Insulin resistance and type 2 diabetes are quintessential complex diseases 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 work is currently focussed in three areas, all of which relate to 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. 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 2 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 (Lotta et al, NG 2017).
Specific research programmes:
1) The molecular basis of human lipodystrophies
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/lipodystrophy. 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/genome sequencing in efforts to identify novel genetic causes of severe insulin resistance.
Having recently shown that subtle forms of lipodystrophy contribute to prevalent human insulin resistance, we are also increasingly involved in characterising coding (missense) variants which affect fat mass/ distribution in the general population.
2) Lipid droplets (LDs)
LDs are unique organelles in being surrounded by a phospholipid monolayer and, presumably related to the unique biophysical properties of this monolayer and the underlying hydrophobic neutral lipid core, are targeted by a specific set of proteins. Our recent discoveries of genetic mutations in LD proteins have led us to explore the fundamental biology underpinning the targeting and subsequent requirement of CIDEC for the formation of a unilocular LD in white adipocytes and also to explore the way in which perilipin1 co-ordinates the sequential activity of triacylglycerol lipases. This work is leading us in entirely new and fascinating directions.
3) In vivo models
Ectopic fat accumulation is strongly linked to insulin resistance although mechanistic details remain incomplete. In order to understand the metabolic pathways responsible for ectopic fat accumulation, a prominent feature in all severe forms of lipodystrophy, we undertake a combination of detailed mouse and human physiological studies.
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.
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