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Cell Metab. 2014 Sep 2;20(3):471-82. doi: 10.1016/j.cmet.2014.06.002. Epub 2014 Jul 10.

Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis.

Author information

1
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Neuroscience, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. Electronic address: kevin.williams@utsouthwestern.edu.
2
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
3
Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard University, Boston, MA 02115, USA.
4
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
5
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
6
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Advanced Imaging Research Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
7
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Obstetrics and Gynecology, The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710061, P.R. China.
8
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; National Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100005, P.R. China.
9
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, P.R. China.
10
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan.
11
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
12
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Science, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100005, P.R. China.
13
Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Cell Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
14
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

Abstract

The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (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.

PMID:
25017942
PMCID:
PMC4186248
DOI:
10.1016/j.cmet.2014.06.002
[Indexed for MEDLINE]
Free PMC Article

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