Epilespy drug may fight obesity-linked disease

Obesity levels in the United States have steadily increased in recent years. Public media has drawn attention to the growth of this condition often describing obesity as a national epidemic. Medically, obesity is classified as a condition in which an individual’s body mass index (BMI), a quantity calculated by dividing the weight in kilograms by the square of the height, exceeds 30. Obesity increases the probability of developing other conditions including cancer and fatty liver disease. While some of these obesity-linked ailments are incurable, researchers at Hopkins have found a drug that can combat one of them. The Hopkins research team discovered that a common medicine for epilepsy can be used to alleviate fatty liver disease.

Valproic acid (VPA), an anticonvulsant drug commonly used to medicate epileptics, was found to have additional physiological benefits during a recent experiment. The drug acts through the AMP-activated protein kinase (AMPK) pathway, a cellular signaling pathway heavily utilized by pharmaceutical companies in their development of drugs targeting metabolic disorders.

When VPA is ingested, it is processed by members of the cytochrome P450 enzyme family. Interestingly, the byproducts from the breakdown of VPA proceeded to activate the AMPK pathway, which is an important regulator of metabolism in the human body. This pathway is the body’s “hunger signal.” Under normal conditions, it is activated when a reduction in energy production within the cell is detected. This pathway increases the available energy in a cell by reducing cellular activities that require energy and by signaling the body to break down fatty acids to produce energy. Therefore, in lieu of AMPK activation, fatty tissues consumption increases and their total volume decreases.

In order to determine whether the drug itself or its post-cytochrome P450 enzyme breakdown byproducts activate the pathway, scientists gave mice cytochrome P450 inhibitors to prevent the breakdown of VPA and therefore prevent the cell from creating VPA byproducts. With the introduction of the inhibitors, the researchers found that AMPK was no longer activated. This suggests that the byproducts of VPA breakdown, rather than VPA molecules, are responsible for pathway activation.

While obesity cannot be directly cured by VPA, fatty liver disease, a serious condition resulting from obesity, can be alleviated through the drug. Fatty liver disease is a medical condition that results from high fat deposits within the liver. Obese individuals have a higher fat content, most of which is found in the liver, and therefore a higher chance of developing fatty liver disease. While people can continue their lifestyles with this condition, fatty liver disease increases the risk of developing liver failure and hepatitis. Fortunately, because VPA promotes the breakdown of fatty acids, the effects of VPA are targeted to the liver where most of the fat is stored. The subsequent activation of AMPK will utilize fat from the liver to produce cellular energy, reducing the fat content within the liver.

The effect of VPA on fatty livers was demonstrated by the Hopkins researchers through animal trials. Obese mice were treated with VPA and the uptake of the drug was monitored. After the administration the mice displayed lowered blood glucose levels and a reduction in the fat deposits within their livers. Moreover, obese mice given VPA maintained their weight while obese mice in the control group continued to gain weight. The researchers are optimistic that valproic acid will be adopted as a option for treating obesity and fatty liver disease.