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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #312399
Title: Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis

Author
item WILLIAMS, KEVIN - University Of Texas Southwestern Medical Center
item LIU, TIEMIN - University Of Texas Southwestern Medical Center
item KONG, XINGXING - University Of Texas Southwestern Medical Center
item FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)
item DENG, YINGFENG - University Of Texas Southwestern Medical Center
item BERGLUND, ERIC - University Of Texas Southwestern Medical Center
item DENG, ZHUO - University Of Texas Southwestern Medical Center
item GAO, YONG - University Of Texas Southwestern Medical Center
item LIU, TIANYA - University Of Texas Southwestern Medical Center
item SOHN, JONG-WOO - University Of Texas Southwestern Medical Center
item JIA, LIN - University Of Texas Southwestern Medical Center
item FUJIKAWA, TEPPEI - University Of Texas Southwestern Medical Center
item KOHNO, DAISUKE - University Of Texas Southwestern Medical Center
item SCOTT, MICHAEL - University Of Virginia School Of Medicine
item LEE, SYAN - University Of Texas Southwestern Medical Center
item LEE, CHARLOTTE - University Of Texas Southwestern Medical Center
item SUN, KAI - University Of Texas Southwestern Medical Center
item CHANG, YONGSHENG - Peking Union Medical College Hospital
item SCHERER, PHILIPP - University Of Texas Southwestern Medical Center
item ELMQUIST, JOEL - University Of Texas Southwestern Medical Center

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/29/2014
Publication Date: 9/2/2014
Citation: Williams, K.W., Liu, T., Kong, X., Fukuda, M., Deng, Y., Berglund, E.D., Deng, Z., Gao, Y., Liu, T., Sohn, J., Jia, L., Fujikawa, T., Kohno, D., Scott, M.M., Lee, S., Lee, C.E., Sun, K., Chang, Y., Scherer, P.E., Elmquist, J.K. 2014. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metabolism. 20(3):471-482.

Interpretive Summary: Insulin and leptin are central hormones to control sugar disposal and body weight, respectively. However, they do not work properly under conditions of obesity and diabetes. These conditions, so called leptin resistance and insulin resistance, are the fundamental processes that underlie metabolic disease. Thus, understanding the underlying mechanisms is key for the development of effective and rational therapeutic approaches. We found that leptin resistance and insulin resistance are both prevented and reversed by manipulating the expression of a single gene (Xbp1s) in the brain. Over-expression of the Xbp1s gene in specific areas of the brain protected against obesity and diabetes. Manipulating this single gene affected glucose and fat metabolisms in the peripheral organs such as fat and liver; demonstrating the brain is controlling glucose production in the liver, and lipid metabolism in the fat. This research potentially provides us with new therapies for the treatment of obesity and diabetes.

Technical Abstract: The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction ofthe unfolded protein response transcription factor spliced X-box binding protein 1(Xbp1s) in pro-opio-melanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes.