Publications
127 results found
Selman C, Partridge L, Withers DJ, 2011, Replication of Extended Lifespan Phenotype in Mice with Deletion of Insulin Receptor Substrate 1, PLOS ONE, Vol: 6, ISSN: 1932-6203
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- Citations: 70
Selman C, Withers DJ, 2011, Mammalian models of extended healthy lifespan, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 366, Pages: 99-107, ISSN: 0962-8436
Over the last two centuries, there has been a significant increase in average lifespan expectancy in the developed world. One unambiguous clinical implication of getting older is the risk of experiencing age-related diseases including various cancers, dementia, type-2 diabetes, cataracts and osteoporosis. Historically, the ageing process and its consequences were thought to be intractable. However, over the last two decades or so, a wealth of empirical data has been generated which demonstrates that longevity in model organisms can be extended through the manipulation of individual genes. In particular, many pathological conditions associated with the ageing process in model organisms, and importantly conserved from nematodes to humans, are attenuated in long-lived genetic mutants. For example, several long-lived genetic mouse models show attenuation in age-related cognitive decline, adiposity, cancer and glucose intolerance. Therefore, these long-lived mice enjoy a longer period without suffering the various sequelae of ageing. The greatest challenge in the biology of ageing is to now identify the mechanisms underlying increased healthy lifespan in these model organisms. Given that the elderly are making up an increasingly greater proportion of society, this focused approach in model organisms should help identify tractable interventions that can ultimately be translated to humans.
Li X, Thomason PA, Withers DJ, et al., 2010, Bio-informatics analysis of a gene co-expression module in adipose tissue containing the diet-responsive gene Nnat, BMC Systems Biology, Vol: 4, ISSN: 1752-0509
Background: Obesity causes insulin resistance in target tissues - skeletal muscle, adipose tissue, liver and the brain.Insulin resistance predisposes to type-2 diabetes (T2D) and cardiovascular disease (CVD). Adipose tissueinflammation is an essential characteristic of obesity and insulin resistance. Neuronatin (Nnat) expression has beenfound to be altered in a number of conditions related to inflammatory or metabolic disturbance, but itsphysiological roles and regulatory mechanisms in adipose tissue, brain, pancreatic islets and other tissues are notunderstood.Results: We identified transcription factor binding sites (TFBS) conserved in the Nnat promoter, and transcriptionfactors (TF) abundantly expressed in adipose tissue. These include transcription factors concerned with the controlof: adipogenesis (Pparg, Klf15, Irf1, Creb1, Egr2, Gata3); lipogenesis (Mlxipl, Srebp1c); inflammation (Jun, Stat3); insulinsignalling and diabetes susceptibility (Foxo1, Tcf7l2). We also identified NeuroD1 the only documented TF thatcontrols Nnat expression. We identified KEGG pathways significantly associated with Nnat expression, includingpositive correlations with inflammation and negative correlations with metabolic pathways (most prominentlyoxidative phosphorylation, glycolysis and gluconeogenesis, pyruvate metabolism) and protein turnover. 27 genes,including; Gstt1 and Sod3, concerned with oxidative stress; Sncg and Cxcl9 concerned with inflammation; Ebf1,Lgals12 and Fzd4 involved in adipogenesis; whose expression co-varies with Nnat were identified, and conservedtranscription factor binding sites identified on their promoters. Functional networks relating to each of these geneswere identified.Conclusions: Our analysis shows that Nnat is an acute diet-responsive gene in white adipose tissue andhypothalamus; it may play an important role in metabolism, adipogenesis, and resolution of oxidative stress andinflammation in response to dietary excess.
Foukas LC, Withers DJ, 2010, Phosphoinositide signalling pathways in metabolic regulation, Current Topics in Microbiology and Immunology, Vol: 346, Pages: 115-141, ISSN: 0070-217X
The Insulin Receptor/PI 3-kinase (INSR/PI3K) signalling pathway is a key regulator of cell and organismal metabolism. Phosphoinositides generated by PI 3-kinases following insulin and other metabolic hormone receptor activation give rise to signalling cascades involving a multitude of effector molecules. The physiological roles of these molecules have been dissected with the use of both pharmacological and genetic tools. Furthermore, tissue-specific mutagenesis has revealed the extent to which individual insulin-target organs and signalling molecules contribute to whole-body carbohydrate and lipid homeostasis. These studies have generated important information with respect to the function of these molecules in normal physiology and their implication in the development of metabolic diseases such as type-2 diabetes and obesity. © Springer-Verlag Berlin Heidelberg 2010.
Cantley J, Grey ST, Maxwell PH, et al., 2010, The hypoxia response pathway and <i>β</i>-cell function, DIABETES OBESITY & METABOLISM, Vol: 12, Pages: 159-167, ISSN: 1462-8902
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- Citations: 83
Beall C, Piipari K, Al-Qassab H, et al., 2010, Loss of AMP-activated protein kinase α2 subunit in mouse β-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia, BIOCHEMICAL JOURNAL, Vol: 429, Pages: 323-333, ISSN: 0264-6021
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- Citations: 48
Emmanuel J, Symmonds M, Drew ME, et al., 2010, Gamble on a Full Stomach: Monetary Risk-Taking Is Altered by Metabolic State in Normal-Weight Human Male Subjects., 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, ISSN: 0163-769X
Piipari K, Beall C, Al-Qassab H, et al., 2010, Key Role of AMP-Activated Protein Kinase in Pancreatic Beta Cell Glucose-Sensing and Whole Body Glucose Homeostasis, 92nd Meeting and Expo of the Endocrine Society (ENDO 2010), Publisher: ENDOCRINE SOC, Pages: S810-S810, ISSN: 0163-769X
Slack C, Werz C, Wieser D, et al., 2010, Regulation of Lifespan, Metabolism, and Stress Responses by the <i>Drosophila</i> SH2B Protein, Lnk, PLOS GENETICS, Vol: 6, ISSN: 1553-7390
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- Citations: 63
Foukas LC, Withers DJ, 2010, Phosphoinositide Signalling Pathways in Metabolic Regulation, PHOSPHOINOSITIDE 3-KINASE IN HEALTH AND DISEASE, VOL 1, Vol: 346, Pages: 115-141, ISSN: 0070-217X
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- Citations: 14
Al-Qassab H, Smith MA, Irvine EE, et al., 2009, Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons, CELL METABOLISM, Vol: 10, Pages: 343-354, ISSN: 1550-4131
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- Citations: 132
Selman C, Tullet JMA, Wieser D, et al., 2009, Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span, SCIENCE, Vol: 326, Pages: 140-144, ISSN: 0036-8075
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- Citations: 837
Killick R, Scales G, Leroy K, et al., 2009, Deletion of <i>Irs2</i> reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 386, Pages: 257-262, ISSN: 0006-291X
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- Citations: 102
Hisadome K, Smith MA, Choudhury AI, et al., 2009, 5-HT INHIBITION OF RAT INSULIN 2 PROMOTER Cre RECOMBINASE TRANSGENE AND PROOPIOMELANOCORTIN NEURON EXCITABILITY IN THE MOUSE ARCUATE NUCLEUS, NEUROSCIENCE, Vol: 159, Pages: 83-93, ISSN: 0306-4522
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- Citations: 8
Cantley J, Selman C, Shukla D, et al., 2009, Deletion of the von Hippel-Lindau gene in pancreatic β cells impairs glucose homeostasis in mice, JOURNAL OF CLINICAL INVESTIGATION, Vol: 119, Pages: 125-135, ISSN: 0021-9738
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- Citations: 103
Selman C, Lingard S, Gems D, et al., 2008, Comment on brain IRS2 signaling coordinates life span and nutrient homeostasis, SCIENCE, Vol: 320, ISSN: 0036-8075
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- Citations: 41
Selman C, Lingard S, Choudhury AI, et al., 2008, Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice, FASEB JOURNAL, Vol: 22, Pages: 807-818, ISSN: 0892-6638
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- Citations: 394
Field BCT, Small CJ, Bloom SR, 2008, Neurobiology of Obesity, Neurobiology of Obesity, Editors: Harvey, Withers, Publisher: Cambridge Univ Pr, Pages: 1-19, ISBN: 9780521860338
Concise overview, for academic researchers and graduates, of recent developments in the field of obesity.
Batterham RL, ffytche DH, Rosenthal JM, et al., 2007, PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans, NATURE, Vol: 450, Pages: 106-+, ISSN: 0028-0836
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- Citations: 329
Claret M, Smith MA, Batterham RL, et al., 2007, AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons, JOURNAL OF CLINICAL INVESTIGATION, Vol: 117, Pages: 2325-2336, ISSN: 0021-9738
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- Citations: 405
Neganova I, Al-Qassab H, Heffron H, et al., 2007, Role of central nervous system and ovarian insulin receptor substrate 2 signaling in female reproductive function in the mouse, BIOLOGY OF REPRODUCTION, Vol: 76, Pages: 1045-1053, ISSN: 0006-3363
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- Citations: 23
Cantley J, Choudhury AI, Asare-Anane H, et al., 2007, Pancreatic deletion of insulin receptor substrate 2 reduces beta and alpha cell mass and impairs glucose homeostasis in mice, DIABETOLOGIA, Vol: 50, Pages: 1248-1256, ISSN: 0012-186X
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- Citations: 66
Smith MA, Hisadome K, Al-Qassab H, et al., 2007, Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances, JOURNAL OF PHYSIOLOGY-LONDON, Vol: 578, Pages: 425-438, ISSN: 0022-3751
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- Citations: 46
McElwee JJ, Schuster E, Blanc E, et al., 2007, Evolutionary conservation of regulated longevity assurance mechanisms, GENOME BIOLOGY, Vol: 8, ISSN: 1474-760X
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- Citations: 152
Selman C, Kerrison ND, Cooray A, et al., 2006, Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice, PHYSIOLOGICAL GENOMICS, Vol: 27, Pages: 187-200, ISSN: 1094-8341
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- Citations: 92
Batterham RL, Heffron H, Kapoor S, et al., 2006, Critical role for peptide YY in protein-mediated satiation and body-weight regulation, CELL METABOLISM, Vol: 4, Pages: 223-233, ISSN: 1550-4131
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- Citations: 434
Foukas LC, Claret M, Pearce W, et al., 2006, Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation, NATURE, Vol: 441, Pages: 366-370, ISSN: 0028-0836
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- Citations: 375
Simmgen M, Knauf C, Lopez M, et al., 2006, Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice, DIABETOLOGIA, Vol: 49, Pages: 552-561, ISSN: 0012-186X
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- Citations: 24
Kerrison ND, Selman C, Lingard SJ, et al., 2005, Living longer by dieting: analysis of transcriptional response after caloric restriction, BMC Bioinformatics, Vol: 6
Choudhury AI, Heffron H, Smith MA, et al., 2005, The role of insulin receptor substrate 2 in hypothalamic and β cell function, JOURNAL OF CLINICAL INVESTIGATION, Vol: 115, Pages: 940-950, ISSN: 0021-9738
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- Citations: 200
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