scholarly journals A brain-specific pgc1α fusion transcript affects gene expression and behavioural outcomes in mice

2021 ◽  
Vol 4 (12) ◽  
pp. e202101122
Author(s):  
Oswaldo A Lozoya ◽  
Fuhua Xu ◽  
Dagoberto Grenet ◽  
Tianyuan Wang ◽  
Korey D Stevanovic ◽  
...  
Keyword(s):  
Simple Sequence Repeat Locus ◽  
Repetitive Sequences ◽  
Fusion Transcript ◽  
Transcriptional Coactivator ◽  
Peripheral Tissues ◽  
Repeat Locus ◽  
Behavioural Phenotypes ◽  
Neuronal Physiology ◽  
The Brain

PGC1α is a transcriptional coactivator in peripheral tissues, but its function in the brain remains poorly understood. Various brain-specific Pgc1α isoforms have been reported in mice and humans, including two fusion transcripts (FTs) with non-coding repetitive sequences, but their function is unknown. The FTs initiate at a simple sequence repeat locus ∼570 Kb upstream from the reference promoter; one also includes a portion of a short interspersed nuclear element (SINE). Using publicly available genomics data, here we show that the SINE FT is the predominant form of Pgc1α in neurons. Furthermore, mutation of the SINE in mice leads to altered behavioural phenotypes and significant up-regulation of genes in the female, but not male, cerebellum. Surprisingly, these genes are largely involved in neurotransmission, having poor association with the classical mitochondrial or antioxidant programs. These data expand our knowledge on the role of Pgc1α in neuronal physiology and suggest that different isoforms may have distinct functions. They also highlight the need for further studies before modulating levels of Pgc1α in the brain for therapeutic purposes.

scholarly journals Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice

2020 ◽  
Author(s):  
Oswaldo A. Lozoya ◽  
Fuhua Xu ◽  
Dagoberto Grenet ◽  
Tianyuan Wang ◽  
Korey D. Stevanovic ◽  
...  
Keyword(s):  
Motor Coordination ◽  
Repetitive Sequences ◽  
Motor Deficits ◽  
Peroxisome Proliferator ◽  
Sexually Dimorphic ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peripheral Tissues ◽  
The Brain ◽  
Simple Sequence

AbstractThe peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1α) is known as a transcriptional co-activator in peripheral tissues but its function in the brain remains poorly understood. Various brain-specific Pgc1α isoforms have been reported in mice and humans, including transcripts derived from a novel promoter about ∼580 Kb upstream from the reference gene. These isoforms incorporate repetitive sequences from the simple sequence repeat (SSR) and short interspersed nuclear element (SINE) classes and are predicted to give rise to proteins with distinct amino-termini. In this study, we show that a SINE-containing isoform is the predominant form of Pgc1α expressed in neurons. We then generated a mouse carrying a mutation within the SINE to study its functional role in the brain. By combining genomics, biochemical and behavioural approaches, we show that this mutation leads to impaired motor coordination in females, but not male mice, associated with the upregulation of hundreds of cerebellar genes. Moreover, our analysis suggests that known nuclear receptors interact with this isoform of PGC1α in the brain to carry out the female transcriptional program. These data expand our knowledge on the role of Pgc1α in the brain and help explain its conflicting roles in neurological disease and behavioural outcomes.

Running the Female Power Grid Across Lifespan Through Brain Estrogen Signaling

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Holly A. Ingraham ◽  
Candice B. Herber ◽  
William C. Krause
Keyword(s):  
Brain Regions ◽  
Estrogen Signaling ◽  
Annual Review ◽  
Publication Date ◽  
Drug Induced ◽  
Peripheral Tissues ◽  
Hormone Sensitive ◽  
The Brain ◽  
Female Power

The role of central estrogen in cognitive, metabolic, and reproductive health has long fascinated the lay public and scientists alike. In the last two decades, insight into estrogen signaling in the brain and its impact on female physiology is beginning to catch up with the vast information already established for its actions on peripheral tissues. Using newer methods to manipulate estrogen signaling in hormone-sensitive brain regions, neuroscientists are now identifying the molecular pathways and neuronal subtypes required to establish crucial sex differences in energy allocation. However, the immense cellular complexity of these hormone-sensitive brain regions makes it clear that more research is needed to fully appreciate how estrogen modulates neural circuits to regulate physiological and behavioral end points. Such insight is essential for understanding how natural or drug-induced hormone fluctuations across lifespan affect women's health. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment

2019 ◽  
Vol 21 (1) ◽  
pp. 255 ◽  
Author(s):  
Oriol Busquets ◽  
Miren Ettcheto ◽  
Amanda Cano ◽  
Patricia R. Manzine ◽  
Elena Sánchez-Lopez ◽  
...  
Keyword(s):  
Potential Role ◽  
Regulatory Function ◽  
Neuroprotective Effects ◽  
Peripheral Tissues ◽  
Therapeutic Value ◽  
Jnk Inhibitors ◽  
The Brain ◽  
Cognitive Alterations ◽  
Synthetic Small Molecule

Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed.

scholarly journals Ablation of kynurenine 3-monooxygenase rescues plasma inflammatory cytokine levels in the R6/2 mouse model of Huntington’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie Katrin Bondulich ◽  
Yilan Fan ◽  
Yeojin Song ◽  
Flaviano Giorgini ◽  
Gillian P. Bates
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Kynurenine Pathway ◽  
Peripheral Inflammation ◽  
Peripheral Tissues ◽  
Inflammatory Parameters ◽  
Cytokine Levels ◽  
Behavioural Phenotypes ◽  
Disease Indicators ◽  
The Brain

AbstractKynurenine 3-monooxygenase (KMO) regulates the levels of neuroactive metabolites in the kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD.

scholarly journals The role of differential oxygen distribution between the brain and peripheral tissues on tolerance to induced central hypovolemia

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Victoria Lee Kay ◽  
Mebin George ◽  
Babs R. Soller ◽  
Kathy L. Ryan ◽  
Carmen Hinojosa‐Laborde ◽  
...  
Keyword(s):  
Oxygen Distribution ◽  
Peripheral Tissues ◽  
The Brain

scholarly journals Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

2020 ◽  
Vol 21 (14) ◽  
pp. 5030
Author(s):  
Elena Vacchi ◽  
Alain Kaelin-Lang ◽  
Giorgia Melli
Keyword(s):  
Neurodegenerative Diseases ◽  
Alpha Synuclein ◽  
Anatomical Connectivity ◽  
Peripheral Tissues ◽  
Parkinson’S Diseases ◽  
Relevant Role ◽  
The Brain ◽  
Dying Back

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

scholarly journals The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease: May Thioredoxin Interacting Protein (TXNIP) Play a Role?

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1652
Author(s):  
Lorena Perrone ◽  
Mariarosaria Valente
Keyword(s):  
Cardiovascular Diseases ◽  
Alzheimer Disease ◽  
Brain Dysfunction ◽  
Metabolic Dysfunction ◽  
Interacting Protein ◽  
Peripheral Tissues ◽  
Thioredoxin Interacting Protein ◽  
Set Up ◽  
The Brain

Alzheimer disease (AD) is the most frequent cause of dementia and up to now there is not an effective therapy to cure AD. In addition, AD onset occurs decades before the diagnosis, affecting the possibility to set up appropriate therapeutic strategies. For this reason, it is necessary to investigate the effects of risk factors, such as cardiovascular diseases, in promoting AD. AD shows not only brain dysfunction, but also alterations in peripheral tissues/organs. Indeed, it exists a reciprocal connection between brain and heart, where cardiovascular alterations participate to AD as well as AD seem to promote cardiovascular dysfunction. In addition, metabolic dysfunction promotes both cardiovascular diseases and AD. In this review, we summarize the pathways involved in the regulation of the brain-heart axis and the effect of metabolism on these pathways. We also present the studies showing the role of the gut microbiota on the brain-heart axis. Herein, we propose recent evidences of the function of Thioredoxin Interacting protein (TXNIP) in mediating the role of metabolism on the brain-heart axis. TXNIP is a key regulator of metabolism at both cellular and body level and it exerts also a pathological function in several cardiovascular diseases as well as in AD.

scholarly journals The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance

2005 ◽  
Vol 27 (1) ◽  
pp. 73-100 ◽  
Author(s):  
Uberto Pagotto ◽  
Giovanni Marsicano ◽  
Daniela Cota ◽  
Beat Lutz ◽  
Renato Pasquali
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Cb1 Receptor ◽  
Endocrine Regulation ◽  
Cb2 Receptor ◽  
Peripheral Tissues ◽  
The Brain

During the last few years, the endocannabinoid system has emerged as a highly relevant topic in the scientific community. Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors, named CB1 receptor and CB2 receptor, first discovered as the molecular targets of the psychotropic component of the plant Cannabis sativa, participate in the physiological modulation of many central and peripheral functions. CB2 receptor is mainly expressed in immune cells, whereas CB1 receptor is the most abundant G protein-coupled receptor expressed in the brain. CB1 receptor is expressed in the hypothalamus and the pituitary gland, and its activation is known to modulate all the endocrine hypothalamic-peripheral endocrine axes. An increasing amount of data highlights the role of the system in the stress response by influencing the hypothalamic-pituitary-adrenal axis and in the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior. The ability of the endocannabinoid system to control appetite, food intake, and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptor and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the gastrointestinal tract, and, possibly, skeletal muscle. The relevance of the system is further strenghtened by the notion that drugs interfering with the activity of the endocannabinoid system are considered as promising candidates for the treatment of various diseases, including obesity.

scholarly journals The role of nesfatin-1 in metabolism regulation: an overview / Rola nesfatyny-1 w regulacji metabolizmu: artykuł przeglądowy

2013 ◽  
Vol 13 (2) ◽  
pp. 195-205
Author(s):  
Michał Bulc ◽  
Sławomir Gonkowski ◽  
Jarosław Całka
Keyword(s):  
Body Weight Gain ◽  
Wide Distribution ◽  
Dark Phase ◽  
Dependent Manner ◽  
Peripheral Tissues ◽  
Functional Studies ◽  
Metabolism Regulation ◽  
Dose Dependent ◽  
The Brain

Abstract The hypothalamus synthesizes molecules involved in the regulation of feeding behaviour. Nesfatin- 1 is a recently discovered substance expressed in both the brain and peripheral tissues and exerts a strong anorectic action. Nesfatin-1-immunoreactive cell bodies are distributed in arcuate (ARC), paraventricular (PVN) and supraoptic (SON) nuclei, where the peptide has been found to be co-expressed with pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), oxytocin (OX) and vasopressin (VP). More detailed studies have shown a wide distribution of nesfatin-1-positive neurons in several brain areas, such as the forebrain, hindbrain, brainstem and spinal cord. Moreover, nesfatin-1 has been also expressed in peripheral tissues, colocalizing with ghrelin in the gastric mucosa and insulin in β-cells of the endocrine pancreas and adipose tissue. Functional studies have revealed that exogenous nesfatin-1 administered into the brain ventricles, subcutaneously or intraperitoneally, was able to decrease both food intake in the dark phase as well as body weight gain in a dose-dependent manner. In addition, recent findings suggest the involvement of nesfatin-1 in the control of insulin secretion as well as immune and stress-related responses. However, since there is still a deficiency of data concerning the nesfatin-1 receptor, the possible implementation of nesfatin-1 analogs during human metabolic disorders requires further study.

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.

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