title: Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance.
abstract: In obese individuals, white adipose tissue (WAT) is infiltrated by large numbers of macrophages, resulting in enhanced inflammatory responses that contribute to insulin resistance. Here we show that expression of the CXC motif chemokine ligand-14 (CXCL14), which targets tissue macrophages, is elevated in WAT of obese mice fed a high fat diet (HFD) compared with lean mice fed a regular diet. We found that HFD-fed CXCL14-deficient mice have impaired WAT macrophage mobilization and improved insulin responsiveness. Insulin-stimulated phosphorylation of Akt kinase in skeletal muscle was severely attenuated in HFD-fed CXCL14+/- mice but not in HFD-fed CXCL14-/- mice. The insulin-sensitive phenotype of CXCL14-/- mice after HFD feeding was prominent in female mice but not in male mice. HFD-fed CXCL14-/- mice were protected from hyperglycemia, hyperinsulinemia, and hypoadiponectinemia and did not exhibit increased levels of circulating retinol-binding protein-4 and increased expression of interleukin-6 in WAT. Transgenic overexpression of CXCL14 in skeletal muscle restored obesity-induced insulin resistance in CXCL14-/- mice. CXCL14 attenuated insulin-stimulated glucose uptake in cultured myocytes and to a lesser extent in cultured adipocytes. These results demonstrate that CXCL14 is a critical chemoattractant of WAT macrophages and a novel regulator of glucose metabolism that functions mainly in skeletal muscle.
authors.affiliation: Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Nara
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Shiki
authors.initials: S
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamura
authors.forename: Mari
authors.initials: M
authors.lastname: Kiyono
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Muraoka
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Tanaka
authors.forename: Choji
authors.initials: C
authors.lastname: Taya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shitara
authors.forename: Rie
authors.initials: R
authors.lastname: Ishii
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Yonekawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hara
mesh_terms: D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000235:genetics; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D012737:Sex Factors
chemical_list: C517518:CXCL14 protein, mouse; D019743:Chemokines, CXC; D004041:Dietary Fats; D007328:Insulin; D015850:Interleukin-6; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose