Professor David Savage

Research Interests

Insulin resistance and type 2 diabetes are quintessential complex disorders involving hormone action or resistance in several different target issues. Unravelling this complexity is impossible in cultured cells alone and unfortunately whilst many disorders can be reliably modelled in rodents, this is not always the case in insulin resistance where my own work has already highlighted some key interspecies differences (Embo Mol Med 2009). Many different approaches are therefore needed to tackle this complex metabolic problem.

Our contributions to the understanding of insulin resistance have for the most part emerged from studies in patients with inherited forms of insulin resistance, particularly lipodystrophies, a cluster of rare disorders, characterised by too little rather than too much fat (obesity). Remarkably, lipodystrophy is associated with all the features of the metabolic syndrome. Within the past decade we identified four novel subtypes of partial lipodystrophy; two caused by mutations in adipocyte lipid droplet proteins, one caused by loss-of-function mutations in Pcyt1a, the rate limiting enzyme in Kennedy pathway phosphatidylcholine synthesis, and one caused by mutations in MFN2, a key regulator of mitochondrial fusion. The group is actively engaged in studies aimed at understanding the key cell biological roles of these and other proteins involved in energy storage (see below).

Within the past 5 years, in collaboration with colleagues in the MRC Epidemiology Unit in Cambridge, we have provided compelling human genetic evidence suggesting that subtle forms of lipodystrophy are a prevalent cause of human insulin resistance. This concept is now quite widely accepted and has significantly increased interest in what were previously considered very rare disorders.

Whilst we continue to focus on projects related to human genetic findings we remain broadly interested in understanding why obesity is so strongly associated with insulin resistance. To this end we also study mice and humans physiologically, particularly trying to understand why calorie restriction can so rapidly reverse insulin resistance.

Group Members

Ms Lucy Davis, PhD Student - lmd74 at medschl.cam.ac.uk

Dr Xiaowen Duan, Research Associate - xd253 at medschl.cam.ac.uk

Dr Satish Patel, Postdoctoral Fellow - sp632 at medschl.cam.ac.uk 

Research Funding

Wellcome

MRC Metabolic Diseases Unit

Cambridge BRC

Publications

Key publications:

Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, Goldspink DA, Miedzybrodzka EL, Konopka AR, Esponda RR, Huang JT, Tung YCL, Rodriguez-Cuenca S, Tomaz RA, Harding HP, Melvin A, Yeo GSH, Preiss D, Vidal-Puig A, Vallier L, Nair KS, Wareham NJ, Ron D, Gribble FM, Reimann F, Sattar N, Savage DB, Allan BB, O’Rahilly S. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020 Feb;578(7795):444-448. doi: 10.1038/s41586-019-1911-y. PMID: 31875646. PMCID: PMC7234839

Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, Cimino I, Maurin AC, Roberts GP, Meek CL, Virtue S, Sparks LM, Parsons SA, Redman LM, Bray GA, Liou AP, Woods RM, Parry SA, Jeppesen PB, Kolnes AJ, Harding HP, Ron D, Vidal-Puig A, Reimann F, Gribble FM, Hulston CJ, Farooqi IS, Fafournoux P, Smith SR, Jensen J, Breen D, Wu Z, Zhang BB, Coll AP, Savage DB, O’Rahilly S. GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell Metab. 2019 Mar 5;29(3):707-718.e8. doi: 10.1016/j.cmet.2018.12.016. PMID: 30639358. PMCID: PMC6408327

Haider A, Wei YC, Lim K, Barbosa AD, Liu CH, Weber U, Mlodzik M, Oras K, Collier S, Hussain MM, Dong L, Patel S, Alvarez-Guaita A, Saudek V, Jenkins BJ, Koulman A, Dymond MK, Hardie RC, Siniossoglou S, Savage DB. PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress. Dev Cell. 2018 May 21;45(4):481-495.e8. doi: 10.1016/j.devcel.2018.04.012.Epub 2018 May 10. PMID:29754800. PMCID: PMC5971203

Rocha N, Bulger DA, Frontini A, Titheradge H, Gribsholt SB, Knox R, Page M, Harris J, Payne F, Adams C, Sleigh A, Crawford J, Gjesing AP, Bork-Jensen J, Pedersen O, Barroso I, Hansen T, Cox H, Reilly M, Rossor A, Brown RJ, Taylor SI, McHale D, Armstrong M, Oral EA, Saudek V, O’Rahilly S, Maher ER*, Richelsen B*, Savage DB*, Semple RK*. *Joint senior and corresponding authors. Human biallelic MFN2 mutations induce mitochondrial dysfunction, upper body adipose hyperplasia, and suppression of leptin expression. Elife. 2017 Apr 19;6. pii: e23813. doi: 10.7554/eLife.23813. PMID: 28414270.   PMCID:PMC5422073

Lotta LA, Gulati P, Day F, Payne F, Ongen H, van de Bunt M, Gaulton KJ, Eicher JD, Sharp SJ, Luan J, De Lucia Rolfe E, Stewart ID, Wheeler E, Willems SM, Adams C, Yaghootkar H, Cambridge FPLD1 Consortium, EPIC-InterAct Consortium, Forouhi NG, Khaw K, Johnson AD, Semple RK, Frayling T, Perry JRB, Dermitzakis E, McCarthy MI, Barroso I*, Wareham NJ*, Savage DB*, Langenberg C*, O’Rahilly S*, Scott RA*. *Joint senior and corresponding author. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nature Genetics 2017. PMID: 27841877. PMCID:PMC5774584

Majithia AR, Tsuda B, Agostini M, Gnanapradeepan K, Rice R, Peloso G, Patel KA, Zhang X, Broekema MF, Patterson N, Duby M, Sharpe T, Kalkhoven E, Rosen ED, Barroso I, Ellard S, UK Monogenic Diabetes Consortium, Kathiresan S, Myocardial Infarction Genetics Consortium, O’Rahilly S, UK Congenital Lipodystrophy Consortium, Chatterjee K, Florez JC, Mikkelsen T, Savage DB*, Altshuler D*. *Joint senior author. Prospective functional classification of all possible missense variants in PPARG. Nature Genetics 2016. PMID: 27749844. PMCID:PMC5131844

Rowe ER, Mimmack ML, Barbosa AD, Haider A, Isaac I, Ouberai MM, Thiam AR, Patel S, Saudek V, Siniossoglou S, Savage DB. Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1-3. J Biol Chem. 2016 Mar 25;291(13):6664-78. PMID: 26742848. PMCID:PMC4807253.

Robbins AL, Savage DB. (2015). The genetics of lipid storage and human lipodystrophies. Trends Mol Med, 2015 Jul;21(7):433-8. doi: 10.1016/j.molmed.2015.04.004. PMID: 25979754.

Zhou L, Park SY, Xu L, Xia X, Ye J, Su L, Jeong KH, Hur, JH, Oh H, Tamori Y, Zingaretti CM, Cini S, Argente J, Yu M, Wu L, Ju S, Guan F, Yang H, Choi CS, Savage DB, Li P. (2015). Insulin resistance and white adipose tissue inflammation and uncoupled in energetically challenged Fsp27-deficient mice. Nat Commun, 2015 Jan 7;6:5949. doi: 10.1038/ncomms6949. PMID: 25565658. PMCID: PMC4354252.

Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delepine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O’Rahilly S, Magre J, Savage DB, Vigourous C. (2011). Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med, 2011 Feb 24;364(8):740-8. doi: 10.1056/NEJMoa1007487. PMID: 21345103. PMCID: PMC3773916.

Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, Cimino I, Maurin AC, Roberts GP, Meek CL, Virtue S, Sparks LM, Parsons SA,Redman LM, Bray GA, Liou AP, Woods RM, Parry SA, Jeppesen PB, Kolnes AJ, Harding HP, Ron D, Vidal-Puig A, Reimann F, Gribble FM, Hulston CJ, Farooqi IS,Fafournoux P, Smith SR, Jensen J, Breen D, Wu Z, Zhang BB, Coll AP, Savage DB, O’Rahilly S. GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell Metab. 2019 Mar 5;29(3):707-718.e8. doi: 10.1016/j.cmet.2018.12.016.Epub 2019 Jan 10. PubMed PMID: 30639358; PubMed Central PMCID: PMC6408327

Research Interests

Group Members

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