Imperial College London

ProfessorDavidCarling

Faculty of MedicineInstitute of Clinical Sciences

Professor of Biochemistry
 
 
 
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Contact

 

+44 (0)20 3313 4313david.carling

 
 
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Location

 

3rd Fl CRBHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

196 results found

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

Johanns M, Lai Y-C, Hsu M-F, Jacobs R, Vertommen D, Van Sande J, Dumont JE, Woods A, Carling D, Hue L, Viollet B, Foretz M, Rider MHet al., 2016, AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B, Nature Communications, Vol: 7, ISSN: 2041-1723

Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the Vmax of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation.

Journal article

Seneviratne A, Carling D, Haskard DO, Boyle JJet al., 2016, Oral metformin profoundly suppresses atherosclerotic lesion development in vivo independently of glucose-lowering in a mild hyperlipidemic model, Atherosclerosis, Vol: 244, Pages: E2-E2, ISSN: 1879-1484

Journal article

Seneviratne A, Carling D, Haskard DO, Boyle JJet al., 2016, Oral metformin profoundly suppresses atherosclerotic lesion development in vivo independently of glucose-lowering in a mild hyperlipidemic model, Atherosclerosis, Vol: 244, Pages: E2-E2, ISSN: 1879-1484

Journal article

Carling D, Viollet B, 2015, Beyond Energy Homeostasis: the Expanding Role of AMP-Activated Protein Kinase in Regulating Metabolism, Publisher: CELL PRESS, Pages: 799-804, ISSN: 1550-4131

Conference paper

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

Rousset CI, Leiper FC, Kichev A, Gressens P, Carling D, Hagberg H, Thornton Cet al., 2015, A dual role for AMP-activated protein kinase (AMPK) during neonatal hypoxic-ischaemic brain injury in mice, JOURNAL OF NEUROCHEMISTRY, Vol: 133, Pages: 242-252, ISSN: 0022-3042

Journal article

Hussain S, Richardson E, Ma Y, Holton C, De Backer I, Buckley N, Dhillo W, Bewick G, Zhang S, Carling D, Bloom S, Gardiner Jet al., 2014, Glucokinase activity in the arcuate nucleus regulates glucose intake, Journal of Clinical Investigation, Vol: 125, ISSN: 1558-8238

Journal article

Ye T, Bendrioua L, Carmena D, Garcia-Salcedo R, Dahl P, Carling D, Hohmann Set al., 2014, The mammalian AMP-activated protein kinase complex mediates glucose regulation of gene expression in the yeast Saccharomyces cerevisiae, FEBS LETTERS, Vol: 588, Pages: 2070-2077, ISSN: 0014-5793

Journal article

Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, Anastasovska J, Ghourab S, Hankir M, Zhang S, Carling D, Swann JR, Gibson G, Viardot A, Morrison D, Thomas EL, Bell JDet al., 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nature Communications, Vol: 5, ISSN: 2041-1723

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo11C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13C high-resolution magic-angle-spinning that 13C acetate from fermentation of 13C-labelled carbohydrate in the colon increases hypothalamic 13C acetate above baseline levels. Hypothalamic 13C acetate regionally increases the 13C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation.

Journal article

Wan X, Huo Y, Johns M, Piper E, Mason JC, Carling D, Haskard DO, Boyle JJet al., 2014, HEME AND METFORMIN COORDINATE HUMAN AND MURINE MACROPHAGE HEME OXYGENASE 1 EXPRESSION WITH FOAM CELL RESISTANCE PARTLY VIA ADENOSINE MONOPHOSPHATE KINASE AND ACTIVATING TRANSCRIPTION FACTOR 1 (AMPK-ATF1), Autumn Meeting of the British-Atherosclerosis-Society (BAS), Publisher: ELSEVIER IRELAND LTD, Pages: E4-E4, ISSN: 0021-9150

Conference paper

Carling D, 2014, The cell cycle, Biochemist, Vol: 36, Pages: 22-23, ISSN: 0954-982X

Journal article

Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, Giordanetto F, Martin SR, Carling D, Gamblin SJet al., 2013, Structural basis of AMPK regulation by small molecule activators, NATURE COMMUNICATIONS, Vol: 4, ISSN: 2041-1723

Journal article

Wan X, Huo Y, Johns M, Piper E, Mason JC, Carling D, Haskard DO, Boyle JJet al., 2013, 5 '-AMP-Activated Protein Kinase-Activating Transcription Factor 1 Cascade Modulates Human Monocyte-Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 33, Pages: 2470-2480, ISSN: 1079-5642

Journal article

Lallet-Daher H, Wiel C, Gitenay D, Navaratnam N, Augert A, Le Calve B, Verbeke S, Carling D, Aubert S, Vindrieux D, Bernard Det al., 2013, Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation, CANCER RESEARCH, Vol: 73, Pages: 5253-5265, ISSN: 0008-5472

Journal article

Ruderman NB, Carling D, Prentki M, Cacicedo JMet al., 2013, AMPK, insulin resistance, and the metabolic syndrome, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 2764-2772, ISSN: 0021-9738

Journal article

Zhao J, Carling D, Wang Z, Muckett P, Leiper J, Woods Aet al., 2013, Loss of CaMKK beta attenuates endotoxin induced hypotension, Spring Meeting for Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 119-119, ISSN: 0140-6736

Conference paper

Johns M, Carling D, Piper EL, Mason JC, Haskard DO, Boyle JJet al., 2012, An Adenosine Monophosphate Activated Protein Kinase / Activating Transcription Factor-1 Cascade Initiates Commitment to Mhem Atheroprotective Macrophages in Response to Heme or Metformin, CIRCULATION, Vol: 126, ISSN: 0009-7322

Journal article

Laine R, Stuckey DW, Manning H, Warren SC, Kennedy G, Carling D, Dunsby C, Sardini A, French PMWet al., 2012, Fluorescence Lifetime Readouts of Troponin-C-Based Calcium FRET Sensors: A Quantitative Comparison of CFP and mTFP1 as Donor Fluorophores, PLOS ONE, Vol: 7, ISSN: 1932-6203

Journal article

Carling D, Thornton C, Woods A, Sanders MJet al., 2012, AMP-activated protein kinase: new regulation, new roles?, BIOCHEMICAL JOURNAL, Vol: 445, Pages: 11-27, ISSN: 0264-6021

Journal article

Oliveira SM, Zhang Y-H, Solis RS, Isackson H, Bellahcene M, Yavari A, Pinter K, Davies JK, Ge Y, Ashrafian H, Walker JW, Carling D, Watkins H, Casadei B, Redwood Cet al., 2012, AMP-Activated Protein Kinase Phosphorylates Cardiac Troponin I and Alters Contractility of Murine Ventricular Myocytes, CIRCULATION RESEARCH, Vol: 110, Pages: 1192-1201, ISSN: 0009-7330

Journal article

Tsuchiya Y, Denison FC, Heath RB, Carling D, Saggerson Det al., 2012, 5 '-AMP-activated protein kinase is inactivated by adrenergic signalling in adult cardiac myocytes, BIOSCIENCE REPORTS, Vol: 32, Pages: 197-209, ISSN: 0144-8463

Journal article

Fritah A, Steel JH, Parker N, Nikolopoulou E, Christian M, Carling D, Parker MGet al., 2012, Absence of RIP140 Reveals a Pathway Regulating glut4-Dependent Glucose Uptake in Oxidative Skeletal Muscle through UCP1-Mediated Activation of AMPK, PLOS ONE, Vol: 7, ISSN: 1932-6203

Journal article

Woods A, Leiper JM, Carling D, 2012, The role of ATM in response to metformin treatment and activation of AMPK., Nature Genetics, Vol: 44, Pages: 360-361

Journal article

Denison FC, Smith LB, Muckett PJ, O'Hara L, Carling D, Woods Aet al., 2011, LKB1 Is an Essential Regulator of Spermatozoa Release during Spermiation in the Mammalian Testis, PLOS ONE, Vol: 6, ISSN: 1932-6203

Journal article

Mayer FV, Heath R, Underwood E, Sanders MJ, Carmena D, McCartney RR, Leiper FC, Xiao B, Jing C, Walker PA, Haire LF, Ogrodowicz R, Martin SR, Schmidt MC, Gamblin SJ, Carling Det al., 2011, ADP regulates SNF1, the Saccharomyces cerevisiae homolog of AMP-activated protein kinase., Cell Metab, Vol: 14, Pages: 707-714

The SNF1 protein kinase complex plays an essential role in regulating gene expression in response to the level of extracellular glucose in budding yeast. SNF1 shares structural and functional similarities with mammalian AMP-activated protein kinase. Both kinases are activated by phosphorylation on a threonine residue within the activation loop segment of the catalytic subunit. Here we show that ADP is the long-sought metabolite that activates SNF1 in response to glucose limitation by protecting the enzyme against dephosphorylation by Glc7, its physiologically relevant protein phosphatase. We also show that the regulatory subunit of SNF1 has two ADP binding sites. The tighter site binds AMP, ADP, and ATP competitively with NADH, whereas the weaker site does not bind NADH, but is responsible for mediating the protective effect of ADP on dephosphorylation. Mutagenesis experiments suggest that the general mechanism by which ADP protects against dephosphorylation is strongly conserved between SNF1 and AMPK.

Journal article

Hardie DG, Carling D, Gamblin SJ, 2011, AMP-activated protein kinase: also regulated by ADP?, TRENDS IN BIOCHEMICAL SCIENCES, Vol: 36, Pages: 470-477, ISSN: 0968-0004

Journal article

Carling D, Mayer FV, Sanders MJ, Gamblin SJet al., 2011, AMP-activated protein kinase: nature's energy sensor, NATURE CHEMICAL BIOLOGY, Vol: 7, Pages: 512-518, ISSN: 1552-4450

Journal article

Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA, Aasland R, Martin SR, Carling D, Gamblin SJet al., 2011, Structure of mammalian AMPK and its regulation by ADP, NATURE, Vol: 472, Pages: 230-233, ISSN: 0028-0836

Journal article

Claret M, Smith MA, Knauf C, Al-Qassab H, Woods A, Heslegrave A, Piipari K, Emmanuel JJ, Colom A, Valet P, Cani PD, Begum G, White A, Mucket P, Peters M, Mizuno K, Batterham RL, Giese KP, Ashworth A, Burcelin R, Ashford ML, Carling D, Withers DJet al., 2011, Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice, DIABETES, Vol: 60, Pages: 735-745, ISSN: 0012-1797

Journal article

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