Kim, Jong HunLee, EunjungFriedline, Randall H.Suk, SujinJung, Dae YoungDagdeviren, SezinHu, XiaodiInashima, KunikazuNoh, Hye LimKwon, Jung YeonNambu, AyaHuh, Jun R.Han, Myoung SoukDavis, Roger J.Lee, Ki WonKim, Jason K2022-08-232022-08-232018-04-012018-11-07<p>FASEB J. 2018 Apr;32(4):2292-2304. doi: 10.1096/fj.201701017R. Epub 2018 Jan 5. <a href="https://doi.org/10.1096/fj.201701017R">Link to article on publisher's site</a></p>0892-6638 (Linking)10.1096/fj.201701017R29242277https://hdl.handle.net/20.500.14038/44494Obesity-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.en-USglucose metabolisminflammationunfolded protein responseAmino Acids, Peptides, and ProteinsBiochemical Phenomena, Metabolism, and NutritionBiochemistry, Biophysics, and Structural BiologyCell BiologyCellsCellular and Molecular PhysiologyEndocrinologyMolecular BiologyNutritional and Metabolic DiseasesPathological Conditions, Signs and SymptomsJournal Articlehttps://escholarship.umassmed.edu/pmm_pp/9013261488pmm_pp/90