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Toronto (Feb. 4, 2007) - Scientists at the Toronto General Hospital Research Institute and at the Albert Einstein College of Medicine in New York have found that the brain controls liver fat production, revealing new ways to lower fat levels in those who are overweight, prediabetic and diabetic and who are predisposed to developing cardiovascular disease (heart attacks, strokes and circulation problems).
Scientists discovered that activating a biochemical pathway in the brain lowers liver fat production and in turn lowers blood fats. These findings pave the way for new treatment strategies down the road, which could lower blood fats in obesity, thereby reducing the risk of cardiovascular disease.
Dr. Tony Lam, who was recruited from the Albert Einstein College of Medicine in New York to the Toronto General Hospital Research Institute on August 1st, 2006, and who holds The John Kitson McIvor (1915 – 1942) Chair in Diabetes Research, is the lead author of the paper published in the February 4, 2007 online edition of the international science journal Nature Medicine. Dr. Lam is also Assistant Professor of Physiology and Medicine at the University of Toronto.
"This work recognizes for the first time that the brain can regulate blood fat (lipid) levels," says Dr. Lam, "However, we found that in conditions of obesity, this regulation breaks down. So the question becomes, 'how can we develop a new biochemical intervention targeting the brain to lower these lipid levels in obesity?'"
As individuals gain weight, their bodies increase the production of fats, and this, in turn, can lead to heart disease. "A similar situation occurs in those who have diabetes or prediabetes, and up to 75% of those who have diabetes will suffer a cardiovascular complication, " pointed out by Dr. Gary Lewis, Head of the Division of Endocrinology and Metabolism at the University Health Network and Mount Sinai Hospitals in Toronto and Professor of Medicine and Physiology at the University of Toronto. He added that, " Dr. Lam and colleagues are the first to reveal the important role of the brain in regulating fat production by the body. This novel finding opens up an area that may be amenable to targeting new treatments that reduce blood fats and cholesterol, thereby preventing cardiovascular complications in susceptible individuals."
Dr. Richard Weisel, Director of the Toronto General Research Institute, Professor and Chairman of Cardiac Surgery at the University of Toronto, welcomes the idea of any potential intervention which could lower blood lipid levels. "We know that the risk of heart disease is linked to obesity and elevated blood lipid levels. Anything we can do to help lower these lipid levels would in turn help lower the development and progression of cardiovascular disease."
Cardiovascular disease accounts for the death of more Canadians than any other disease. In 2002 (the latest year for which Statistics Canada has data), cardiovascular disease accounted for 74,626 Canadian deaths. 32% of all male deaths in Canada in 2002 were due to heart diseases, diseases of the blood vessels and stroke. For women, the toll was even higher – 34% of all female deaths in 2002 were due to cardiovascular disease.
Working with rat models, Dr. Lam and colleagues performed a series of experiments that showed for the first time that increased metabolism of glucose to lactate in the brain lowers liver lipid production in normal rats. If the rats overeat with high fat diet for three days, the effect of brain glucose on liver lipid production is lost. In contrast, the effect of brain lactate, the by-product of glucose metabolism, is preserved in overfed rats. "These findings indicated that high fat diet induces defects in the conversion of brain glucose to lactate. Bypassing these defects by directly administering lactate to the brain causes liver lipid production and blood lipid levels to be restored back to normal in this diet-induced obese model." explains Dr. Lam. "The future direction will be to locate these defects in the brain and discover new potential therapeutic targets to lower blood lipids in obesity and cardiovascular disease," says Dr. Lam.
The study was carried out in the laboratory of Dr. Luciano Rossetti (senior author). Other Albert Einstein College of Medicine researchers involved in this study include Roger Gutierrez-Juarez, Alessandro Pocai, Gary Schwartz, as well as Sanjay Bhanot of ISIS Pharmaceuticals and Patrick Tso of the University of Cincinatti.
The work was funded by the US National Institutes of Health.
Toronto General Hospital is a partner in the University Health Network, along with the Toronto Western Hospital and the Princess Margaret Hospital. These teaching hospitals are affiliated with the University of Toronto. The scope of research at Toronto General Hospital has made this institution a national and international source for cardiovascular discovery, education and patient care, as well as for its innovations in transplantation, cardiology, surgical innovation, infectious diseases, diabetes and genomic medicine. In addition, the Peter Munk Cardiac Centre at Toronto General Hospital trains more cardiologists and cardiovascular surgeons than any hospital in Canada.
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