Inflammation Improves Glucose Homeostasis through IKKβ-XBP1s Interaction.
It is widely believed that inflammation associated with obesity has an important role in the development of type 2 diabetes. IκB kinase beta (IKKβ) is a crucial kinase that responds to inflammatory stimuli such as tumor necrosis factor α (TNF-α) by initiating a variety of intracellular signaling cascades and is considered to be a key element in the inflammation-mediated development of insulin resistance. We show here, contrary to expectation, that IKKβ-mediated inflammation is a positive regulator of hepatic glucose homeostasis. IKKβ phosphorylates the spliced form of X-Box Binding Protein 1 (XBP1s) and increases the activity of XBP1s. We have used three experimental approaches to enhance the IKKβ activity in the liver of obese mice and observed increased XBP1s activity, reduced ER stress, and a significant improvement in insulin sensitivity and consequently in glucose homeostasis. Our results reveal a beneficial role of IKKβ-mediated hepatic inflammation in glucose homeostasis.
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Junli
J
Liu
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Dorina
D
Ibi
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
Koji
K
Taniguchi
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Jaemin
J
Lee
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Hilde
H
Herrema
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Bedia
B
Akosman
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Patrick
P
Mucka
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Mario Andres
MA
Salazar Hernandez
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Muhemmet Fatih
MF
Uyar
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA.
Sang Won
SW
Park
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
Michael
M
Karin
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02130, USA. Electronic address: umut.ozcan@childrens.harvard.edu.
Umut
U
Ozcan
D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation; D055550:Protein Stability; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*
D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D005947:Glucose
ER stress; IKKβ; UPR; XBP1s; diabetes; glucose metabolism; inflammation; insulin resistance; obesity; unfolded protein response