Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity
Program in Molecular Medicine; Division of Infectious Diseases and Immunology, Department of Medicine; Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine; Davis Lab
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Cell Biology | Cells | Cellular and Molecular Physiology | Endocrinology | Molecular Biology | Nutritional and Metabolic Diseases | Pathological Conditions, Signs and Symptoms
Obesity-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.
glucose metabolism, inflammation, unfolded protein response
DOI of Published Version
FASEB J. 2018 Apr;32(4):2292-2304. doi: 10.1096/fj.201701017R. Epub 2018 Jan 5. Link to article on publisher's site
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Kim, Jong Hun; Lee, Eunjung; Friedline, Randall H.; Suk, Sujin; Jung, Dae Young; Dagdeviren, Sezin; Hu, Xiaodi; Inashima, Kunikazu; Noh, Hye Lim; Kwon, Jung Yeon; Nambu, Aya; Huh, Jun R.; Han, Myoung Souk; Davis, Roger J.; Lee, Ki Won; and Kim, Jason K., "Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity" (2018). Program in Molecular Medicine Publications and Presentations. 90.