Inhibition of secreted frizzled-related protein 5 improves glucose metabolism

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 hyperglyce...

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Bibliographic Details
Published in:American journal of physiology: endocrinology and metabolism 2014-12, Vol.307 (12), p.E1144-E1152
Main Authors: Rulifson, Ingrid C, Majeti, Jiangwen Z, Xiong, Yumei, Hamburger, Agi, Lee, Ki Jeong, Miao, Li, Lu, Mei, Gardner, Jonitha, Gong, Yan, Wu, Hai, Case, Ryan, Yeh, Wen-Chen, Richards, William G, Baribault, Helene, Li, Yang
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - immunology
Diabetes
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Genotype & phenotype
Glucose
Glucose - metabolism
Immunoglobulin G - immunology
Insulin-Secreting Cells - drug effects
Insulin-Secreting Cells - metabolism
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - physiology
Male
Metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Monoclonal antibodies
Obesity
Obesity - complications
Obesity - genetics
Obesity - metabolism
Proteins
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Summary: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.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00283.2014