Prof Dominic Withers
The work undertaken in my group has focussed on the role of insulin signalling pathways in metabolic and neuro-endocrine diseases including diabetes, obesity and infertility. The experimental strategies we have adopted are broad ranging from detailed in vitro cell signalling studies to the use of post-genomic techniques such as microarrays, metabonomics and proteomics but are always underpinned by the use of sophisticated gene targeting strategies in mice. Specifically we have identified roles for insulin receptor substrate proteins in the CNS regulation of energy homeostasis. We have developed mice lacking signalling components in chemically defined hypothalamic neurons using BAC transgenesis. We have studied these mice in feeding behaviour paradigms and used electrophysiological approaches on identified neurons to understand the hypothalamic circuits that both sense and regulate energy status in the intact organism. We also have also developed a major interest in nutrient sensing pathways and have recently identified a key role for AMP kinase in hypothalamic function. In the last 3-4 years, my research has also branched out into other areas in which it has become apparent that insulin and other signalling pathways play key roles. This has included the investigation of insulin signalling in the regulation of mammalian lifespan, in age-related cognitive decline and in the pathophysiology of Alzheimer's disease. These studies have involved detailed behavioural analysis of mouse mutants as they age. We are also examining hippocampal electrophysiological function with collaborators at UCL as well as studying signalling and anatomy. In this programme of research we have identified 2 novel gene-targeted long-lived mouse models which are resistant to age-related diseases. We are now extending these observations to test the impact of these gene manipulations upon age-related cognitive decline and a range of neurodegenerative diseases. As well as the core programmes on signal transduction we are also investigating the role of gut hormones in the regulation of energy homeostasis. These studies led by Dr Rachel Batterham, Reader in the Centre of Dianetes and Endocrinology, have involved both mouse gene targeting strategies and human physiological analysis and functional magnetic resonance imaging. This programme of research has started to reveal the CNS circuits, both homeostatic and hedonic, that regulate food intake in man. In summary our work moves from the manipulation of single signalling molecules in defined neurons in mice through to the functional imaging of humans to try and understand the neural circuits that underlie both feeding behaviour and learning and memory, the interplay between these processes and their impact upon diseases such as obesity, neurodegeneration and age-related cognitive decline.
Genetics of ageing and age-related disease in Caenorhabditis elegans
Mechanisms regulating lymphocyte differentiation i
Regulation of signal processing in neurons
The VHL-HIF pathway
The central nervous system regulation of energy homeostasis
Prof David Gems; Prof Linda Partridge; Dr Martin Stocker; Dr Paola Pedarzani; Prof John Greenwood; Prof Mala Maini; Prof Ivan Gout; Prof Nigel Klein; Prof Chris Richards; Prof Arne Akbar; Prof Patrick Maxwell; Prof Michael Duchen; Dr Julie Pitcher; Prof Margaret Ashcroft; Dr Rachel Batterham
- Selman C, Lingard S, Gems D, Partridge L, Withers DJ (2008). Comment on "Brain IRS2 signaling coordinates life span and nutrient homeostasis". Science, 320(5879), 1012 - .
- McElwee JJ, Schuster E, Blanc E, Piper MD, Thomas JH, Patel DS, Selman C, Withers DJ, Thornton JM, Partridge L, Gems DH (2007). Evolutionarily conservation of regulated longevity assurance mechanisms. Genome Biology, 8(7), R132 - . doi:10.1186/gb-2007-8-7-r132
- Claret M, Smith MA, Batterham RL, Selman C, Choudhury A, Fryer LGD, Clements M, Al-Qassab H, Heffron H X, A W S, J R B, G S V, B V, S A, M L J C, D W, D J (2007). AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons.. Journal of Clinical Investigation, 117(8), 2325 - 2336. doi:10.1172/JCI31516
- McElwee JJ, Schuster E, Piper M, Thomas JH, Blanc E, Patel DS, Selman C, Kerrison N, Thornton J, Withers D, Partridge LG, D (2006). A public regulator of longevity acts via lineage-specific effectors.. Genome Research, Submitted, - .
- Selman C, Kerrison ND, Cooray A, Piper MD, Lingard SJ, Barton RH, Schuster EF, Blanc E, Gems D, Nicholson JK, Thornton JM, Partridge L, Withers DJ (2006). Coordinated multitissue transcriptional and plasma metabonomic profiles following acute caloric restriction in mice. Physiol Genomics, 27(3), 187 - 200.
- Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ, Vanhaesebroeck B (2006). Critical role for the p110alpha phosphoinisitide-3-OH kinase in growth and metabolic regulation.. Nature, May 18(441(7091)), 366 - 370. doi:10.1038/nature04694
- Simmgen M, C L, M C, A I C, M C, J B, D C C, M I, M A H, H C, P D V-PA, Burcelin R, Withers DJ (2006). Liver-specific deletion of insulin receptor substrate 2 does not impair hepatic glucose and lipid metabolism in mice.. Diabetologia, 49, 552 - 561.
- Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ (2006). Critical role for peptide YY in protein-mediated satiation and body-weight regulation.. Cell Metabolism, 4(3), 223 - 233. doi:10.1016/j.cmet.2006.08.001
- Broughton SJ, Piper MD, Ikeya T, Bass TM, Jacobson J, Driege Y, Martinez P, Hafen E, Withers DJ, Leevers SJ, Partridge L (2005). Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands.. Proceedings of the National Academy of Sciences of the United States of America, 102(8), 3105 - 3110.
- Choudhury AI, Heffron H, Smith MA, Al-Qassab H, Xu AW, Selman C, Simmgen M, Clements M, Claret M, MacColl G, Bedford DC, Hisadome K, Diakonov I, Moosajee V, Bell JD, Speakman JR, Batterham RL, Barsh GS, Ashford MLJ, Withers DJ (2005). The role of insulin receptor substrate 2 in hypothalamic and beta cell function.. Journal of Clinical Investigation, 115, 940 - 950. doi:10.1172/JCI200524445
- Partridge L, Gems D, Withers DJ (2005). Sex and death: What's the connection?. Cell, 120, 461 - 472.
- Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR (2003). Inhibition of food intake in obese subjects by peptide YY3-36.. New England Journal of Medicine, 349(10), 926 - 928.
- Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, Ghatei MA, Bloom SR (2003). Inhibition of food intake in obese subjects by peptide YY3-36. New England Journal of Medicine, 349(10), 941 - 948. doi:10.1056/NEJMoa030204
- Wurster AL, Withers DJ, Uchida T, White MF, Grusby MJ (2002). Stat6 and IRS-2 cooperate in interleukin 4 (IL-4)-induced proliferation and differentiation but are dispensable for IL-4-dependent rescue from apoptosis.. Molecular and Cellular Biology, 22(1), 117 - 126.
- Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR (1999). Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochemical Journal, 344, 427 - 431.
- Shepherd PR, Withers DJ, Siddle K (1998). Phosphoinositide 3-kinase: The key switch mechanism in insulin signalling. Biochemical Journal, 333, 471 - 490.
- (1997). Expression, enzyme activity and sub cellular localization of mammalian target of rapamycin in insulin responsive cells. Biochemical and Biophysical Research Communications, 241, 704 - 709.
- Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LGD, Clements M, Al-Qassab H, Heffron H, Xu AW, Speakman JR, Barsh GS, Viollet B, Vaulont S, Ashford MLJ, Carling D, Withers DJ (). AMPK is essential for energy homeostasis regulation and glucose-sensing by POMC and AgRP neurons. Journal of Clinical Investigation, , - .
- Batterham RL, ffytche D, Rosenthal M, Zelaya F, Barker G, Withers DJ, Williams S (). PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature, , - . doi:10.1038/nature06212