Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity
dc.contributor.author | Kim, Jong Hun | |
dc.contributor.author | Lee, Eunjung | |
dc.contributor.author | Friedline, Randall H. | |
dc.contributor.author | Suk, Sujin | |
dc.contributor.author | Jung, Dae Young | |
dc.contributor.author | Dagdeviren, Sezin | |
dc.contributor.author | Hu, Xiaodi | |
dc.contributor.author | Inashima, Kunikazu | |
dc.contributor.author | Noh, Hye Lim | |
dc.contributor.author | Kwon, Jung Yeon | |
dc.contributor.author | Nambu, Aya | |
dc.contributor.author | Huh, Jun R. | |
dc.contributor.author | Han, Myoung Souk | |
dc.contributor.author | Davis, Roger J. | |
dc.contributor.author | Lee, Ki Won | |
dc.contributor.author | Kim, Jason K | |
dc.date | 2022-08-11T08:10:18.000 | |
dc.date.accessioned | 2022-08-23T17:03:45Z | |
dc.date.available | 2022-08-23T17:03:45Z | |
dc.date.issued | 2018-04-01 | |
dc.date.submitted | 2018-11-07 | |
dc.identifier.citation | <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> | |
dc.identifier.issn | 0892-6638 (Linking) | |
dc.identifier.doi | 10.1096/fj.201701017R | |
dc.identifier.pmid | 29242277 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/44494 | |
dc.description.abstract | 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. | |
dc.language.iso | en_US | |
dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=29242277&dopt=Abstract">Link to Article in PubMed</a></p> | |
dc.relation.url | https://doi.org/10.1096/fj.201701017R | |
dc.subject | glucose metabolism | |
dc.subject | inflammation | |
dc.subject | unfolded protein response | |
dc.subject | Amino Acids, Peptides, and Proteins | |
dc.subject | Biochemical Phenomena, Metabolism, and Nutrition | |
dc.subject | Biochemistry, Biophysics, and Structural Biology | |
dc.subject | Cell Biology | |
dc.subject | Cells | |
dc.subject | Cellular and Molecular Physiology | |
dc.subject | Endocrinology | |
dc.subject | Molecular Biology | |
dc.subject | Nutritional and Metabolic Diseases | |
dc.subject | Pathological Conditions, Signs and Symptoms | |
dc.title | Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity | |
dc.type | Journal Article | |
dc.source.journaltitle | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | |
dc.source.volume | 32 | |
dc.source.issue | 4 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/pmm_pp/90 | |
dc.identifier.contextkey | 13261488 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | pmm_pp/90 | |
dc.contributor.department | Medicine | |
dc.contributor.department | Program in Molecular Medicine | |
dc.source.pages | 2292-2304 |