Elucidating the Function of BSCL2, a Critical Regulator of Human Fat Development

Lead Research Organisation: University of Cambridge
Department Name: Clinical Biochemist

Abstract

Given the high and increasing rates of obesity, the harmful effects of excess fat on health are well known. However, conditions in which fat mass is abnormally low (lipodystrophies) are much rarer and so receive far less attention. In fact, having either too much or too little body fat are each strongly associated with similar diseases such as diabetes and heart disease which are major causes of suffering and mortality. This shows that it is important for us to develop just the right amount of fat and for it to be able to work efficiently to store and release nutrients and secrete the hormones it produces appropriately. Increasing fat mass involves making new fat cells (adipocytes) from precursor cells, and carefully controlling this process is therefore critical for health. This work examines this process mainly using cells that can be turned into adipocytes in the lab and studying the genes that regulate this process. Specifically we are focussing on a gene called BSCL2 which we know is critical for making fat tissue in humans as its disruption causes almost complete lack of fat. We have recently discovered that this gene regulates the process of adipocyte formation but the precise mechanism by which it does this is not clear. This work aims to define how BSCL2 controls the formation of fat cells, to identify the proteins it interacts with to do this, and how BSCL2 itself is regulated. In this way we will learn much more about how fat cells develop. This information will not only be critical for ultimately finding ways to treat patients with this very specific, rare but devastating form of lipodystrophy, but is also extremely relevant to understanding the development and treatment of obesity.

Technical Summary

Homozygous mutations in the gene BSCL2 cause the most severe form of congenital lipodystrophy, Berardinelli-Seip congenital lipodystrophy type 2, in which there is a near complete absence of adipose tissue. Remarkably, the mechanism whereby this occurs has remained unclear as very little is understood about the BSCL2 protein. The severity of the disease has led to speculation that BSCL2 may play a role in stem cell commitment to adipogenesis. However, the expression of BSCL2 in the brain has also led to suggestions of a centrally mediated role in fat formation. The first insights into the cellular function of BSCL2 have come through the recent identification of the yeast orthologue of BSCL2. Yeast lacking this gene fail to appropriately generate intracellular lipid droplets, and a similar phenotype was also described in fibroblasts isolated from a BSCL2 patient. However, this study did not elucidate the mechanism behind this phenomenon and the molecular role of BSCL2 remained unclear. We have now shown that BSCL2 is highly expressed in mature adipocytes, is induced during adipogenesis, and that BSCL2 expression is essential for adipocyte formation. This proposal aims to build on these data to more clearly define the role and regulation of BSCL2 in adipogenesis. Specifically the work will: 1. Characterise the effects of BSCL2 inhibition, determine how BSCL2 controls adipocyte formation, and delineate the transcriptional regulation of the BSCL2. Each of these may suggest therapeutic strategies for altering BSCL2 expression; 2. Identify new binding partners for BSCL2 and thereby give further insight into its function; 3. Attempt to rescue the effects of lipodystrophy-causing mutations in BSCL2 in vitro and so ultimately inform treatment of BSCL2 patients; 4. Determine whether polymorphisms in BSCL2 may influence adiposity and metabolic disease traits in the general population. This research will give exciting molecular insights into this devastating form of lipodystrophy. As BSCL2 is a key regulator of adipogenesis, a process whose perturbation is at the heart of other conditions of altered fat mass, this research is also of major relevance to highly prevalent disorders including obesity and associated conditions such as diabetes and cardiovascular disease.

Publications

10 25 50
 
Description Fellowship for Advanced Researchers
Amount £56,000 (GBP)
Organisation Swiss National Science Foundation 
Sector Public
Country Switzerland
Start 11/2010 
End 11/2012
 
Description Analysis of seipin and its binding proteins by AFM 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation of constructs to be used in experiments to determine the stoichiomettry and geometry of seipin and its interacting partners in complexes by Atomic Force Microscopy
Collaborator Contribution Expression of proteins and analysis of complexes by Atomic Force Microscopy
Impact Initial work now published. Continued collaboration ongoing with 2 further manuscripts in preparation for submission
Start Year 2012
 
Description Identifying novel binding partners for BSCL2/Seipin 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Confirmation and determination of the function of seipin interacting partners identified through the proteomic screen
Collaborator Contribution Proteomic analysis of peptides associated with immunoprecipitated seipin isolated from differentiating adipocytes
Impact Identified interactions currently being confirmed and function determined.
Start Year 2011
 
Description Investigating the role of DGKdelta in adipocyte develpment and function 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution Cellular studies of DGKdelta in differentiating adipocytes
Collaborator Contribution Analysis of affected cellular lipid species by lipodomics
Impact Manuscript published in 2013: Lowe CE, Zhang Q, Aubry EM, O'Rahilly S, Wakelam MJO and Rochford JJ. (2013) Knockdown of DGK Delta Inhibits Adipocyte Differentiation and Alters Lipid Synthesis. Obesity. 21(9):1823-9
Start Year 2010
 
Description Cambridge Science Festival, 2011, 2012 and 2013 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Large groups of families and interested individuals attended our display/event entitled 'fantastic fat' with interactive games and displays. Significant interest, discussion and positive feedback.

Sixth form pupils have visit to the lab for work experience
Year(s) Of Engagement Activity 2011,2012
 
Description Public Engagement Talk at Satrosphere Aberdeen ads part of Aberdeen Techfest Sept 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk entitled "Good or bad: Can we learn to love our fat?" attended by around 50 members of the public with Q&A afterwards


Requests for further similar talks in future.
Year(s) Of Engagement Activity 2014
 
Description Student from Nuffield Bursary Scheme 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact Hosted a Nuffield student for 5 weeks in the lab and took part in a "Celebration" afternoon for the regional students from the scheme at which work from the lab was presented.

Student now interested in pursuing a career in science.
Year(s) Of Engagement Activity 2009
 
Description Talk to Grampian Branch of The Society of Chiropodists and Podiatrists. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk sparked discussion after the presentation

Participants reported that the talk had improved their understanding of factors affecting body weight and metabolic health which would inform their approach to patient advice and care.
Year(s) Of Engagement Activity 2014
 
Description Talk to clinical geneticists Aberdeen Royal Infirmary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk gave rise to discussion and questions.

I was asked by a family member of an attendee who is a school student if they could join my laboratory for a summer placement.
Year(s) Of Engagement Activity 2014