APPL1 transgenic mice are protected from high-fat diet-induced cardiac dysfunction

Min Park, Donghai Wu, Taesik Park, Cheol Soo Choi, Ren Ke Li, King Yip Cheng, Aimin Xu, Gary Sweeney

Research output: Journal article publicationJournal articleAcademic researchpeer-review

27 Citations (Scopus)

Abstract

APPL1 (adaptor protein containing PH domain, PTB domain, and leucine zipper motif 1) has been established as an important mediator of insulin and adiponectin signaling. Here, we investigated the influence of transgenic (Tg) APPL1 overexpression in mice on high-fat diet (HFD)-induced cardiomyopathy in mice. Wild-type (WT) mice fed an HFD for 16 wk showed cardiac dysfunction, determined by echocardiography, with decreased ejection fraction, decreased fractional shortening, and increased end diastolic volume. HFD-fed APPL1 Tg mice were significantly protected from this dysfunction. Speckle tracking echocardiography to accurately assess cardiac tissue deformation strain and wall motion also indicated dysfunction in WT mice and a similar improvement in Tg vs. WT mice on HFD. APPL1 Tg mice had less HFD-induced increase in circulating nonesteridied fatty acid levels and myocardial lipid accumulation. Lipidomic analysis using LC-MS-MS showed HFD significantly increased myocardial contents of distinct ceramide, sphingomyelin, and diacylglycerol (DAG) species, of which increases in C16:0 and C18:0 ceramides plus C16:0 and C18:1 DAGs were attenuated in Tg mice. A glucose tolerance test indicated less peripheral insulin resistance in response to HFD in Tg mice, which was also apparent by measuring cardiac Akt phosphorylation and cardiomyocyte glucose uptake. In summary, APPL1 Tg mice exhibit improved peripheral metabolism, reduced cardiac lipotoxicity, and improved insulin sensitivity. These cellular effects contribute to protection from HFD-induced cardiomyopathy.
Original languageEnglish
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume305
Issue number7
DOIs
Publication statusPublished - 1 Oct 2013
Externally publishedYes

Keywords

  • Cardiac function
  • Cardiomyopathy
  • High-fat diet
  • Insulin sensitivity
  • Lipotoxicity
  • Nonesterified
  • Oxidative stress

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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