High-fat diet in a mouse insulin-resistant model induces widespread rewiring of the phosphotyrosine signaling network

Mol Syst Biol. 2019 Aug;15(8):e8849. doi: 10.15252/msb.20198849.


Obesity-associated type 2 diabetes and accompanying diseases have developed into a leading human health risk across industrialized and developing countries. The complex molecular underpinnings of how lipid overload and lipid metabolites lead to the deregulation of metabolic processes are incompletely understood. We assessed hepatic post-translational alterations in response to treatment of cells with saturated and unsaturated free fatty acids and the consumption of a high-fat diet by mice. These data revealed widespread tyrosine phosphorylation changes affecting a large number of enzymes involved in metabolic processes as well as canonical receptor-mediated signal transduction networks. Targeting two of the most prominently affected molecular features in our data, SRC-family kinase activity and elevated reactive oxygen species, significantly abrogated the effects of saturated fat exposure in vitro and high-fat diet in vivo. In summary, we present a comprehensive view of diet-induced alterations of tyrosine signaling networks, including proteins involved in fundamental metabolic pathways.

Keywords: diabetes; free fatty acids; high-fat diet; obesity; phosphoproteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Fatty Acids / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Obesity / etiology
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Phosphorylation / drug effects
  • Phosphotyrosine / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational*
  • Proteomics / methods
  • Rats
  • Reactive Oxygen Species / agonists
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism


  • Fatty Acids
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • Phosphotyrosine
  • src-Family Kinases