Rachel Fisher

While an inflammatory state is a well recognised risk factor for cardiovascular disease, low grade systemic inflammation and insulin resistance also occur together with adipose tissue being a site of inflammation. In adipose tissue of obese and insulin resistant subjects the number of macrophages and the production of inflammatory cytokines is increased, while adiponectin production is decreased. Inflammation within adipose tissue has been shown to directly promote the development of atherosclerosis in mouse models and to be associated with cardiovascular risk factors in humans. Why macrophages are recruited into adipose tissue is unknown, although a key role for the chemokine CCL2 (monocyte chemoattractant protein 1, MCP-1) and has been demonstrated. Adipocyte death has been proposed as a stimulus for macrophage infiltration, but the underlying mechanism remains unclear.

The research in the team focuses on understanding the relationships between adipose tissue metabolism, insulin resistance and cardiovascular risk factors. A range of techniques are used to achieve this goal, combining molecular genetic, human metabolic and epidemiological approaches. To study pathways of relevance for insulin resistance in human adipose tissue in vivo, biopsies are investigated using techniques such as quantification of gene expression (mRNA and microRNA) and immunohistochemistry. To investigate the impact of common genetic variation in candidate genes, a combination of genotyping and subsequent in vitro characterisation is used. Finally, cardiovascular risk factors, markers of insulin resistance/metabolic syndrome and adipose tissue metabolism are evaluated cross-sectionally and prospectively in well-characterised cohort studies.

Investigating inflammation and macrophage accumulation within human adipose tissue is of particular interest. Specific projects include:

1. Determining how local ceramide production in adipose tissue is related to macrophage accumulation, inflammation and insulin resistance in this tissue, since data from the team have implicated ceramides in this process.

2. Investigating whether inflammation within adipose tissue is a contributor to the systemic inflammation and insulin resistance observed in patients with chronic kidney disease. Ceramide concentrations are elevated in these patients and therefore mechanisms of ceramide-mediated adipose tissue inflammation are also investigated.

3. Defining microRNA profiles of inflamed adipose tissue, as an alternative approach to gene expression analysis, to identify regulatory pathways underlying inflammation and macrophage accumulation.

4. Establishing relationships between adipose tissue inflammation and systemic inflammation by investigating the effect of anti-inflammatory therapy on inflammation within adipose tissue in patients with rheumatoid arthritis.

5. Investigating the effects of a moderate increase in physical activity on inflammation within adipose tissue and related metabolic parameters.

Composition of the team and collaborators

Members of the project team are Professor Rachel Fisher (PhD, team leader), Louisa Cheung (PhD, post-doc), Joanna Chmielewska (PhD student), Olivera Werngren (BMA 50%).

The team has worked closely with Professor Hannele Yki-Järvinen, Division of Diabetes, University of Helsinki, Finland. There are ongoing collaborations with a number of groups at KI: the Clinical Epidemiology Unit (Professor Mai-Lis Hellénius), the Cardiology Unit at Danderyd Hospital (Dr Pia Lundman), the Renal Medicine group at Huddinge University Hospital (Dr Jonas Axelsson, Docent Annette Bruchfeld, Peter Hemmingson (PhD student)), and the Rheumatology Unit (Dr Anca Catrina, Aase Hensvold).

Selected publications

Jormsjö S, Ye S, Moritz J, Walter DH, Dimmeler S, Zeiher AM, Henney A, Hamsten A, Eriksson P. Differential regulation of matrix metalloelastase gene activity influeces coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease. Circ. Res. 2000;86:998-1003.

Jormsjö S, Whatling C, Walter DH, Zeiher AM, Hamsten A, Eriksson P. Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions amongst hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2001;21:1834-1839.

Jormsjö S, Wuttge DM, Sirsjö A, Wahtling C, Hamsten A, Stemme S, Eriksson P. Differential expression of cysteine proteases during progression of atherosclerosis in apoE-deficient mice. Am J Pathol 2002;161:939-945.

Beyzade S, Zhang S, Wong Y, Day INM, Eriksson P, Ye S. Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction. JACC 2003;41:2130-2137.

Whatling C, Björk H, Gredmark S, Hamsten A, Eriksson P. The impact of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes. J Lipid Res 2004;45:1768-1776.

Samnegård A, Silveira A, Lundman P, Boquist S, Odeberg J, Hulthe J, McPheat W, Tornvall P, Bergstrand L, Ericsson C-G, Hamsten A, Eriksson P. Serum matrix metalloproteinase  3 (MMP-3) concentration is strongly influenced by MMP-3 -1171 5A/6A promoter genotype and associated with myocardial infarction. J Int Med. 2005;258:411-19.

Wang X, Ria M, Kelmenson PM, Eriksson P, Higgins DC, Samnegård A, Petros C , Rollins J, Bennet AM, Wiman B, de Faire U, Wennberg C, Olsson PG, Ishii N, Sugamura K, Hamsten A, Forsman-Semb K, Lagercrantz J, Paigen B. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genet 2005;37:365-372.

Swanberg M, Lidman O, Padyukov L, Eriksson P, Åkesson E, Jagodic M, Lobell A, Khademi M, Börjesson O, Lindgren CM, Lundman P, Brookes AJ, Kere J, Luthman H, Alfredsson L, Hillert J, Klareskog L, Hamsten A, Piehl F, Olsson T. MHC2TA is association with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nature Genet 2005;37:486-494.