The over-expression of the Xbp1s gene in mice who were fed a high fat diet protected them against developing obesity and diabetes. In general these mice were 30% leaner than mice fed the same food. The responsible metabolic pathway was traced to pro-opiomelanocortin (Pomc) neurons in the hypothalamic region of the brain. Elevated Xbp1s levels in Pomc neurons mimicked a satiated signal, resulting in improved body weight, decreased blood glucose levels, and improved insulin sensitivity in the liver. Insulin and leptin are hormones vital to the body’s regulation of food intake and sugar disposal, and obesity and diabetes are conditions under which the body develops resistance to their actions.
“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 Dr. Kevin Williams, Assistant Professor of Internal Medicine and co-first author of the study with Dr. Tiemin Liu, a postdoctoral research fellow in Internal Medicine.
“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, Director of the Division of Hypothalamic Research, Professor of Internal Medicine, Pharmacology, and Psychiatry, and holder of the Carl H. Westcott Distinguished Chair in Medical Research, and the Maclin Family Distinguished Professorship in Medical Science, in Honor of Dr. Roy A. Brinkley.
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