title: Roles for Cell-Cell Adhesion and Contact in Obesity-Induced Hepatic Myeloid Cell Accumulation and Glucose Intolerance.
abstract: Obesity promotes infiltration of inflammatory cells into various tissues, leading to parenchymal and stromal cell interaction and development of cellular and organ dysfunction. Liver sinusoidal endothelial cells (LSECs) are the first cells that contact portal blood cells and substances in the liver, but their functions in the development of obesity-associated glucose metabolism remain unclear. Here, we find that LSECs are involved in obesity-associated accumulation of myeloid cells via VLA-4-dependent cell-cell adhesion. VLA-4 blockade in mice fed a high-fat diet attenuated myeloid cell accumulation in the liver to improve hepatic inflammation and systemic glucose intolerance. Ex vivo studies further show that cell-cell contact between intrahepatic leukocytes and parenchymal hepatocytes induces gluconeogenesis via a Notch-dependent pathway. These findings suggest that cell-cell interaction between parenchymal and stromal cells regulates hepatic glucose metabolism and offers potential strategies for treatment or prevention of obesity-associated glucose intolerance.
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Miyachi
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan. Electronic address: ktsuchiya.mem@tmd.ac.jp.
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Komiya
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Shiba
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Shimazu
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Deushi
authors.affiliation: Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Mizuko
authors.initials: M
authors.lastname: Osaka
authors.affiliation: Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Kanagawa 230-8501, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: Department of Anatomy and Histocytology, School of Dental Medicine, Tsurumi University, Yokohama, Kanagawa 230-8501, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Wake
authors.affiliation: Department of Life Science and Bioethics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8582, Japan; Japan Agency for Medical Research and Development, CREST, Chiyoda-ku, Tokyo 100-0004, Japan. Electronic address: ogawa.mem@tmd.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000150:complications* / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D039041:Integrin alpha4beta1 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology*; D009765:Obesity / Q000150:complications* / Q000473:pathology*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D051880:Receptors, Notch; D005947:Glucose
keywords: Notch signaling; diabetes; inflammation; insulin resistance; liver sinusoidal endothelial cells; macrophages; monocytes; neutrophils; obesity