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

Antje Dittmann,Miyeko D Mana,Norman J Kennedy,Nina L Soltero,Roger J Davis,Ömer H Yilmaz,Nader Morshed,Forest M White

doi:10.15252/msb.20198849

Abstract

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.

Highlights

Metabolic syndrome, characterized by insulin resistance, dyslipidemia, hyperglycemia, elevated blood pressure, and hepatic steatosis, predisposes individuals to the development of a range of disorders including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, and cancer (Almind et al, 2005; Biddinger & Kahn, 2006; Font-Burgada et al, 2016)
We sought to elucidate the effects of acutely elevated free fatty acids (FFAs) on hepatic signaling networks with the goal of identifying new network nodes whose activities are modified by FFAs
Consistent with palmitic acid (PA) promoting an insulin resistance-like phenotype (Stabile et al, 1998; Xu et al, 2007; Nakamura et al, 2009; Egnatchik et al, 2014; Gurzov et al, 2014), treating the rat hepatoma cell line H4IIE with PA for 24 h led to an attenuated pAkt (S473) response to insulin (Figs 1A and EV1A), and increased reactive oxygen species (ROS) (Fig 1B) and G6Pase mRNA, relative to oleic acid (OA), without impairing the expected insulin-induced increase of Insulin receptor (INSR)/IGF1R phosphorylation and reduction of G6Pase expression (Fig 1C)

Summary

Introduction

Metabolic syndrome, characterized by insulin resistance, dyslipidemia, hyperglycemia, elevated blood pressure, and hepatic steatosis, predisposes individuals to the development of a range of disorders including type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease, and cancer (Almind et al, 2005; Biddinger & Kahn, 2006; Font-Burgada et al, 2016). A combination of environmental and genetic factors such as overnutrition, increased lipolytic activity, and adipocyte hypertrophy has been found to be important for the development of the syndrome, and insulin resistance appears to be central to the establishment of disease (Dahlman et al, 2017; Gustafson et al, 2015). Insulin resistance describes a range of molecular phenotypes in which physiological regulatory functions of insulin are suppressed or altered. In peripheral tissues such as skeletal muscle and adipose tissue, insulin regulates glucose uptake, whereas in the liver, it suppresses gluconeogenesis. The liver plays a central role in many of these processes, and hepatic insulin resistance is thought to contribute to glycemic dysregulation whereby insulin fails to suppress hepatic gluconeogenesis but still activates lipogenesis (Brown & Goldstein, 2008)

Methods

Results

Conclusion