title: Inhibition of secreted frizzled-related protein 5 improves glucose metabolism.
abstract: Elucidating the role of secreted frizzled-related protein 5 (SFRP5) in metabolism and obesity has been complicated by contradictory findings when knockout mice were used to determine metabolic phenotypes. By overexpressing SFRP5 in obese, prediabetic mice we consistently observed elevated hyperglycemia and glucose intolerance, supporting SFRP5 as a negative regulator of glucose metabolism. Accordingly, Sfrp5 mRNA expression analysis of both epididymal and subcutaneous adipose depots of mice indicated a correlation with obesity. Thus, we generated a monoclonal antibody (mAb) against SFRP5 to ascertain the effect of SFRP5 inhibition in vivo. Congruent with SFRP5 overexpression worsening blood glucose levels and glucose intolerance, anti-SFRP5 mAb therapy improved these phenotypes in vivo. The results from both the overexpression and mAb inhibition studies suggest a role for SFRP5 in glucose metabolism and pancreatic β-cell function and thus establish the use of an anti-SFRP5 mAb as a potential approach to treat type 2 diabetes.
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Rulifson
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Jiangwen Z
authors.initials: JZ
authors.lastname: Majeti
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Amgen Incorporated, Thousand Oaks, California.
authors.forename: Agi
authors.initials: A
authors.lastname: Hamburger
authors.affiliation: Amgen Incorporated, Thousand Oaks, California.
authors.forename: Ki Jeong
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Li
authors.initials: L
authors.lastname: Miao
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Jonitha
authors.initials: J
authors.lastname: Gardner
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Hai
authors.initials: H
authors.lastname: Wu
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Ryan
authors.initials: R
authors.lastname: Case
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Wen-Chen
authors.initials: WC
authors.lastname: Yeh
authors.affiliation: Amgen Incorporated, Thousand Oaks, California.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Amgen Incorporated, South San Francisco, California; and.
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.affiliation: Amgen Incorporated, South San Francisco, California; and yangl@amgen.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007074:Immunoglobulin G / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D005947:Glucose; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; C487972:Sfrp5 protein, mouse; D000094742:Secreted Frizzled-Related Proteins
keywords: Wnt; diabetes; obesity; pancreatic β-cell; secreted frizzled-related protein 5