Fat rats reveal why short-term overeating can lead to obesity and diabetes

Obesity is due to a mismatch between the number of calories we consume and the amount of physical activity we undertake. In the brain, a region called the hypothalamus control ours eating behavior through its metabolism of fat molecules called fatty acids. Interestingly, eating too much in the short-term can result in a severe drop in the ability of the body (and brain) to be satisfied by fat and to control blood sugar levels.

In a study appearing online on March 9 in advance of print publication in the April issue of the Journal of Clinical Investigation, Luciano Rossetti and colleagues at Albert Einstein College of Medicine in New York report that inhibiting an enzyme in the liver called carnitine palmitoyltransferase-1 (CPT1A), which is involved in metabolizing fatty acids, inhibits feeding.

The researchers placed normal rats on a lard-based diet, which stimulated the animals to voluntarily overeat and gain weight. When the researchers inhibited CPT1A by delivering special molecules called “ribozymes” into the brain of the rats, the animals ate dramatically less. The treatment also improved the blood sugar levels of these animals, who suffered from a common metabolic impairment known as insulin resistance, in which the body is unable to respond properly to insulin.

The authors report that this animal model of diet-induced obesity and insulin resistance displayed defective adaptation to an increase in fat availability coupled with a severe impairment in the ability of the brain to sense fat intake. Further studies will be required to establish the critical role of this biochemical pathway in nutrient sensing in other animal models and, critically, in humans.

From Journal of Clinical Investigation