. In contrast to the in vitro results, we found no difference in the expression of both IFNγ and Foxp3 amongst Stat4-/-Apoe-/- and Apoe-/- lymph nodes and splenic CD4+ T cells; suggesting that additional cytokines in vivo may induce IFNγ+Th1 and inhibit Treg differentiation. Stat4 deficiency also resulted in increased splenic B cell numbers and a slight increase in B1a dependent T15/E06 mRNA expression. Stat4 is a powerful regulator of chemokine expression within peripheral tissues. Adoptively transferred Apoe-/- B cells and CD11b+ cells migrated more efficiently into Stat4-/-Apoe-/- aortas compared to Apoe-/- recipients. However, percentages of macrophages, as determined by CD11b+CD68+ were reduced within the spleens and aortas of Stat4-/-Apoe-/- mice as compared to Apoe-/- controls at steady state conditions. In conclusion, Stat4 deficiency results in reduced atherosclerosis via the modulation of B cell function and aortic leukocyte content.

scholarly journals Neuropeptide Y in normal eating and in genetic and dietary-induced obesity

2006 ◽  
Vol 361 (1471) ◽  
pp. 1159-1185 ◽  
Author(s):  
B Beck
Keyword(s):  
Neuropeptide Y ◽  
Diet Composition ◽  
High Energy ◽  
Glucose Sensing ◽  
Feeding Regulation ◽  
Treatment Of Obesity ◽  
The Brain ◽  
Diet Type

Neuropeptide Y (NPY) is one the most potent orexigenic peptides found in the brain. It stimulates food intake with a preferential effect on carbohydrate intake. It decreases latency to eat, increases motivation to eat and delays satiety by augmenting meal size. The effects on feeding are mediated through at least two receptors, the Y1 and Y5 receptors. The NPY system for feeding regulation is mostly located in the hypothalamus. It is formed of the arcuate nucleus (ARC), where the peptide is synthesized, and the paraventricular (PVN), dorsomedial (DMN) and ventromedial (VMN) nuclei and perifornical area where it is active. This activity is modulated by the hindbrain and limbic structures. It is dependent on energy availability, e.g. upregulation with food deprivation or restriction, and return to baseline with refeeding. It is also sensitive to diet composition with variable effects of carbohydrates and fats. Leptin signalling and glucose sensing which are directly linked to diet type are the most important factors involved in its regulation. Absence of leptin signalling in obesity models due to gene mutation either at the receptor level, as in the Zucker rat, the Koletsky rat or the db / db mouse, or at the peptide level, as in ob / ob mouse, is associated with increased mRNA abundance, peptide content and/or release in the ARC or PVN. Other genetic obesity models, such as the Otsuka–Long–Evans–Tokushima Fatty rat, the agouti mouse or the tubby mouse, are characterized by a diminution in NPY expression in the ARC nucleus and by a significant increase in the DMN. Further studies are necessary to determine the exact role of NPY in these latter models. Long-term exposure to high-fat or high-energy palatable diets leads to the development of adiposity and is associated with a decrease in hypothalamic NPY content or expression, consistent with the existence of a counter-regulatory mechanism to diminish energy intake and limit obesity development. On the other hand, an overactive NPY system (increased mRNA expression in the ARC associated with an upregulation of the receptors) is characteristic of rats or rodent strains sensitive to dietary-induced obesity. Finally, NPY appears to play an important role in body weight and feeding regulation, and while it does not constitute the only target for drug treatment of obesity, it may nevertheless provide a useful target in conjunction with others.

The role of amylin in the control of energy homeostasis

2010 ◽  
Vol 298 (6) ◽  
pp. R1475-R1484 ◽  
Author(s):  
Thomas A. Lutz
Keyword(s):  
Energy Homeostasis ◽  
Area Postrema ◽  
Body Weight Gain ◽  
Direct Action ◽  
Central Administration ◽  
Experimental Conditions ◽  
Hypothalamic Area ◽  
Chronic Infusion ◽  
The Brain

Amylin is an important player in the control of nutrient fluxes. Amylin reduces eating via a meal size effect by promoting meal-ending satiation. This effect seems to depend on a direct action in the area postrema (AP), which is an area rich in amylin receptors. Subsequent to the activation of AP neurons, the neural signal is conveyed to the forebrain via relays involving the nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (lPBN) to the lateral hypothalamic area (LHA) and other hypothalamic nuclei. While the NTS and lPBN seem to be necessary for amylin's eating inhibitory effect, the role of the LHA has not yet been fully investigated. Amylin may also act as an adiposity signal. Plasma levels of amylin are higher in obese individuals, and chronic infusion of amylin into the brain reduces body weight gain and adiposity; chronic infusion of an amylin receptor antagonist into the brain increases body adiposity. Amylin increases energy expenditure in rats; this effect occurs under various experimental conditions after peripheral and central administration. Together, these animal data, but also clinical data in humans, indicate that amylin is a promising candidate for the treatment of obesity; effects are most pronounced when amylin is combined with leptin. Finally, recent findings indicate that amylin acts as a neurotrophic factor in specific brain stem areas. Whether this effect may be relevant under physiological conditions requires further studies.

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

2007 ◽  
Vol 292 (1) ◽  
pp. R575-R585 ◽  
Author(s):  
Éva Szentirmai ◽  
Levente Kapás ◽  
James M. Krueger
Keyword(s):  
Food Intake ◽  
Suppressive Effect ◽  
Hormone Release ◽  
Central Administration ◽  
Rapid Eye Movement Sleep ◽  
Regulatory Circuit ◽  
Intracerebroventricular Injections ◽  
The Brain ◽  
Brain Peptide

Ghrelin, a gut-brain peptide, is best known for its role in the stimulation of feeding and growth hormone release. In the brain, orexin, neuropeptide Y (NPY), and ghrelin are parts of a food intake regulatory circuit. Orexin and NPY are also implicated in maintaining wakefulness. Previous experiments in our laboratory revealed that intracerebroventricular injections of ghrelin induce wakefulness in rats. To further elucidate the possible role of ghrelin in the regulation of arousal, we studied the effects of microinjections of ghrelin into hypothalamic sites, which are implicated in the regulation of feeding and sleep, such as the lateral hypothalamus (LH), medial preoptic area (MPA), and paraventricular nucleus (PVN) on sleep in rats. Sleep responses, motor activity, and food intake after central administration of 0.04, 0.2, or 1 μg (12, 60, or 300 pmol) ghrelin were recorded. Microinjections of ghrelin into the LH had strong wakefulness-promoting effects lasting for 2 h. Wakefulness was also stimulated by ghrelin injection into the MPA and PVN; the effects were confined to the first hour after the injection. Ghrelin's non-rapid-eye-movement sleep-suppressive effect was accompanied by attenuation in the electroencephalographic (EEG) slow-wave activity and changes in the EEG power spectrum. Food consumption was significantly stimulated after microinjections of ghrelin into each hypothalamic site. Together, these results are consistent with the hypothesis that forebrain ghrelinergic mechanisms play a role in the regulation of vigilance, possibly through activating the components of the food intake- and arousal-promoting network formed by orexin and NPY.

scholarly journals The potential role for sphingolipids in neuropathogenesis of Alzheimer’s disease

2013 ◽  
Vol 59 (1) ◽  
pp. 25-50 ◽  
Author(s):  
A.V. Alessenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Role ◽  
Potential Role ◽  
Early Stage ◽  
New Drugs ◽  
Neuronal Function ◽  
Sphingosine 1 Phosphate ◽  
The Brain

The review discusses the functional role of sphingolipids in the pathogenesis of Alzheimer's disease. Certain evidence exist that the imbalance of sphingolipids such as sphingomyelin, ceramide, sphingosine, sphingosine-1-phosphate and galactosylceramide in the brain of animals and humans, in the cerebrospinal fluid and blood plasma of patients with Alzheimer's disease play a crucial role in neuronal function by regulating growth, differentiation and cell death in CNS. Activation of sphingomyelinase, which leads to the accumulation of the proapoptotic agent, ceramide, can be considered as a new mechanism for AD and may be a prerequisite for the treatment of this disease by using drugs that inhibit sphingomyelinase activity. The role of sphingolipids as biomarkers for the diagnosis of the early stage of Alzheimer's disease and monitoring the effectiveness of treatment with new drugs is discussed.

scholarly journals Avoidance response to CO2 in the lateral horn

2018 ◽  
Author(s):  
Nélia Varela ◽  
Miguel Gaspar ◽  
Sophie Dias ◽  
Maria Luísa Vasconcelos
Keyword(s):  
Calcium Imaging ◽  
Mushroom Body ◽  
Antennal Lobe ◽  
Functional Role ◽  
Direct Evidence ◽  
Physiological Responses ◽  
Lateral Horn ◽  
The One ◽  
The Brain

ABSTRACTIn flies, the olfactory information is carried from the first relay in the brain, the antennal lobe, to the mushroom body (MB) and the lateral horn (LH). Olfactory associations are formed in the MB. The LH was ascribed a role in innate responses based on the stereotyped connectivity with the antennal lobe, stereotyped physiological responses to odors and MB silencing experiments. Direct evidence for the functional role of the LH is still missing. Here we investigate the behavioral role of the LH neurons directly, using the CO2 response as a paradigm. Our results show the involvement of the LH in innate responses. Specifically, we demonstrate that activity in two sets of neurons is required for the full behavioral response to CO2. Using calcium imaging we observe that the two sets of neurons respond to CO2 in different manners. Using independent manipulation and recording of the two sets of neurons we find that the one that projects to the SIP also outputs to the local neurons within the LH. The design of simultaneous output at the LH and the SIP, an output of the MB, allows for coordination between innate and learned responses.

scholarly journals Co-infections as Modulators of Disease Outcome: Minor Players or Major Players?

2021 ◽  
Vol 12 ◽  
Author(s):  
Priti Devi ◽  
Azka Khan ◽  
Partha Chattopadhyay ◽  
Priyanka Mehta ◽  
Shweta Sahni ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Disease Severity ◽  
Functional Role ◽  
Biological Models ◽  
Immunological Responses ◽  
Immunodeficiency Virus ◽  
Physiological Outcome

Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.

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