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

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

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)471-482
Number of pages12
JournalCell Metabolism
Volume20
Issue number3
DOIs
StatePublished - Sep 2 2014

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Pro-Opiomelanocortin
Insulin Resistance
Homeostasis
Leptin
Neurons
Glucose
Obesity
Liver
Diet
Unfolded Protein Response
Transcription Factors

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. / Williams, Kevin W.; Liu, Tiemin; Kong, Xingxing; Fukuda, Makoto; Deng, Yingfeng; Berglund, Eric D.; Deng, Zhuo; Gao, Yong; Liu, Tianya; Sohn, Jong Woo; Jia, Lin; Fujikawa, Teppei; Kohno, Daisuke; Scott, Michael M.; Lee, Syann; Lee, Charlotte E.; Sun, Kai; Chang, Yongsheng; Scherer, Philipp E.; Elmquist, Joel K.

In: Cell Metabolism, Vol. 20, No. 3, 02.09.2014, p. 471-482.

Research output: Contribution to journalArticle

Williams, KW, Liu, T, Kong, X, Fukuda, M, Deng, Y, Berglund, ED, Deng, Z, Gao, Y, Liu, T, Sohn, JW, Jia, L, Fujikawa, T, Kohno, D, Scott, MM, Lee, S, Lee, CE, Sun, K, Chang, Y, Scherer, PE & Elmquist, JK 2014, 'Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis', Cell Metabolism, vol. 20, no. 3, pp. 471-482. https://doi.org/10.1016/j.cmet.2014.06.002
Williams, Kevin W. ; Liu, Tiemin ; Kong, Xingxing ; Fukuda, Makoto ; Deng, Yingfeng ; Berglund, Eric D. ; Deng, Zhuo ; Gao, Yong ; Liu, Tianya ; Sohn, Jong Woo ; Jia, Lin ; Fujikawa, Teppei ; Kohno, Daisuke ; Scott, Michael M. ; Lee, Syann ; Lee, Charlotte E. ; Sun, Kai ; Chang, Yongsheng ; Scherer, Philipp E. ; Elmquist, Joel K. / Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. In: Cell Metabolism. 2014 ; Vol. 20, No. 3. pp. 471-482.
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