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dc.contributor.authorKim, Jong Hun
dc.contributor.authorLee, Eunjung
dc.contributor.authorFriedline, Randall H.
dc.contributor.authorSuk, Sujin
dc.contributor.authorJung, Dae Young
dc.contributor.authorDagdeviren, Sezin
dc.contributor.authorHu, Xiaodi
dc.contributor.authorInashima, Kunikazu
dc.contributor.authorNoh, Hye Lim
dc.contributor.authorKwon, Jung Yeon
dc.contributor.authorNambu, Aya
dc.contributor.authorHuh, Jun R.
dc.contributor.authorHan, Myoung Souk
dc.contributor.authorDavis, Roger J.
dc.contributor.authorLee, Ki Won
dc.contributor.authorKim, Jason K.
dc.date2022-08-11T08:10:18.000
dc.date.accessioned2022-08-23T17:03:45Z
dc.date.available2022-08-23T17:03:45Z
dc.date.issued2018-04-01
dc.date.submitted2018-11-07
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.issn0892-6638 (Linking)
dc.identifier.doi10.1096/fj.201701017R
dc.identifier.pmid29242277
dc.identifier.urihttp://hdl.handle.net/20.500.14038/44494
dc.description.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.
dc.language.isoen_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.urlhttps://doi.org/10.1096/fj.201701017R
dc.subjectglucose metabolism
dc.subjectinflammation
dc.subjectunfolded protein response
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemical Phenomena, Metabolism, and Nutrition
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCell Biology
dc.subjectCells
dc.subjectCellular and Molecular Physiology
dc.subjectEndocrinology
dc.subjectMolecular Biology
dc.subjectNutritional and Metabolic Diseases
dc.subjectPathological Conditions, Signs and Symptoms
dc.titleEndoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity
dc.typeJournal Article
dc.source.journaltitleFASEB journal : official publication of the Federation of American Societies for Experimental Biology
dc.source.volume32
dc.source.issue4
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pmm_pp/90
dc.identifier.contextkey13261488
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.submissionpathpmm_pp/90
dc.contributor.departmentDavis Lab
dc.contributor.departmentDivision of Endocrinology, Metabolism, and Diabetes, Department of Medicine
dc.contributor.departmentDivision of Infectious Diseases and Immunology, Department of Medicine
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages2292-2304


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