Imperial College London

ProfessorDominicWithers

Faculty of MedicineInstitute of Clinical Sciences

Clinical Chair in Diabetes & Endocrinology
 
 
 
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Contact

 

d.withers

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

100 results found

Millership SJ, Da Silva Xavier G, Choudhury AI, Bertazzo S, Chabosseau P, Pedroni SM, Irvine EE, Montoya A, Faull P, Taylor WR, Kerr-Conte J, Pattou F, Ferrer J, Christian M, John RM, Latreille M, Liu M, Rutter GA, Scott J, Withers DJet al., 2018, Neuronatin regulates pancreatic β cell insulin content and secretion., J Clin Invest

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.

JOURNAL ARTICLE

Page MM, Schuster EF, Mudaliar M, Herzyk P, Withers DJ, Selman Cet al., 2018, Common and unique transcriptional responses to dietary restriction and loss of insulin receptor substrate 1 (IRS1) in mice, AGING-US, Vol: 10, Pages: 1027-1052, ISSN: 1945-4589

JOURNAL ARTICLE

Sandhu EC, Fernando ABP, Irvine EE, Tossell K, Kokkinou M, Glegola J, Smith MA, Howes OD, Withers DJ, Ungless MAet al., 2018, Phasic Stimulation of Midbrain Dopamine Neuron Activity Reduces Salt Consumption, ENEURO, Vol: 5, ISSN: 2373-2822

JOURNAL ARTICLE

Hine C, Kim H-J, Zhu Y, Harputlugil E, Longchamp A, Matos MS, Ramadoss P, Bauerle K, Brace L, Asara JM, Ozaki CK, Cheng S-Y, Singha S, Ahn KH, Kimmelman A, Fisher FM, Pissios P, Withers DJ, Selman C, Wang R, Yen K, Longo VD, Cohen P, Bartke A, Kopchick JJ, Miller R, Hollenberg AN, Mitchell JRet al., 2017, Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production, CELL METABOLISM, Vol: 25, Pages: 1320-+, ISSN: 1550-4131

JOURNAL ARTICLE

Kokkinou M, Irvine EE, Bonsall DR, Ungless MA, Withers DJ, Howes ODet al., 2017, Modulation of sub-chronic ketamine-induced locomotor sensitisation by midbrain dopamine neuron firing, 30th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S925-S926, ISSN: 0924-977X

CONFERENCE PAPER

Liao C-Y, Anderson SS, Chicoine NH, Mayfield JR, Garrett BJ, Kwok CS, Academia EC, Hsu Y-M, Miller DM, Bair AM, Wilson JA, Tannady G, Stewart EM, Adamson SS, Wang J, Withers DJ, Kennedy BKet 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

JOURNAL ARTICLE

Selman C, Withers DJ, 2017, PHYSIOLOGY An atypical switch for metabolism and ageing, NATURE, Vol: 542, Pages: 299-300, ISSN: 0028-0836

JOURNAL ARTICLE

Van de Pette M, Abbas A, Feytout A, McNamara G, Bruno L, To WK, Dimond A, Sardini A, Webster Z, McGinty J, Paul EJ, Ungless MA, French PMW, Withers DJ, Uren A, Ferguson-Smith AC, Merkenschlager M, John RM, Fisher AGet al., 2017, Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults, CELL REPORTS, Vol: 18, Pages: 1090-1099, ISSN: 2211-1247

JOURNAL ARTICLE

Viskaitis P, Irvine EE, Smith MA, Choudhury AI, Alvarez-Curto E, Glegola JA, Hardy DG, Pedroni SMA, Pessoa MRP, Fernando ABP, Katsouri L, Sardini A, Ungless MA, Milligan G, Withers DJet al., 2017, Modulation of SF1 Neuron Activity Coordinately Regulates Both Feeding Behavior and Associated Emotional States, CELL REPORTS, Vol: 21, Pages: 3559-3572, ISSN: 2211-1247

JOURNAL ARTICLE

Gil J, Withers DJ, 2016, AGEING Out with the old, NATURE, Vol: 530, Pages: 164-165, ISSN: 0028-0836

JOURNAL ARTICLE

Selman C, Sinclair A, Pedroni SMA, Irvine EE, Michie AM, Withers DJet 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

JOURNAL ARTICLE

Yavari A, Stocker CJ, Ghaffari S, Wargent ET, Steeples V, Czibik G, Pinter K, Bellahcene M, Woods A, Martínez de Morentin PB, Cansell C, Lam BY, Chuster A, Petkevicius K, Nguyen-Tu MS, Martinez-Sanchez A, Pullen TJ, Oliver PL, Stockenhuber A, Nguyen C, Lazdam M, O'Dowd JF, Harikumar P, Tóth M, Beall C, Kyriakou T, Parnis J, Sarma D, Katritsis G, Wortmann DD, Harper AR, Brown LA, Willows R, Gandra S, Poncio V, de Oliveira Figueiredo MJ, Qi NR, Peirson SN, McCrimmon RJ, Gereben B, Tretter L, Fekete C, Redwood C, Yeo GS, Heisler LK, Rutter GA, Smith MA, Withers DJ, Carling D, Sternick EB, Arch JR, Cawthorne MA, Watkins H, Ashrafian Het 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.

JOURNAL ARTICLE

Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martinez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, Gill Jet al., 2015, mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype, NATURE CELL BIOLOGY, Vol: 17, Pages: 1205-+, ISSN: 1465-7392

JOURNAL ARTICLE

Pienaar IS, Gartside SE, Sharma P, De Paola V, Gretenkord S, Withers D, Elson JL, Dexter DTet 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

JOURNAL ARTICLE

Smith MA, Katsouri L, Irvine EE, Hankir MK, Pedroni SMA, Voshol PJ, Gordon MW, Choudhury AI, Woods A, Vidal-Puig A, Carling D, Withers DJet 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

JOURNAL ARTICLE

Deas E, Piipari K, Machhada A, Li A, Gutierrez-del-Arroyo A, Withers DJ, Wood NW, Abramov AYet al., 2014, PINK1 deficiency in beta-cells increases basal insulin secretion and improves glucose tolerance in mice, OPEN BIOLOGY, Vol: 4, ISSN: 2046-2441

JOURNAL ARTICLE

Jove M, Naudi A, Ramirez-Nunez O, Portero-Otin M, Selman C, Withers DJ, Pamplona Ret 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

JOURNAL ARTICLE

Page MM, Sinclair A, Robb EL, Stuart JA, Withers DJ, Selman Cet 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

JOURNAL ARTICLE

Yousseif A, Emmanuel J, Karra E, Millet Q, Elkalaawy M, Jenkinson AD, Hashemi M, Adamo M, Finer N, Fiennes AG, Withers DJ, Batterham RLet al., 2014, Differential Effects of Laparoscopic Sleeve Gastrectomy and Laparoscopic Gastric Bypass on Appetite, Circulating Acyl-ghrelin, Peptide YY3-36 and Active GLP-1 Levels in Non-diabetic Humans, OBESITY SURGERY, Vol: 24, Pages: 241-252, ISSN: 0960-8923

JOURNAL ARTICLE

Chandarana K, Gelegen C, Irvine EE, Choudhury AI, Amouyal C, Andreelli F, Withers DJ, Batterham RLet al., 2013, Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance, MOLECULAR METABOLISM, Vol: 2, Pages: 142-152, ISSN: 2212-8778

JOURNAL ARTICLE

Foukas LC, Bilanges B, Bettedi L, Pearce W, Ali K, Sancho S, Withers DJ, Vanhaesebroeck Bet al., 2013, Long-term p110 PI3K inactivation exerts a beneficial effect on metabolism, EMBO MOLECULAR MEDICINE, Vol: 5, Pages: 563-571, ISSN: 1757-4676

JOURNAL ARTICLE

Karra E, O'Daly OG, Choudhury AI, Yousseif A, Millership S, Neary MT, Scott WR, Chandarana K, Manning S, Hess ME, Iwakura H, Akamizu T, Millet Q, Gelegen C, Drew ME, Rahman S, Emmanuel JJ, Williams SCR, Ruether UU, Bruening JC, Withers DJ, Zelaya FO, Batterham RLet al., 2013, A link between FTO, ghrelin, and impaired brain food-cue responsivity, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 3539-3551, ISSN: 0021-9738

JOURNAL ARTICLE

Page MM, Withers DJ, Selman C, 2013, Longevity of insulin receptor substrate1 null mice is not associated with increased basal antioxidant protection or reduced oxidative damage, AGE, Vol: 35, Pages: 647-658, ISSN: 0161-9152

JOURNAL ARTICLE

Scott WR, Gelegen C, Chandarana K, Karra E, Yousseif A, Amouyal C, Choudhury AI, Andreelli F, Withers DJ, Batterham RLet al., 2013, Differential Pre-mRNA Splicing Regulates Nnat Isoforms in the Hypothalamus after Gastric Bypass Surgery in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203

JOURNAL ARTICLE

Costello DA, Claret M, Al-Qassab H, Plattner F, Irvine EE, Choudhury AI, Giese KP, Withers DJ, Pedarzani Pet al., 2012, Brain Deletion of Insulin Receptor Substrate 2 Disrupts Hippocampal Synaptic Plasticity and Metaplasticity, PLOS ONE, Vol: 7, ISSN: 1932-6203

JOURNAL ARTICLE

Gelegen C, Chandarana K, Choudhury AI, Al-Qassab H, Evans IM, Irvine EE, Hyde CB, Claret M, Andreelli F, Sloan SE, Leiter AB, Withers DJ, Batterham RLet al., 2012, Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 303, Pages: E659-E668, ISSN: 0193-1849

JOURNAL ARTICLE

Neuhaus B, Niessen CM, Mesaros A, Withers DJ, Krieg T, Partridge Let al., 2012, Experimental analysis of risk factors for ulcerative dermatitis in mice, EXPERIMENTAL DERMATOLOGY, Vol: 21, Pages: 712-713, ISSN: 0906-6705

JOURNAL ARTICLE

Page MM, Withers DJ, Selman C, 2012, An evaluation of cellular stress resistance in long-lived insulin receptor substrate-1 (Irs1) null mice, FREE RADICAL BIOLOGY AND MEDICINE, Vol: 53, Pages: S75-S75, ISSN: 0891-5849

JOURNAL ARTICLE

Wijeyesekera A, Selman C, Barton RH, Holmes E, Nicholson JK, Withers DJet al., 2012, Metabotyping of Long-Lived Mice using H-1 NMR Spectroscopy, JOURNAL OF PROTEOME RESEARCH, Vol: 11, Pages: 2224-2235, ISSN: 1535-3893

JOURNAL ARTICLE

Chandarana K, Gelegen C, Karra E, Choudhury AI, Drew ME, Fauveau V, Viollet B, Andreelli F, Withers DJ, Batterham RLet al., 2011, Diet and Gastrointestinal Bypass-Induced Weight Loss The Roles of Ghrelin and Peptide YY, DIABETES, Vol: 60, Pages: 810-818, ISSN: 0012-1797

JOURNAL ARTICLE

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