Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity
AuthorsKim, Jong Hun
Friedline, Randall H.
Jung, Dae Young
Noh, Hye Lim
Kwon, Jung Yeon
Huh, Jun R.
Han, Myoung Souk
Davis, Roger J.
Lee, Ki Won
Kim, Jason K.
UMass Chan AffiliationsDavis Lab
Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine
Division of Infectious Diseases and Immunology, Department of Medicine
Program in Molecular Medicine
Document TypeJournal Article
unfolded protein response
Amino Acids, Peptides, and Proteins
Biochemical Phenomena, Metabolism, and Nutrition
Biochemistry, Biophysics, and Structural Biology
Cellular and Molecular Physiology
Nutritional and Metabolic Diseases
Pathological Conditions, Signs and Symptoms
MetadataShow full item record
AbstractObesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage-selective ablation of GRP78 (Lyz- GRP78(-/-)) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow-derived macrophages from Lyz- GRP78(-/-) mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by > 4-fold in Lyz- GRP78(-/-) mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz- GRP78(-/-) mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.
FASEB J. 2018 Apr;32(4):2292-2304. doi: 10.1096/fj.201701017R. Epub 2018 Jan 5. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/44494