Journal article
Functional resilience of C57BL/6J mouse heart to dietary fat overload
American journal of physiology. Heart and circulatory physiology, Vol.321(5), pp.H850-H864
Integrative Cardiovascular Physiology and Pathophysiology
09/03/2021
DOI: 10.1152/ajpheart.00419.2021
PMCID: PMC8616610
PMID: 34477461
Abstract
Molecular mechanisms underlying cardiac dysfunction and subsequent heart failure in diabetic cardiomyopathy are incompletely understood. Initially we intended to test the role of G protein-coupled receptor kinase 2 (GRK2), a potential mediator of cardiac dysfunction in diabetic cardiomyopathy, but found that control animals on HFD did not develop cardiomyopathy. Cardiac function was preserved in both wild-type and
GRK2
knockout animals fed high-fat diet as indicated by preserved left ventricular ejection fraction (LVEF) although heart mass was increased. The absence of cardiac dysfunction led us to rigorously evaluate the utility of diet-induced obesity to model diabetic cardiomyopathy in mice. Using pure C57BL/6J animals and various diets formulated with different sources of fat-lard (32% saturated fat, 68% unsaturated fat) or hydrogenated coconut oil (95% saturated fat), we consistently observed left ventricular hypertrophy, preserved LVEF, and preserved contractility measured by invasive hemodynamics in animals fed high-fat diet. Gene expression patterns that characterize pathological hypertrophy were not induced, but a modest induction of various collagen isoforms and matrix metalloproteinases was observed in heart with high-fat diet feeding. PPARα-target genes that enhance lipid utilization such as
Pdk4
,
CD36
,
AcadL
, and
Cpt1b
were induced, but mitochondrial energetics was not impaired. These results suggest that although long-term fat feeding in mice induces cardiac hypertrophy and increases cardiac fatty acid metabolism, it may not be sufficient to activate pathological hypertrophic mechanisms that impair cardiac function or induce cardiac fibrosis. Thus, additional factors that are currently not understood may contribute to the cardiac abnormalities previously reported by many groups.
NEW & NOTEWORTHY
Dietary fat overload (DFO) is widely used to model diabetic cardiomyopathy but the utility of this model is controversial. We comprehensively characterized cardiac contractile and mitochondrial function in C57BL6/J mice fed with lard-based or saturated fat-enriched diets initiated at two ages. Despite cardiac hypertrophy, contractile and mitochondrial function is preserved, and molecular adaptations likely limit lipotoxicity. The resilience of these hearts to DFO underscores the need to develop robust alternative models of diabetic cardiomyopathy.
Details
- Title: Subtitle
- Functional resilience of C57BL/6J mouse heart to dietary fat overload
- Creators
- Satya Murthy Tadinada - University of IowaEric T. Weatherford - University of IowaGreg V. Collins - Carver College of Medicine, University of IowaGourav Bhardwaj - University of IowaJesse Cochran - University of IowaWilliam Kutschke - University of IowaKathy Zimmerman - University of IowaAlyssa Bosko - University of IowaBrian T. O’Neill - University of IowaRobert M. Weiss - University of IowaE. Dale Abel - University of Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of physiology. Heart and circulatory physiology, Vol.321(5), pp.H850-H864
- Publisher
- American Physiological Society
- Series
- Integrative Cardiovascular Physiology and Pathophysiology
- DOI
- 10.1152/ajpheart.00419.2021
- PMID
- 34477461
- PMCID
- PMC8616610
- ISSN
- 0363-6135
- eISSN
- 1522-1539
- Grant note
- S10OD019941 / ; R01HL142935 / ; R01HL112413 / ; R01HL127764 / ; 20SFRN35120123 / ;
- Alternative title
- CARDIAC FUNCTION IN DIET-INDUCED OBESITY
- Language
- English
- Date published
- 09/03/2021
- Academic Unit
- Radiology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359840402771
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