Critical Enzyme in Fat Metabolism Provides Protection against Diet-induced Insulin Resistance in Mice
By: Almas Eftekhari
Excess body weight and obesity are linked to the development of chronic diseases such as diabetes, and the effects are particularly obvious in people who consume a high-fat diet. By overeating foods containing high amounts of saturated fat, overweight and obese individuals (those whose body mass index exceeds 25 kg/m2 and 30 kg/m2 respectively) can develop insulin resistance and different types of inflammation in body tissues.
Studies from American Diabetes Association-funded researcher Robert Farese, MD, in collaboration with other scientists from the J. David Gladstone Institutes, have shown that a specific enzyme may offer protection against the complications of excess body fat. In a series of experiments with mice, Dr. Farese discovered that high levels of this enzyme, DGAT1 – key to the synthesis of fats called triglycerides, can prevent insulin resistance and the development of type 2 diabetes.
Diet-induced obesity causes fat cells to swell beyond their normal size, leading to inflammation and cell death. Important immune system cells called macrophages collect into the area to help remove the dead fat cells. Due to the toxic exposure of extra fatty acids (fat fragments), the macrophages activate a response that produces even more inflammation throughout the body. With the extra fat, inflamed fat tissue, and high levels of fatty acids, the body develops resistance to the effects of insulin. Yet, Dr. Farese’s research shows that increased DGAT1 levels in macrophages offers protection by limiting the ability for this series of events to be triggered. "Our results are very exciting," says Dr. Farese. "We have used DGAT1 as a tool to uncover a mechanism by which macrophages might protect individuals from developing serious consequences of obesity."
After administering a high-fat diet to mice with elevated levels of DGAT1 for 16 weeks, the scientists found that, despite resulting obesity, the mice had better insulin responses and less inflammation in the liver and skeletal muscle than that of the control group. In addition, the mice showed improvement in their fasting-glucose levels, another indication that their response to insulin had increased. The results of the experiment were published in the March 2010 edition of the Journal of Clinical Investigation.
DGAT1 also plays a vital role in controlling fat synthesis in humans, and these findings provide hope that the protection from diabetes and other obesity-related diseases may apply to the individuals at risk. Moreover, Dr. Farese’s contribution to the understanding of these metabolic processes could potentially lead to the development of drug therapy aimed to prevent chronic inflammation and type 2 diabetes.
(Koliwad SK, Streeper RS, Monetti M, Chan L, Rao M, Terayama K, Naylor S, Marmor S, Hubbard B, Farese RV. DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. Journal of Clinical Investigation. 2010 Mar; 120(3): 756-767.)
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