Preventing a nuclear receptor from being activated in a small part of the brain proved to be the key to preventing obesity, which can eventually lead to diabetes.
The Yale University study, showed that when the nuclear receptor PPARgamma was blocked in a small number of rodent brain cells, the animals ate less and were more resistant to a high fat diet. The research was published in the Aug. 1 issue of The Journal of Clinical Investigation (JCI).
"These animals ate fat and sugar, and did not gain weight, while their control littermates did," said lead author Sabrina Diano, professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine. "We showed that the PPARgamma receptor in neurons that produce POMC could control responses to a high-fat diet without resulting in obesity."
POMC neurons are locate in the hypothalamus and are responsible for regulating food intake; when activated these neurons help curb appetite. PPARgamma works to regulate the activation of the POMC neurons. The researchers looked at transgenic mice that were genetically engineered to block the PPARgamma receptor from POMC neurons.
"When we blocked PPARgamma in these hypothalamic cells, we found an increased level of free radical formation in POMC neurons, and they were more active," Diano said.
The findings could be a step towards the development of better methods of diabetes prevention. The type 2 diabetes drug thiazolidinedione (TZD) helps lower blood glucose levels, but patients often gain weight on the medication. PPARgamma could be an effective target for the drug.
"Our study suggests that the increased weight gain in diabetic patients treated with TZD could be due to the effect of this drug in the brain, therefore, targeting peripheral PPARgamma to treat type 2 diabetes should be done by developing TZD compounds that can't penetrate the brain," Diano said. "We could keep the benefits of TZD without the side-effects of weight gain. Our next steps in this research are to test this theory in diabetes mouse models."
