112 results found
Kokkinou M, Irvine EE, Bonsall DR, et al., 2020, Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine, Molecular Psychiatry, ISSN: 1359-4184
Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schiz
Guerrero A, Guiho R, Herranz N, et al., 2020, Galactose-modified duocarmycin prodrugs as senolytics, Aging Cell, ISSN: 1474-9718
Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with diseases, such as cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal β-galactosidase this has been exploited as a marker for senescence (senescence-associated β-galactosidase activity). Consequently, we hypothesised that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal β-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole body irradiation or doxorubicin treatment of mice. Moreover, taking advantage of a mouse model of human adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD pro-drug result selectively reduced the number of β-catenin-positive preneoplastic senescent cells, what could have therapeutic implications. In summary, the above results show that galactose-modified duocarmycin prodrugs behave as senolytics, suggesting that they could be used to treat a wide range of senescence-related pathologies.</jats:p>
Smith MA, Choudhury AI, Glegola JA, et al., 2020, Extrahypothalamic GABAergic nociceptin-expressing neurons regulate AgRP neuron activity to control feeding behavior, Journal of Clinical Investigation, Vol: 130, Pages: 126-142, ISSN: 0021-9738
Arcuate nucleus agouti-related peptide (AgRP) neurons play a central role in feeding and are under complex regulation by both homeostatic hormonal and nutrient signals and hypothalamic neuronal pathways. Feeding may also be influenced by environmental cues, sensory inputs and other behaviors implying the involvement of higher brain regions. However, whether such pathways modulate feeding through direct synaptic control of AgRP neuron activity is unknown. Here we show that nociceptin-expressing neurons in the anterior bed nuclei of the stria terminalis (aBNST) make direct GABAergic inputs onto AgRP neurons. We found that activation of these neurons inhibited AgRP neurons and feeding. Activity of these neurons increased upon food availability and their ablation resulted in obesity. Furthermore, these neurons received afferent inputs from a range of upstream brain regions as well as hypothalamic nuclei. Therefore, aBNST nociceptin/GABAergic neurons may act as a gateway to feeding behavior by connecting AgRP neurons to both homeostatic and non-homeostatic neuronal inputs.
Irvine E, Katsouri L, Plattner F, et al., 2019, Genetic deletion of S6k1 does not rescue the phenotypic deficits observed in the R6/2 mouse model of Huntington’s disease, Scientific Reports, Vol: 9, ISSN: 2045-2322
Huntington’s disease (HD) is a fatal inherited autosomal dominant neurodegenerative disorder caused by an expansion in the number of CAG trinucleotide repeats in the huntingtin gene. The disease is characterized by motor, behavioural and cognitive symptoms for which at present there are no disease altering treatments. It has been shown that manipulating the mTOR (mammalian target of rapamycin) pathway using rapamycin or its analogue CCI-779 can improve the cellular and behavioural phenotypes of HD models. Ribosomal protein S6 kinase 1 (S6K1) is a major downstream signalling molecule of mTOR, and its activity is reduced by rapamycin suggesting that deregulation of S6K1 activity may be beneficial in HD. Furthermore, S6k1 knockout mice have increased lifespan and improvement in age-related phenotypes. To evalute the potential benefit of S6k1 loss on HD-related phenotypes, we crossed the R6/2 HD model with the long-lived S6k1 knockout mouse line. We found that S6k1 knockout does not ameliorate behavioural or physiological phenotypes in the R6/2 mouse model. Additionally, no improvements were seen in brain mass reduction or huntingtin protein aggregate levels. Therefore, these results suggest that while a reduction in S6K1 signalling has beneficial effects on ageing it is unlikely to be a therapeutic strategy for HD patients.
Senescence is a cellular stress response that results in the stable arrest of old, damaged or pre-neoplastic cells. Oncogene-induced senescence is tumour suppressive but can also exacerbate tumorigenesis through the secretion of proinflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed ‘senolytics’, have proved beneficial in animal models of many age-associated diseases. In the present study, we show that the cardiac glycoside ouabain is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the proapoptotic Bcl-2 family protein NOXA. We demonstrate that cardiac glycosides synergize with anti-cancer drugs to kill tumour cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent pre-neoplastic cells. The findings of the present study suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanisms. Given the broad range of senescent cells targeted by cardiac glycosides, their use against age-related diseases warrants further exploration.
Millership SJ, Van de Pette M, Withers DJ, 2019, Genomic imprinting and its effects on postnatal growth and adult metabolism, Cellular and Molecular Life Sciences, Vol: 76, Pages: 4009-4021, ISSN: 1420-682X
Imprinted genes display parent-of-origin-specific expression with this epigenetic system of regulation found exclusively in therian mammals. Historically, defined imprinted gene functions were almost solely focused on pregnancy and the influence on the growth parameters of the developing embryo and placenta. More recently, a number of postnatal functions have been identified which converge on resource allocation, both for animals in the nest and in adults. While many of the prenatal functions of imprinted genes that have so far been described adhere to the "parental conflict" hypothesis, no clear picture has yet emerged on the functional role of imprints on postnatal metabolism. As these roles are uncovered, interest in the potential for these genes to influence postnatal metabolism and associated adult-onset disease outcomes when dysregulated has gathered pace. Here, we review the published data on imprinted genes and their influence on postnatal metabolism, starting in the nest, and then progressing through to adulthood. When observing the functional effects of these genes on adult metabolism, we must always be careful to acknowledge the influence both of direct expression in the relevant metabolic tissue, but also indirect metabolic programming effects caused by their modulation of both in utero and postnatal growth trajectories.
Malehmir M, Pfister D, Gallage S, et al., 2019, Platelet GPIb alpha is a mediator and potential interventional target for NASH and subsequent liver cancer, Nature Medicine, Vol: 25, Pages: 641-655, ISSN: 1078-8956
Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet–immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
Rached M-T, Millership SJ, Pedroni SMA, et al., 2019, Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity, Molecular Metabolism, Vol: 20, Pages: 38-50, ISSN: 2212-8778
ObjectiveSympathetic nervous system and immune cell interactions play key roles in the regulation of metabolism. For example, recent convergent studies have shown that macrophages regulate obesity through brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT) via effects upon local catecholamine availability. However, these studies have raised issues about the underlying mechanisms involved including questions regarding the production of catecholamines by macrophages, the role of macrophage polarization state and the underlying intracellular signaling pathways in macrophages that might mediate these effects.MethodsTo address such issues we generated mice lacking Irs2, which mediates the effects of insulin and interleukin 4, specifically in LyzM expressing cells (Irs2LyzM−/− mice).ResultsThese animals displayed obesity resistance and preservation of glucose homeostasis on high fat diet feeding due to increased energy expenditure via enhanced BAT activity and WAT beiging. Macrophages per se did not produce catecholamines but Irs2LyzM−/− mice displayed increased sympathetic nerve density and catecholamine availability in adipose tissue. Irs2-deficient macrophages displayed an anti-inflammatory transcriptional profile and alterations in genes involved in scavenging catecholamines and supporting increased sympathetic innervation.ConclusionsOur studies identify a critical macrophage signaling pathway involved in the regulation of adipose tissue sympathetic nerve function that, in turn, mediates key neuroimmune effects upon systemic metabolism. The insights gained may open therapeutic opportunities for the treatment of obesity.
Borgan F, O'Daly O, Hoang K, et al., 2019, Neural Responsivity to Food Cues in Patients With Unmedicated First-Episode Psychosis, JAMA NETWORK OPEN, Vol: 2, ISSN: 2574-3805
Millership S, Tunster SJ, Van de Pette M, et al., 2018, Neuronatin deletion causes postnatal growth restriction and adult obesity in 129S2/Sv mice, Molecular Metabolism, Vol: 18, Pages: 97-106, ISSN: 2212-8778
ObjectiveImprinted genes are crucial for the growth and development of fetal and juvenile mammals. Altered imprinted gene dosage causes a variety of human disorders, with growth and development during these crucial early stages strongly linked with future metabolic health in adulthood. Neuronatin (Nnat) is a paternally expressed imprinted gene found in neuroendocrine systems and white adipose tissue and is regulated by the diet and leptin. Neuronatin expression is downregulated in obese children and has been associated with stochastic obesity in C57BL/6 mice. However, our recent studies of Nnat null mice on this genetic background failed to display any body weight or feeding phenotypes but revealed a defect in glucose-stimulated insulin secretion due to the ability of neuronatin to potentiate signal peptidase cleavage of preproinsulin. Nnat deficiency in beta cells therefore caused a lack of appropriate storage and secretion of mature insulin.MethodsTo further explore the potential role of Nnat in the regulation of body weight and adiposity, we studied classical imprinting-related phenotypes such as placental, fetal, and postnatal growth trajectory patterns that may impact upon subsequent adult metabolic phenotypes.ResultsHere we find that, in contrast to the lack of any body weight or feeding phenotypes on the C57BL/6J background, deletion of Nnat in mice on 129S2/Sv background causes a postnatal growth restriction with reduced adipose tissue accumulation, followed by catch up growth after weaning. This was in the absence of any effect on fetal growth or placental development. In adult 129S2/Sv mice, Nnat deletion was associated with hyperphagia, reduced energy expenditure, and partial leptin resistance. Lack of neuronatin also potentiated obesity caused by either aging or high fat diet feeding.ConclusionsThe imprinted gene Nnat plays a key role in postnatal growth, adult energy homeostasis, and the pathogenesis of obesity via catch up growth effects, but this role
Paul EJ, Kalk E, Tossell K, et al., 2018, nNOS-expressing neurons in the ventral tegmental area and substantia nigra pars compacta, eNeuro, Vol: 5, ISSN: 2373-2822
GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear whether some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesized that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell type-specific virus-based anterograde tracing in mice. We found that nNOS-expressing neurons, in the parabrachial pigmented (PBP) part of the VTA and the SNc were GABAergic and did not make detectable projections, suggesting they may be interneurons. In contrast, nNOS-expressing neurons in the rostral linear nucleus (RLi) were mostly glutamatergic and projected to a number of regions, including the lateral hypothalamus (LH), the ventral pallidum (VP), and the median raphe (MnR) nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically-distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc.
Smith MA, Katsouri L, Virtue S, et al., 2018, Calcium channel CaV2.3 subunits regulate hepatic glucose production by modulating leptin-induced excitation of arcuate pro-opiomelanocortin neurons, Cell Reports, Vol: 25, Pages: 278-287, ISSN: 2211-1247
Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the “R-type” channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes.
Millership S, Da Silva Xavier G, Choudhury A, et al., 2018, Neuronatin regulates pancreatic beta cell insulin content and secretion, Journal of Clinical Investigation, Vol: 128, Pages: 3369-3381, ISSN: 0021-9738
Neuronatin (Nnat) is an imprinted gene implicated in human obesity and widely expressed in neuroendocrine and metabolic tissues in a hormone and nutrient-sensitive manner. However, its molecular and cellular functions and precise role in organismal physiology remain only partly defined. Here we demonstrate that mice lacking Nnat globally or specifically in β cells display impaired glucose-stimulated insulin secretion leading to defective glucose handling under conditions of nutrient-excess. In contrast, we report no evidence for any feeding or body weight phenotypes in global Nnat null mice. At the molecular level neuronatin augments insulin signal peptide cleavage by binding to the signal peptidase complex and facilitates translocation of the nascent preprohormone. Loss of neuronatin expression in β cells therefore reduces insulin content and blunts glucose-stimulated insulin secretion. Nnat expression, in turn, is glucose-regulated. This mechanism therefore represents a novel site of nutrient-sensitive control of β cell function and whole animal glucose homeostasis. These data also suggest a potential wider role for Nnat in the regulation of metabolism through the modulation of peptide processing events.
Page MM, Schuster EF, Mudaliar M, et al., 2018, Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice, Aging, Vol: 10, Pages: 1027-1052, ISSN: 1945-4589
Dietary restriction (DR) is the most widely studied non-genetic intervention capable of extending lifespan across multiple taxa. Modulation of genes, primarily within the insulin/insulin-like growth factor signalling (IIS) and the mechanistic target of rapamycin (mTOR) signalling pathways also act to extend lifespan in model organisms. For example, mice lacking insulin receptor substrate-1 (IRS1) are long-lived and protected against several age-associated pathologies. However, it remains unclear how these particular interventions act mechanistically to produce their beneficial effects. Here, we investigated transcriptional responses in wild-type and IRS1 null mice fed an ad libitum diet (WTAL and KOAL) or fed a 30% DR diet (WTDR or KODR). Using an RNAseq approach we noted a high correlation coefficient of differentially expressed genes existed within the same tissue across WTDR and KOAL mice and many metabolic features were shared between these mice. Overall, we report that significant overlap exists in the tissue-specific transcriptional response between long-lived DR mice and IRS1 null mice. However, there was evidence of disconnect between transcriptional signatures and certain phenotypic measures between KOAL and KODR, in that additive effects on body mass were observed but at the transcriptional level DR induced a unique set of genes in these already long-lived mice.
Sandhu EC, Fernando ABP, Irvine E, et al., 2018, Phasic stimulation of midbrain dopamine neuron activity reduces salt consumption, eNeuro, Vol: 5, ISSN: 2373-2822
Salt intake is an essential dietary requirement, but excessive consumption is implicated in hypertension and associated conditions. Little is known about the neural circuit mechanisms that control motivation to consume salt, although the midbrain dopamine system, which plays a key role in other reward-related behaviours, has been implicated. We, therefore, examined the effects on salt consumption of either optogenetic excitation or chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons in male mice. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic excitation was not aversive, did not induce hyperactivity, and did not alter salt concentration preferences in a need-free state. In addition, we found that chemogenetic inhibition of dopamine neurons had no effect on salt intake. Lastly, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, suggesting a more general role of VTA dopamine neuron excitation in organising motivated behaviors.
Viskaitis P, Irvine EE, Smith MA, et al., 2017, Modulation of SF1 neuron activity co-ordinately regulates both feeding behaviour and associated emotional states, Cell Reports, Vol: 21, Pages: 3559-3572, ISSN: 2211-1247
Feeding requires the integration of homeostatic drives with emotional states relevant to food procurement in potentially hostile environments. The ventromedial hypothalamus (VMH) regulates feeding and anxiety, but how these are controlled in a concerted manner remains unclear. Using pharmacogenetic, optogenetic, and calcium imaging approaches with a battery of behavioral assays, we demonstrate that VMH steroidogenic factor 1 (SF1) neurons constitute a nutritionally sensitive switch, modulating the competing motivations of feeding and avoidance of potentially dangerous environments. Acute alteration of SF1 neuronal activity alters food intake via changes in appetite and feeding-related behaviors, including locomotion, exploration, anxiety, and valence. In turn, intrinsic SF1 neuron activity is low during feeding and increases with both feeding termination and stress. Our findings identify SF1 neurons as a key part of the neurocircuitry that controls both feeding and related affective states, giving potential insights into the relationship between disordered eating and stress-associated psychological disorders in humans.
Liao C-Y, Anderson SS, Chicoine NH, et al., 2017, Evidence that S6K1, but not 4E-BP1, mediates skeletal muscle pathology associated with loss of A-type lamins, Cell Discovery, Vol: 3, ISSN: 2056-5968
The mechanistic target of rapamycin (mTOR) signaling pathway plays a central role in aging and a number of different disease states. Rapamycin, which suppresses activity of the mTOR complex 1 (mTORC1), shows preclinical (and sometimes clinical) efficacy in a number of disease models. Among these are Lmna−/− mice, which serve as a mouse model for dystrophy-associated laminopathies. To confirm that elevated mTORC1 signaling is responsible for the pathology manifested in Lmna−/− mice and to decipher downstream genetic mechanisms underlying the benefits of rapamycin, we tested in Lmna−/− mice whether survival could be extended and disease pathology suppressed either by reduced levels of S6K1 or enhanced levels of 4E-BP1, two canonical mTORC1 substrates. Global heterozygosity for S6K1 ubiquitously extended lifespan of Lmna−/− mice (Lmna−/− S6K1+/− mice). This life extension is due to improving muscle, but not heart or adipose, function, consistent with the observation that genetic ablation of S6K1 specifically in muscle tissue also extended survival of Lmna−/− mice. In contrast, whole-body overexpression of 4E-BP1 shortened the survival of Lmna−/− mice, likely by accelerating lipolysis. Thus, rapamycin-mediated lifespan extension in Lmna−/− mice is in part due to the improvement of skeletal muscle function and can be phenocopied by reduced S6K1 activity, but not 4E-BP1 activation.
Hine C, Kim H-J, Zhu Y, et al., 2017, Hypothalamic-pituitary axis regulates hydrogen sulfide production, Cell Metabolism, Vol: 25, Pages: 1320-+, ISSN: 1550-4131
Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine γ-lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones.
Selman C, Withers DJ, 2017, Physiology: an atypical switch for metabolism and ageing, NATURE, Vol: 542, Pages: 299-300, ISSN: 0028-0836
Van de Pette M, Abbas A, Feytout A, et al., 2017, Visualizing changes in Cdkn1c expression links early life adversity to imprint mis-regulation in adults, Cell Reports, Vol: 31, Pages: 1090-1099, ISSN: 2211-1247
Imprinted genes are regulated according to parental origin and can influence embryonic growth and metabolism and confer disease susceptibility.Here we designed sensitive allele-specific reporters to non-invasively monitor imprinted Cdkn1cexpression in mice and showed that expression was modulated by environmental factors encounteredin utero.Acute exposure to chromatin modifyingdrugs resulted in de-repression of paternally inherited (silent) Cdkn1calleles in embryos that was temporary and resolved after birth.In contrast, deprivation of maternal dietary proteinin uteroprovoked permanent de-repression of imprinted Cdkn1cexpression that was sustained into adulthood and occurred through a folate-dependent mechanism of DNA methylation loss.Given the function of imprinted genes in regulating behavior and metabolic processes in adults, these results establish imprinting deregulation as a credible mechanism linking early life adversity to later-life outcomes.Furthermore,Cdkn1c-luciferasemice offer non-invasivetools to identify factors that disrupt epigenetic processes and strategies to limit their long-term impact.
Yavari A, Stocker CJ, Ghaffari S, et al., 2016, Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function., Cell Metabolism, Vol: 23, Pages: 821-836, ISSN: 1932-7420
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.
Selman C, Sinclair A, Pedroni S, et al., 2016, Evidence that hematopoietic stem cell function is preserved during aging in long-lived S6K1 mutant mice, Oncotarget, Vol: 7, Pages: 29937-29943, ISSN: 1949-2553
The mechanistic target of rapamycin (mTOR) signalling pathway plays a highly conserved role in aging; mice lacking ribosomal protein S6 kinase 1 (S6K1-/-) have extended lifespan and healthspan relative to wild type (WT) controls. Exactly how reduced mTOR signalling induces such effects is unclear, although preservation of stem cell function may be important. We show, using gene expression analyses, that there was a reduction in expression of cell cycle genes in young (12 week) and aged (80 week) S6K1-/- BM-derived c-Kit+ cells when compared to age-matched WT mice, suggesting that these cells are more quiescent in S6K1-/- mice. In addition, we investigated hematopoietic stem cell (HSC) frequency and function in young and aged S6K1-/- and WT mice. Young, but not aged, S6K1-/- mice had more LSK (lineage-, c-Kit+, Sca-1+) cells (% of bone marrow (BM)), including the most primitive long-term repopulating HSC (LT-HSC) relative to WT controls. Donor-derived engraftment of LT-HSCs in recipient mice was unaffected by genotype in young mice, but was enhanced in transplants using LT-HSCs derived from aged S6K1-/- mice. Our results are the first to provide evidence that age-associated HSC functional decline is ameliorated in a long-lived mTOR mutant mouse.
Gil J, Withers DJ, 2016, Ageing: out with the old, Nature, Vol: 530, Pages: 164-165, ISSN: 0028-0836
The selective elimination of cells that have adopted an irreversible, senescent state has now been shown to extend the lifespan of mice and to ameliorate some age-related disease processes.
Herranz N, Gallage S, Mellone M, et al., 2015, Erratum: mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype., Nat Cell Biol, Vol: 17
Ilse S Pienaar, Sarah E Gartside, Puneet Sharma, et al., 2015, Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson’s disease, Molecular Neurodegeneration, Vol: 10, ISSN: 1750-1326
Background: Patients with advanced Parkinson's disease (PD) often present with axial symptoms, includingpostural- and gait difficulties that respond poorly to dopaminergic agents. Although deep brain stimulation (DBS) ofa highly heterogeneous brain structure, the pedunculopontine nucleus (PPN), improves such symptoms, theunderlying neuronal substrate responsible for the clinical benefits remains largely unknown, thus hamperingoptimization of DBS interventions. Choline acetyltransferase (ChAT)::Cre+ transgenic rats were sham-lesioned orrendered parkinsonian through intranigral, unihemispheric stereotaxic administration of the ubiquitin-proteasomalsystem inhibitor, lactacystin, combined with designer receptors exclusively activated by designer drugs (DREADD),to activate the cholinergic neurons of the nucleus tegmenti pedunculopontine (PPTg), the rat equivalent of thehuman PPN. We have previously shown that the lactacystin rat model accurately reflects aspects of PD, including apartial loss of PPTg cholinergic neurons, similar to what is seen in the post-mortem brains of advanced PD patients.Results: In this manuscript, we show that transient activation of the remaining PPTg cholinergic neurons in thelactacystin rat model of PD, via peripheral administration of the cognate DREADD ligand, clozapine-N-oxide (CNO),dramatically improved motor symptoms, as was assessed by behavioral tests that measured postural instability, gait,sensorimotor integration, forelimb akinesia and general motor activity. In vivo electrophysiological recordingsrevealed increased spiking activity of PPTg putative cholinergic neurons during CNO-induced activation. c-Fosexpression in DREADD overexpressed ChAT-immunopositive (ChAT+) neurons of the PPTg was also increased byCNO administration, consistent with upregulated neuronal activation in this defined neuronal population.Conclusions: Overall, these findings provide evidence that functional modulation of PPN cholinergic neuronsalleviates parkinson
Herranz N, Gallage S, Mellone M, et al., 2015, mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype, Nature Cell Biology, Vol: 17, Pages: 1205-1217, ISSN: 1476-4679
Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.
Smith MA, Katsouri L, Irvine EE, et al., 2015, Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice, Cell Reports, Vol: 11, Pages: 335-343, ISSN: 2211-1247
Jove M, Naudi A, Ramirez-Nunez O, et al., 2014, Caloric restriction reveals a metabolomic and lipidomic signature in liver of male mice, AGING CELL, Vol: 13, Pages: 828-837, ISSN: 1474-9726
Page MM, Sinclair A, Robb EL, et al., 2014, Fibroblasts derived from long-lived insulin receptor substrate 1 null mice are not resistant to multiple forms of stress, AGING CELL, Vol: 13, Pages: 962-964, ISSN: 1474-9718
Deas E, Piipari K, Machhada A, et al., 2014, PINK1 deficiency in beta-cells increases basal insulin secretion and improves glucose tolerance in mice, OPEN BIOLOGY, Vol: 4, ISSN: 2046-2441
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