David Savage
Wellcome Trust Senior Clinical Fellow
Department of Clinical Biochemistry
Research Interests
Insulin resistance is a major pathogenic factor in the tight association between obesity and many of its prevalent metabolic sequelae such as type 2 diabetes, fatty liver disease and dyslipidaemia. The overall aim of the group is to understand the molecular events responsible for insulin resistance and its contribution to the pathogenesis of type 2 diabetes. We approach these issues in two general ways:
Human disorders and their molecular basis
Understanding the molecular basis of rare human inherited diseases has, over many decades, provided key insights into both the pathophysiology of disease and more fundamental understanding of cell biology and human physiology. We have access to a unique population of patients with extreme insulin resistance. Mutations detected in candidate gene studies are explored further for their role in human disease by linkage studies in pedigrees, functional studies of the properties of the mutant variant and detailed in vivo studies in humans. More recently, we have switched from a candidate based approach to the use of next generation whole exome sequencing in efforts to identify novel genetic causes of severe insulin resistance.
I am particularly interested in lipodystrophy, a rare cluster of disorders, characterised by too little rather than too much fat (obesity). Remarkably, lipodystrophy is associated with all the features of the metabolic syndrome. We recently identified two novel subtypes of partial lipodystrophy caused by mutations in adipocyte lipid droplet proteins. The group is actively engaged in studies aimed at understanding the key cell biological roles of these lipid droplet proteins.
In vivo models
Recently we have also begun to use mouse models to explore certain aspects of the molecular pathogenesis of human diseases. This work is generally closely linked to relevant human conditions e.g. generation of mouse 'knock in' models of human variants identified; and/or the use of animal models to facilitate efforts to understand the tissue and cellular consequences of genetic defects.
We are funded by the Wellcome Trust, MRC CORD, Cambridge BRC and the Evelyn Trust.
Selected Publications
Sleigh A, Stears A, Thackray K, Watson L, Gambineri A, Nag S, Campi VI, Schoenmakers N, Brage S, Carpenter TA, Murgatroyd PR, O'Rahilly S, Kemp GJ, Savage DB. (2012). Mitochondrial Oxidative Phosphorylation Is Impaired in Patients with Congenital Lipodystrophy. J Clin Endocrinol Metab, 2012 Jan 11. [Epub ahead of print]. PMID: 22238385.
Gandotra S, Lim K, Girousse A, Saudek V, O'Rahilly S, Savage DB. (2011). Human Frame Shift Mutations Affecting the Carboxyl Terminus of Perilipin Increase Lipolysis by Failing to Sequester the Adipose Triglyceride Lipase (ATGL) Coactivator AB-hydrolase-containing 5 (ABHD5). J Biol Chem, 286(40):34998-5006. PMID: 21757733.
Sleigh A, Raymond-Barker P, Thackray K, Porter D, Hatunic M, Vottero A, Burren C, Mitchell C, McIntyre M, Brage S, Carpenter TA, Murgatroyd PR, Brindle KM, Kemp GJ, O'Rahilly S, Semple RK, Savage DB. (2011). Mitochondrial dysfunction in patients with primary congenital insulin resistance. J Clin Invest. 2011 May 9. pii: 46405. doi: 10.1172/JCI46405. [Epub ahead of print]. PMID: 21555852.
Semple RK, Savage DB, Cochran EK, Gorden P, O'Rahilly S. (2011). Genetic Syndromes of Severe Insulin Resistance. Endocr Rev. 2011 May 2. [Epub ahead of print]. PMID: 21536711.
Langenberg C, Savage DB. (2011). Nat Med. 2011 Apr;17(4):418-20. PMID: 21475231.
Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O'Rahilly S, Magré J, Savage DB, Vigouroux C. (2011). Perilipin deficiency and autosomal dominant partial lipodystrophy. New Eng J Med. 2011 Feb 24:364(8):740-8. PMID: 21345103.
Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D, Halsall D, Northcott S, Raymond-Barker P, Curran S, Henning E, Keogh J, Owen P, Lazarus J, Rothman DL, Farooqi IS, Shulman GI, Chatterjee K, Petersen KF. (2010). Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest. 2010 April 1:120(4):1345-54. PMID: 20237409. PMCID: PMC2846038. Free PMC Article.
Huang-Doran I, Sleigh A, Rochford JJ, O'Rahilly S, Savage DB. (2010). Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol, 207(3):245-55. Review. PMID: 20870709. Free Article.
Dash S, Sano H, Rochford JJ, Semple RK, Yeo G, Hyden CS, Soos MA, Clark J, Rodin A, Langenberg C, Druet C, Fawcett KA, Tung YC, Wareham NJ, Barroso I, Lienhard GE, O'Rahilly S, Savage DB. (2009). A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia. Proc Natl Acad Sci USA, 106(23):9350-5. PMID: 19470471. PMCID: PMC2695078.
Cabezas OR, Puri V, Murano I, Saudek V, Semple RK, Hyden CSS, Bottomley W, Vigouroux C, Magre J, Dash S, Raymond-Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee K, Suliman S, LD Screening Consortium, Patch A-M, Barroso I, Cinti S, Czech MP, Argente J, O’Rahilly S, Savage DB. (2009). Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Molecular Medicine, 1(5):280-7. PMID: 20049731. PMCID: PMC2891108.
Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O'Rahilly S, Savage DB. (2009). Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis.
J Clin Invest, 119(2):315-22. PMID: 19164855. PMCID: PMC2631303.
Savage DB. (2009). Mouse models of inherited lipodystrophy. Dis Model Mech, 2(11-12):554-62. Review. PMID: 19892886. Free Article.
Tan GD, Savage DB, Fielding BA, Collins J, Hodson L, Humphreys SM, O'Rahilly S, Chatterjee K, Frayn KN, Karpe F. (2008). Fatty acid metabolism in patients with PPARgamma mutations. J Clin Endocrinol Metab, 93(11):4462-70. PMID: 18713822.
Savage DB, Zhai L, Ravikumar B, Choi CS, Snaar JE, McGuire AC, Wou SE, Medina-Gomez G, Kim S, Bock CB, Segvich DM, Vidal-Puig A, Wareham NJ, Shulman GI, Karpe F, Taylor R, Pederson BA, Roach PJ, O'Rahilly S, DePaoli-Roach AA. (2008). A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice. PLoS Med. 5(1):e27. PMID: 18232732. PMCID: PMC2214798.
Savage DB, Semple RK, Chatterjee VK, Wales JK, Ross RJ, O'Rahilly S. (2007). A clinical approach to severe insulin resistance. Endocr Dev, 11:122-32. Review. PMID: 17986832.
Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, Kulkarni A, Distefano A, Hwang YJ, Reznick RM, Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI. (2007). Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A, 104(42):16480-5. PMID: 17923673. PMCID: PMC2034222.
Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, Cline GW, Befroy D, Zemany L, Kahn BB, Papademetris X, Rothman DL, Shulman GI. (2007). The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A, 104(31):12587-94. PMID: 17640906. PMCID: PMC1924794.
Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. (2007). Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem, 282(31):22678-88. PMID: 17526931.
Savage DB, Petersen KF, Shulman GI. (2007). Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev, 87(2):507-20. PMID: 17429039.
Savage DB, Choi CS, Samuel VT, Liu Z-X, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, Bhanot S, Monia BP, Shulman GI. (2006). Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylase 1 and 2. J Clin Invest, 116(3):817-24. PMID: 16485039. PMCID: PMC1366503.
Savage DB, Murgatroyd PR, Chatterjee VKK, O’Rahilly S. (2005). Energy expenditure and adaptive responses to an acute hypercaloric fat load in humans with lipodystrophy. J Clin Endocrinol Metab, 90(3):1446-52. PMID: 15613417.
Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams RL, Umpleby MA, Thomas EL, Bell JD, Dixon AK, Dunne F, Boiani R, Cinti S, Barroso I, Schafer AJ, Vidal-Puig A, Karpe F, Chatterjee VKK, O’Rahilly S. Human Metabolic Syndrome Resulting from Dominant Negative Mutations in the Nuclear Receptor PPARg. Diabetes, 52(4):910-7. PMID: 12663460.
Savage DB, O’Rahilly S. (2002). Leptin: a novel therapeutic role in lipodystrophy. J Clin Invest, 109(10):1285-6. PMID: 12021242. PMCID: PMC150984.
Savage DB, Agostini MA, Barroso I, Gurnell M, Luan J, Meirhaeghe A, Harding A-H, Ihrke G, Rajanayagam O, Soos MA, George S, Berger D, Thomas EL, Bell JD, Meeran K, Ross RJ, Vidal-Puig A, Wareham NJ, O’Rahilly S, Chatterjee VKK, Schafer AJ. (2002). Digenic inheritance of severe insulin resistance in a human pedigree. Nature Genetics, 31(4):379-84. PMID: 12118251.
Savage DB, Sewter C, Klenk ES, Vidal-Puig A, Considine RV, O’Rahilly S. (2001). Resistin/ Fizz3 Expression in relation to Obesity and PPARg action in Humans. Diabetes, 50(10):2199-202. PMID: 11574398.