In December 1994 the first hormone-like protein signal (adipokine) derived from the adipose tissue was cloned and sequenced and this started an avalanche of research into this novel endocrine organ, namely the adipose organ. 1996-1998, in collaboration with Dr Simon Coppack, the microenvironment surrounding the abdominal sub-cutaneous adipose tissue. Using these techniques we were the first to show in vivo release of IL-6 and leptin from human adipose tissue. These papers have been seen as seminal in the field and cited over a 1000 times.
Subsequent research in my group, in collaboration with Professor Gokhan Hotamisligil, Harvard School of Public Health, and Professor Jan Kopecky, Charles University, Prague, has focussed on the mechanisms of adipokine release. We have found that adipose tissue prostaglandins, specifically PGI2 and PGE2, mediated by constitutive COX-2 expression in the tissue, and modulated by changes mainly in intracellular cAMP, regulate the release of several adipokines. We also noted that the adrenergic pathway is equally important is regulating adipokine release. This work has been published.
In 2005, I was awarded a European Union FP6 collaborative grant to investigate the autocrine /paracrine consequences to of this chronic production of cytokines by the tissue, both in vitro in cell and organ cultures of mouse and human adipose tissue and in a diet-induced obese mouse model. Also in this year with a grant from The Wellcome Trust, in collaboration with Professor Patrick Vallance and Dr James Leiper, we found that the adipose tissue is a significant source of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide (NO). NO plays an important role in several metabolic and vascular functions of the adipose tissue. Our data shows that several components of the NO pathway are expressed in adipose tissue and are modifiable by other adipokines, diet and pharmacological agents. There is also a significant gender difference in these responses.
The investigation of the cross-talk between adipokines, the NO and prostaglandin pathways forms the current and future focus of my group’s research. Specific areas include the effect of IL-6 and adiponectin on this pathway. Our pilot data show that the effects of these adipokines on several adipocyte functions are NO mediated. A clearer understanding of these pathways in the adipose tissue is significant in elucidating any causal links between signals from adipose tissue and obesity-related pathologies. To facilitate these studies monoclonal antibodies to many of these enzymes are currently being raised by my group and will be characterised. We have also established a gel electrophoretic assay for the multimeric forms of adiponectin.
It is important to note that secretory differences in adipose tissue can arise dependent and independent of the anatomical location of this tissue, which can accumulate in different compartments within the body. Accumulation of excess fat in the visceral compartment, such as the omental and epicardial depots, even if subcutaneous fat mass is normal, carries the greater metabolic risk. These compartments are being characterised by my group in collaboration with surgeons at the Whittington (Mr Pratik Sufi and Mr Dugal Heath), St George’s (Professor Marjan Jahangiri) and the Heart Hospital (Mr Shyam Kolvekar) using tissue from bariatric and cardiothoracic surgery. Conditioned media from these tissues is being tested on monocytes and endothelial cells to establish a causal role for these signals in the development of insulin resistance and endothelial dysfunction leading to type 2 diabetes and coronary artery disease. These data have already formed the basis of several grants and publications.
- Protein Engineering of Glucarpidase to Improve Cancer Therapy Strategies: New synthesis of novel bioactive class of natural products
- Mast cell proteases as key clinical markers in allergic disease
- Production of Novel superantigen fusion proteins as therapeutics for different diseases.
- Vascular functions in health and disease and the underlying molecular mechanisms, currently concentrating on vascular biology of obesity.
- Investigating the etiology of obesity-induced insulin resistance; in particular the molecular mechanisms marking adipocyte dysfunction in the pathologically obese subjects and factors underlying the “protective phenotype” seen in their metabolically healthy counterparts.
- Studying primary preadipocytes isolated from different fat depots of insulin sensitive and insulin resistance subjects; in particular the role of impaired proliferation and differentiation in adipocyte hypertrophy, ectopic fat storage and development of insulin resistance.
Mashael Al Jaber