Phosphorylation status of fetuin-A is critical for inhibition of insulin action and is correlated with obesity and insulin resistance

• Published in: American journal of physiology: endocrinology and metabolism Vol. 317; no. 2; pp. E250 - E260
• Main Authors: Ren, Guang, Kim, Teayoun, Papizan, James B, Okerberg, Carl K, Kothari, Vishal M, Zaid, Hilal, Bilan, Phillip J, Araya-Ramirez, Felipe, Littlefield, Laurel A, Bowers, Robert L, Mahurin, A Jack, Nickles, Mary M, Ludvigsen, Rebecca, He, Xiaoming, Grandjean, Peter W, Mathews, Suresh T
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2019
• Subjects: 3T3-L1 Cells; Adult; Aged; alpha-2-HS-Glycoprotein - metabolism; alpha-2-HS-Glycoprotein - pharmacology; Animals; Body weight; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Glucose; Glycogen; Hepatoma; High fat diet; Humans; Insulin; Insulin - metabolism; Insulin Antagonists - metabolism; Insulin Antagonists - pharmacology; Insulin resistance; Insulin Resistance - physiology; Kinases; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mutants; Myoblasts; Obesity; Obesity - metabolism; Phosphorylation; Protein Kinases - metabolism; Rats; Rats, Zucker; Synthesis; obesity metabolism; fetuin-A; insulin signaling; glucose uptake; insulin resistance
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00089.2018

Fetuin-A (Fet-A), a hepatokine associated with insulin resistance, obesity, and incident type 2 diabetes, is shown to exist in both phosphorylated and dephosphorylated forms in circulation. However, studies on fetuin-A phosphorylation status in insulin-resistant conditions and its functional significance are limited. We demonstrate that serum phosphofetuin-A (Ser312) levels were significantly elevated in high-fat diet-induced obese mice, insulin-resistant Zucker diabetic fatty rats, and in individuals with obesity who are insulin resistant. Unlike serum total fetuin-A, serum phosphofetuin-A was associated with body weight, insulin, and markers of insulin resistance. To characterize potential mechanisms, fetuin-A was purified from Hep3B human hepatoma cells. Hep3B Fet-A was phosphorylated (Ser312) and inhibited insulin-stimulated glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Furthermore, single (Ser312Ala) and double (Ser312Ala + Ser120Ala) phosphorylation-defective Fet-A mutants were without effect on glucose uptake and glycogen synthesis in L6GLUT4 myoblasts. Together, our studies demonstrate that phosphorylation status of Fet-A (Ser312) is associated with obesity and insulin resistance and raise the possibility that Fet-A phosphorylation may play a role in regulation of insulin action.