Functional resilience of C57BL/6J mouse heart to dietary fat overload

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 f...

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Published in:American journal of physiology. Heart and circulatory physiology 2021-11, Vol.321 (5), p.H850-H864
Main Authors: Tadinada, Satya Murthy, Weatherford, Eric T, Collins, Greg V, Bhardwaj, Gourav, Cochran, Jesse, Kutschke, William, Zimmerman, Kathy, Bosko, Alyssa, O'Neill, Brian T, Weiss, Robert M, Abel, E Dale
Format: Article
Language:English
Subjects:
Abnormalities
Age Factors
Animals
b-Adrenergic-receptor kinase
Cardiac function
Cardiomyopathy
CD36 antigen
Coconut oil
Collagen
Congestive heart failure
Diabetes
Diabetes mellitus
Diabetic Cardiomyopathies - enzymology
Diabetic Cardiomyopathies - etiology
Diabetic Cardiomyopathies - pathology
Diabetic Cardiomyopathies - physiopathology
Diet
Diet, High-Fat
Disease Models, Animal
Energy Metabolism
Fatty acids
Female
Fibrosis
G protein-coupled receptor kinase
G protein-coupled receptor kinase 2
G-Protein-Coupled Receptor Kinase 2 - genetics
G-Protein-Coupled Receptor Kinase 2 - metabolism
Gene expression
Heart
Hemodynamics
High fat diet
Hypertrophy
Hypertrophy, Left Ventricular - enzymology
Hypertrophy, Left Ventricular - etiology
Hypertrophy, Left Ventricular - pathology
Hypertrophy, Left Ventricular - physiopathology
Isoforms
Kinases
Lipids
Male
Matrix metalloproteinase
Matrix metalloproteinases
Metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Mitochondria, Heart - enzymology
Mitochondria, Heart - pathology
Molecular modelling
Muscle contraction
Myocardium - enzymology
Myocardium - pathology
Obesity - complications
Stroke Volume
Ventricle
Ventricular Dysfunction, Left - enzymology
Ventricular Dysfunction, Left - etiology
Ventricular Dysfunction, Left - pathology
Ventricular Dysfunction, Left - physiopathology
Ventricular Function, Left
Ventricular Remodeling
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Summary: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 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. PPARĪ±-target genes that enhance lipid utilization such as , , , and 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. 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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00419.2021