Adipocyte Development and Function

My research focusses on understanding how fat develops and how altering the function of fat cells could improve health in obese individuals.

We now know that many of the negative effects of obesity can be attributed to abnormal function of fat tissue, rather than because fat is somehow inherently bad. In fact, fat tissue is really important for health. Fat cells are renewed throughout life so understanding how they form and improving the function of these new cells could be a good way to improve health.

We are also interested in understanding more about mature fat cells and whether the function of these could be altered to treat medical conditions associated with obesity.

Research focus

My group focuses on the molecular mechanisms controlling adipocyte differentiation and the functions of mature fat cells generated by this process. Humans turn over adipocytes at a rate of approximately 10% each year so adipocyte development is a process relevant throughout life. Having appropriately functioning fat cells is critical for human health as these cells provide an essential safe store for dietary nutrients, particularly lipids, and protect other tissues in the body from their harmful effects. This is perhaps most clearly demonstrated by individuals with severe forms of lipodystrophy who fail to appropriately develop or maintain adipose tissue and suffer severe insulin resistance and metabolic disease as a consequence. Lipid is stored in adipocytes in a large fat droplet mainly comprised of triglyceride. The storage and release of this lipid is highly regulated and is a defining function of mature adipocytes. In addition adipocytes secrete many factors that affect appetite, insulin sensitivity and metabolic health.  In obesity, despite abundant adipose tissue, the adipocytes appear to be dysfunctional and their lipid storage capacity may be exceeded, leading to overflow of lipids to other tissues. For this reason obese individuals may suffer similar metabolic problems to patients with lipodystrophy. Overall, this means that understanding the development and function of adipocytes may lead us to new therapies by which these can be modified to treat both rare lipodystrophies and common obesity.

Lipodystrophy genes as critical regulators of human fat development:

A key approach we are taking is to investigate the functional roles of genes known to cause lipodystrophy in humans, particularly those whose disruption causes severe loss of adipose tissue. Evidently the products of these genes are critical for the development of adipose tissue in humans, however, relatively little is known about their molecular role in developing adipocytes. We use a range of techniques to understand the function of these proteins including immunofluorescence/confocal microscopy to examine subcellular localisation and trafficking, transcriptional and protein analyses to determine their importance in adipogenesis, binding studies and proteomics to identify and characterise novel binding partners and lipidomics to investigate their involvement in lipid biosynthesis, a key component of adipocyte differentiation.

This work is exemplified by our studies of the protein seipin, encoded by the gene BSCL2. Patients with disruption of seipin have almost no detectable adipose tissue and we were the first to show that this may result from an inability to make new fat cells from stem cells lacking seipin. However, the precise function of seipin has remained unknown until very recently. We have now shown that seipin acts as a binding protein for a known regulator of adipogenesis which may at least partly explain why it is needed for adipocyte development (Sim et al., Molecular Metabolism 2013). However, we have also identified multiple other binding proteins, both in developing and in mature adipocytes. A major component of our research is to investigate these further both in vitro and in vivo.

Understanding what the products of lipodystrophy genes do, the pathways they influence and the proteins they regulate will give key insights into human adipose tissue development and function. By identifying novel pathways and proteins that can influence adipocyte function, this work may also reveal new therapeutic targets for the treatment of common obesity and metabolic disease. This work is funded by the MRC.

Investigating the role of gamma-synuclein in adipocyte function:

We recently showed that the loss of gamma-synuclein can protect against the development of obesity following high fat diet feeding (Millership et al., PNAS 2012). This was associated with increased energy expenditure, probably linked to activation of a distinct type of fat tissue called brown adipose tissue (BAT). BAT differs from majority of lipid storing adipose tissue in the body which is referred to as white adipose tissue (WAT) as BAT tends to ‘burn’ rather than store fat using lipids as a fuel source. There is a great deal of interest in activating BAT to burn lipids in this way to reduce fat mass and treat obesity. At a molecular level we identified a novel role for gamma-synuclein altering adipocyte lipolysis, the process via which the lipid droplet is broken down so that lipid can be released from the fat cell. This may be mechanistically linked to increased energy expenditure with increased breakdown of the lipid droplets in WAT adipocytes feeding substrates to the activated BAT adipocytes where they are burnt and the energy dissipated as heat.

We are now investigating precisely how gamma-synuclein controls these processes, and how we might alter gamma-synuclein expression and/or function in an attempt to treat obesity. This work is funded by the BBSRC.

Research Team

Boris Monge Roffarello - Post-Doctoral Fellow
George Mcilroy - Post-Doctoral Fellow
 
Alasdair Leeson-Payne - Research Postgraduate
Elisa Persiani - Research Postgraduate

Grants
  • ISSF grant "
  • MRC Project Grant “Defining the Role of the Human Lipodystrophy Protein Seipin in Adipose Tissue Development and Metabolic Disease”.  PI: JJ Rochford.  £435,613
  • BBSRC Project Grant “Delineating the regulation and function of gamma-synuclein in adipocyte lipid metabolism”.  PI: JJ Rochford.  £376,972
     
Publications
  • Burke, LK., Doslikova, B., D'Agostino, G., Greenwald-Yarnell, M., Georgescu, T., Chianese, R., Martinez de Morentin, PB., Ogunnowo-Bada, E., Cansell, C., Valencia-Torres, L., Garfield, AS., Apergis-Schoute, J., Lam, DD., Speakman, JR., Rubinstein, M., Low, MJ., Rochford, JJ., Myers, MG., Evans, ML. & Heisler, LK. (2016). 'Sex difference in physical activity, energy expenditure and obesity driven by a subpopulation of hypothalamic POMC neurons'. Molecular Metabolism, vol 5, no. 3, pp. 245-252.
    [Online] DOI: 10.1016/j.molmet.2016.01.005
    [Online] AURA: 1_s2.0_S221287781600017X_main.pdf
  • Talukder, MMU., Sim, MFM., O'Rahilly, S., Edwardson, JM. & Rochford, JJ. (2015). 'Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis'. Molecular Metabolism, vol 4, no. 3, pp. 199-209.
    [Online] DOI: 10.1016/j.molmet.2014.12.013
    [Online] AURA: 1_s2.0_S2212877814002269_main.pdf
  • Sim, MFM., Talukder, MMU., Dennis, RJ., Edwardson, JM. & Rochford, JJ. (2014). 'Analyzing the functions and structure of the human lipodystrophy protein seipin'. Methods in Enzymology, vol 537, pp. 161-175.
    [Online] DOI: 10.1016/B978-0-12-411619-1.00009-4
  • Rochford, JJ. (2014). 'Mouse models of lipodystrophy and their significance in understanding fat regulation'. Current topics in developmental biology, vol 109, pp. 53-96.
    [Online] DOI: 10.1016/B978-0-12-397920-9.00005-6
  • Lowe, CE., Zhang, Q., Dennis, RJ., Aubry, EM., O'Rahilly, S., Wakelam, MJO. & Rochford, JJ. (2013). 'Knockdown of diacylglycerol kinase delta inhibits adipocyte differentiation and alters lipid synthesis'. Obesity, vol 21, no. 9, pp. 1823-1829.
    [Online] DOI: 10.1002/oby.20297
  • Sim, MFM., Talukder, MMU., Dennis, RJ., O'Rahilly, S., Edwardson, JM. & Rochford, JJ. (2013). 'Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms'. Diabetologia, vol 56, no. 11, pp. 2498-2506.
    [Online] DOI: 10.1007/s00125-013-3029-3
    [Online] AURA: Sim_Diabetologia.pdf
Additional activities

Biography

2013: Senior Lecturer, Rowett Institute of Nutrition and Health, University of Aberdeen.

2009-2012: Senior Research Associate (MRC-NIRG), IMS-MRL, University of Cambridge.

2006-2009: BHF Intermediate Research Fellow, Dept. of Clinical Biochemistry, University of Cambridge.

2000-2006: Research Associate, Dept. of Clinical Biochemistry, University of Cambridge.

1998-2000: INSERM Poste Vert Fellow, INSERM Unit 145, Nice, France.

1994-1998: PhD , Department of Biochemistry and Genetics, University of Newcastle upon Tyne.