Metabolic syndrome diminishes insulin-induced Akt activation and causes a redistribution of Akt-interacting proteins in cardiomyocytes.

Huguet V Landa-Galvan,Jesus Alberto Olivares-Reyes,Emmanuel Rios-Castro,Tatiana Romero-Garcia,Angelica Rueda,Luc Bertrand

doi:10.1371/journal.pone.0228115

Abstract

Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors, with insulin resistance as a critical component for its development. Insulin signaling in the heart leads to Akt (also known as PKB) activation, a serine/threonine protein kinase, which regulates cardiac glucose metabolism and growth. Cardiac metabolic inflexibility, characterized by impaired insulin-induced glucose uptake and oxidation, has been reported as an early and consistent change in the heart of different models of MetS and diabetes; however, the evaluation of Akt activation has yielded variable results. Here we report in cardiomyocytes of MetS rats, diminished insulin-induced glucose uptake and Akt activation, evaluated by its impaired mobilization towards the plasma membrane and phosphorylation, and reflected in a re-distribution of its interacting proteins, assessed by label-free mass spectrometry (data are available via ProteomeXchange with identifier PXD013260). We report 45 proteins with diminished abundance in Akt complex of MetS cardiomyocytes, mainly represented by energy metabolism-related proteins, and also, 31 Akt-interacting proteins with increased abundance, which were mainly related to contraction, endoplasmic reticulum stress, and Akt negative regulation. These results emphasize the relevance of Akt in the regulation of energy metabolism in the heart and highlight Akt-interacting proteins that could be involved in the detrimental effects of MetS in the heart.

Highlights

Metabolic syndrome (MetS) is a highly prevalent condition characterized by a constellation of physiological and biochemical disorders, such as insulin resistance (IR), obesity and dyslipidemias, which increase the risk of cardiovascular disease [1, 2].MetS and diabetes mellitus type 2 (DM2) are interrelated conditions that often coexist, and, those people diagnosed with MetS without DM2 are at a significant risk of developing it [1]
We aimed to evaluate insulin-induced glucose uptake and Akt activation in cardiomyocytes of MetS rats, and quantify changes in the abundance of proteins that form a complex with Akt by using a co-immunoprecipitation (CoIP) and label-free mass spectrometry approach, in order to provide proteomic support to the Akt activation status and to explore the molecular mechanisms related to Akt regulation that could be involved in the heart IR condition and the diabetic cardiomyopathy development
Metabolic syndrome impairs insulin-induced Akt signaling in the heart triturated for 3 min with a plastic pipette to disperse myocytes

Summary

Introduction

MetS is a highly prevalent condition characterized by a constellation of physiological and biochemical disorders, such as insulin resistance (IR), obesity and dyslipidemias, which increase the risk of cardiovascular disease [1, 2]. MetS and diabetes mellitus type 2 (DM2) are interrelated conditions that often coexist, and, those people diagnosed with MetS without DM2 are at a significant risk of developing it [1]. Metabolic syndrome impairs insulin-induced Akt signaling in the heart. Grant A1-S-9082 (to A.R.); PRODEP-SEP grant to the Academic Group Cinvestav-CA-10, ID 28915/ 2018 (to A.R. and J.A.O-R.); SEP-CINVESTAV 2018 grant #2 (to A.R.); Estimulo a la Investigacion Medica “Miguel Aleman Valdes” 2018 (to J.A.O-R.) and by a CONACYT scholarship grant, No 278067 (to H.V.L-G.) and No 295776 (to T.R-G.)

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