Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice

Karla Maria Pires; Marcio Buffolo; Christin Schaaf; J. David Symons; James Cox; E Dale Abel; Craig H Selzman; Sihem Boudina

doi:10.1016/j.yjmcc.2017.10.001

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Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice

Journal article

Open access

Peer reviewed

Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice

Karla Maria Pires, Marcio Buffolo, Christin Schaaf, J. David Symons, James Cox, E Dale Abel, Craig H Selzman and Sihem Boudina

Journal of molecular and cellular cardiology, Vol.113, pp.39-50

12/2017

DOI: 10.1016/j.yjmcc.2017.10.001

PMCID: PMC5689477

PMID: 28987875

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https://www.ncbi.nlm.nih.gov/pmc/articles/5689477View

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Abstract

Autophagy plays an important role in the maintenance of normal heart function. However, the role of autophagy in the inulin resistant and diabetic heart is not well understood. Furthermore, the upstream signaling and the downstream targets involved in cardiac autophagy regulation during obesity and type 2 diabetes mellitus (T2DM) are not fully elucidated. The aim of this study was to measure autophagic flux and to dissect the upstream and downstream signaling involved in cardiac autophagy regulation in the hearts of obese T2DM mice. Our study demonstrated that cardiac autophagic flux is suppressed in the heart of obese diabetic (ob/ob) mice due to impaired autophagosome formation. We showed that suppression of autophagy was due to sustained activation of mTOR as we could restore cardiac autophagy by inhibiting mTOR. Moreover, the novel finding of this study is that while IGF-1 receptor-mediated Akt activation contributes to cardiac hypertrophy, it is not involved in mTOR activation and autophagy suppression in obesity and T2DM. In contrast, inhibition of ERK signaling abolished mTOR activation and restored autophagy in the heart of obese diabetic (ob/ob) mice. The study identifies mechanisms regulating cardiac autophagy in obesity and T2DM that are mediated by ERK/mTOR but are distinct from Akt. The findings are of significant importance as they demonstrate for the first time the contribution of IGF-1 receptors (IGF-1R) and Akt signaling in cardiac hypertrophy but not in cardiac autophagy regulation in obesity and T2DM.

Hyperinsulinism - metabolism

Receptor, IGF Type 1 - metabolism

TOR Serine-Threonine Kinases - metabolism

Heart - physiology

Mice, Inbred C57BL

Male

Autophagy - physiology

Diabetes Mellitus, Type 2 - metabolism

Obesity - metabolism

Animals

Mice, Obese

Signal Transduction - physiology

Mice

Diabetes Mellitus, Experimental - metabolism

Proto-Oncogene Proteins c-akt - metabolism

Cardiomegaly - metabolism

Details

Title: Subtitle: Activation of IGF-1 receptors and Akt signaling by systemic hyperinsulinemia contributes to cardiac hypertrophy but does not regulate cardiac autophagy in obese diabetic mice
Creators: Karla Maria Pires - Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA
Marcio Buffolo - Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA
Christin Schaaf - Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
J. David Symons - Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA
James Cox - Department of Biochemistry, University of Utah, Salt Lake City, UT, USA
E Dale Abel - Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA
Craig H Selzman - Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA
Sihem Boudina - Department of Nutrition and Integrative Physiology, University of Utah School of Medicine, Salt Lake City, UT, USA. Electronic address: sihem.boudina@hmbg.utah.edu
Resource Type: Journal article
Publication Details: Journal of molecular and cellular cardiology, Vol.113, pp.39-50
DOI: 10.1016/j.yjmcc.2017.10.001
PMID: 28987875
PMCID: PMC5689477
NLM abbreviation: J Mol Cell Cardiol
ISSN: 0022-2828
eISSN: 1095-8584
Publisher: England
Grant note: R01 HL127764 / NHLBI NIH HHS P30 DK020579 / NIDDK NIH HHS R01 DK099110 / NIDDK NIH HHS R01 HL112413 / NHLBI NIH HHS R03 AG052848 / NIA NIH HHS R01 DK098646 / NIDDK NIH HHS
Language: English
Date published: 12/2017
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984025285802771

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