Alexander Sorisky, MD
asorisky@ohri.ca
Heart disease, hypertension, elevated blood cholesterol levels, and diabetes: perhaps no other group of disorders has a greater negative impact on modern-day health than do these four, taken together. Interestingly, these very common conditions seem to cluster together, and appear to share at least one risk factor: obesity.
Dr. Alexander Sorisky is interested how fat cells form, a process that contributes to each individual's fat-cell mass. A major theme of his research centers on studying cells (called preadipocytes) that are precursors to fat cells (adipocytes), and what controls their differentiation into mature fat cells. For this basic cellular investigation, Dr. Sorisky is working with cell lines derived originally from a mouse, as well as with human cells. When these preadipocytes, which look more like regular fibrous tissue cells than fat cells, are exposed to certain hormones and chemicals, they can be induced to become mature adipocytes. Dr. Sorisky's particular interest in this process centers on the role of insulin and other hormones. In order to exert an effect, some of these hormones must bind to a receptor on the cell's surface. This activates the receptor, causing a cascade of reactions that results in the activation of particular molecules in the cell's nucleus to turn specific genes either on or off, thus causing differentiation into fat cells.
In a separate project, Dr. Sorisky has recently turned to the question of how obesity affects the human patient. This condition is not simply a matter of being overweight: Like much else in the complicated network of systems that comprises the human body, it is quite a bit more complex. One important factor in the kinds of health risks an obese person runs is the regional distribution of the fat in other words, in which areas of the body the fat has accumulated. In recent years, the description of overweight people as being either apple-shaped or pear-shaped has become very familiar. These different shapes can be an indication of what kinds of health risks a person might run. In the patient who is described as being apple-shaped, the accumulation of fat is around the middle of the body. As it happens, this build-up of fat in the intra-abdominal, or visceral, area is more often associated with the incidence of all four of the disorders that are the particular aim of Dr. Sorisky's investigations than is the case with the pear-shaped patient. With the cooperation of surgeons at the Ottawa Hospital, Dr. Sorisky's project will allow him to investigate this further.
Patients undergoing routine, scheduled surgery at the Civic are asked if they would like to participate by allowing their surgeon to provide Dr. Sorisky with samples of adipocytes from two different sites: one, of subcutaneous fat that is, from just under the skin and the other of fat from within the abdominal (visceral) region, which is thought to be more involved in this cluster of disorders. Back in the lab, Dr. Sorisky isolates the precursor cells from these samples. This will accomplish two things: First, it will give him information that is specific to human adipocyte differentiation, and second, it will allow comparison of intra-abdominal adipocytes to subcutaneous fat cells, helping to provide insight into their role in cardiovascular and diabetes risk.
How the accumulation of this fat is linked to the four clustered disorders is not entirely clear. One possible explanation hinges on the fact that the drainage system for this visceral area feeds into the liver. When, as in an obese person, the fat-cell mass is enlarged, adipocyte breakdown products called free fatty acids drain toward the liver in excessive amounts. In a complicated series of steps, this may impair insulin action, thus possibly leading to diabetes and/or perturbing the regulation of cholesterol and triglycerides. Further, the higher levels of insulin that result as the body manufactures more to compensate may be linked to blood pressure problems. If this is indeed the case, it could be the unifying factor that ties fat cell accumulation in the abdominal area to these four disorders. Adipose tissue is also known to release bioactive factors called adipokines that may also affect insulin action and metabolic and vascular health.
In the future, Dr. Sorisky hopes to orient his research even more toward the bedside, to benefit patients. Based on what his lab results show, he would like to design clinical trials to study some particular dietary factor or drug that might have an effect in vivo, perhaps by preventing preadipocyte cells from differentiating into adipocytes. Working with nonsurgical outpatients, the trials might use a biopsy technique to sample patients' fat, which can then be examined in the lab for the effects of the dietary manipulation or pharmacologic agent being tested. This could lead to important advances in the treatment of these four widespread disorders that shorten lifespans and reduce the quality of life for so many people.
