Brain Protein Key to Potential Obesity, Diabetes Therapies

How involved is the brain in regulating metabolism? This question is just of the fronts on the wars against obesity and diabetes.

Now, researchers have found a protein that commands genes to switch on or off has an important role in certain areas of the brain which control metabolism. The discovery has the potential of leading to new therapies for treatment of obesity and diabetes.

The transcription factor involved, called spliced X-box binding protein 1, appears to influence the body’s sensitivity to insulin and leptin signaling. Both insulin and leptin are hormones vital to the body’s regulation of food intake and sugar clearance. The body develops resistance to the actions of these hormones in obesity and diabetes.

“This study identifies critical molecular mechanisms that link the brain and peripheral endocrine tissues and that ultimately contribute to the regulation of body weight and glucose metabolism,” said co-first author Dr. Kevin Williams, of University of Texas Southwestern Medical Center.

30 Percent Leaner

Excess expression of the gene Xbp1s in mice that were fed a high-fat diet protected them against obesity and diabetes, according to the recent study. These mice were, on average, 30 percent leaner than mice fed the same food.

The gene’s actions took place in pro-opiomelanocortin (Pomc) neurons in the hypothalamic region of the brain. Elevated Xbp1s levels in Pomc neurons mimicked a “fed” signal, resulting in improved body weight, decreased blood glucose levels, and improved insulin sensitivity in the liver.

“Manipulating this one gene in the brain affected metabolism in the liver. This result shows that the brain is controlling glucose production by the liver,” said Dr. Joel Elmquist, Professor of Internal Medicine, Pharmacology, and Psychiatry.

Currently, no drug form of Xbp1s exists, so it is not possible to test whether the gene is a target for the treatment of diabetes or obesity. The researchers do envision such a drug as a potential outgrowth of their research.

“We have studied one transcription factor out of many that participate in a large, complex cellular process,” said Dr. Williams of Xbp1s and its role during times of cellular stress.

Dr. Williams said other transcription factors involved in the same metabolic pathway will be studied to see if they have similar effects.


Kevin W. Williams, Tiemin Liu, Xingxing Kong, Makoto Fukuda, Yingfeng Deng, Eric D. Berglund, Zhuo Deng, Yong Gao, Tianya Liu, Jong-Woo Sohn, Lin Jia, Teppei Fujikawa, Daisuke Kohno, Michael M. Scott, Syann Lee, Charlotte E. Lee, Kai Sun, Yongsheng Chang, Philipp E. Scherer, Joel K. Elmquist.
Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis.
Cell Metabolism, 2014; DOI: 10.1016/j.cmet.2014.06.002

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