title: Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis.
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.
authors.affiliation: 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.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Williams
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Tiemin
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Harvard University, Boston, MA 02115, USA.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Kong
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Yingfeng
authors.initials: Y
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.affiliation: 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.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Tianya
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujikawa
authors.affiliation: 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.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kohno
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Scott
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Syann
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: 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.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D007328:Insulin; D020738:Leptin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D011333:Pro-Opiomelanocortin; D005947:Glucose