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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.
AuthorsIngrid C Rulifson, Jiangwen Z Majeti, Yumei Xiong, Agi Hamburger, Ki Jeong Lee, Li Miao, Mei Lu, Jonitha Gardner, Yan Gong, Hai Wu, Ryan Case, Wen-Chen Yeh, William G Richards, Helene Baribault, Yang Li
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 307 Issue 12 Pg. E1144-52 (Dec 15 2014) ISSN: 1522-1555 [Electronic] United States
PMID25370851 (Publication Type: Journal Article)
CopyrightCopyright © 2014 the American Physiological Society.
Chemical References
  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • Immunoglobulin G
  • Intercellular Signaling Peptides and Proteins
  • Sfrp5 protein, mouse
  • Glucose
Topics
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antibodies, Monoclonal (immunology)
  • Diabetes Mellitus, Type 2 (genetics, metabolism)
  • Glucose (metabolism)
  • Immunoglobulin G (immunology)
  • Insulin-Secreting Cells (drug effects, metabolism)
  • Intercellular Signaling Peptides and Proteins (genetics, physiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity (complications, genetics, metabolism)

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