Effect of Sfrp5 on cytokine release and insulin action in primary human adipocytes and skeletal muscle cells.
Secreted frizzled-related protein 5 (Sfrp5) is an adipokine with anti-inflammatory and insulin-sensitizing properties in mice. However, the mechanism of Sfrp5 action, especially in humans, is largely unknown. Therefore, cytokine release and insulin signaling were analyzed to investigate the impact of Sfrp5 on inflammation and insulin signaling in primary human adipocytes and skeletal muscle cells (hSkMC). Sfrp5 neither affected interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and adiponectin release from human adipocytes, nor IL-6 and IL-8 release from hSkMC. In tumor necrosis factor (TNF) α-treated adipocytes, Sfrp5 reduced IL-6 release by 49% (p<0.05), but did not affect MCP-1 and adiponectin release. In MCP-1-treated hSkMC, Sfrp5 did not affect cytokine secretion. In untreated adipocytes, Sfrp5 decreased the insulin-mediated phosphorylation of Akt-Ser473, Akt-Thr308, GSK3α-Ser21 and PRAS40-Thr246 by 34% (p<0.01), 31% (p<0.05), 37% (p<0.05) and 34% (p<0.01), respectively, and the stimulation of glucose uptake by 25% (p<0.05). Incubation with TNFα increased the phosphorylation of JNK and NFκB, and impaired insulin signaling. When Sfrp5 and TNFα were combined, there was no additional effect on insulin signaling and JNK phosphorylation, but phosphorylation of NFκB was reversed to basal levels. Sfrp5 had no effect on insulin signaling in untreated or in MCP-1 treated hSkMC. Thus, Sfrp5 lowered IL-6 release and NFκB phosphorylation in cytokine-treated human adipocytes, but not under normal conditions, and decreased insulin signaling in untreated human adipocytes. Sfrp5 did not act on hSkMC. Therefore, the cellular actions of Sfrp5 seem to depend on the type of tissue as well as its inflammatory and metabolic state.
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany ; German Center for Diabetes Research (DZD), Düsseldorf, Germany.
Maren
M
Carstensen
German Center for Diabetes Research (DZD), Düsseldorf, Germany ; Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Claudia
C
Wiza
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany ; German Center for Diabetes Research (DZD), Düsseldorf, Germany.
Karin
K
Röhrig
German Center for Diabetes Research (DZD), Düsseldorf, Germany ; Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Pia
P
Fahlbusch
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany ; German Center for Diabetes Research (DZD), Düsseldorf, Germany ; Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
Michael
M
Roden
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany ; German Center for Diabetes Research (DZD), Düsseldorf, Germany.
Christian
C
Herder
German Center for Diabetes Research (DZD), Düsseldorf, Germany ; Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany ; Department of Endocrinology, Ghent University Hospital, Ghent, Belgium.
D Margriet
DM
Ouwens
D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005136:Eye Proteins / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008875:Middle Aged; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D055815:Young Adult; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D005136:Eye Proteins; D005947:Glucose; D007328:Insulin; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C118511:SFRP5 protein, human; D000094742:Secreted Frizzled-Related Proteins; C085389:WNT5A protein, human