High-fructose and high-fat feeding correspondingly lead to the development of lysoPC-associated apoptotic cardiomyopathy and adrenergic signaling-related cardiac hypertrophy.
BACKGROUND
The heart is a highly adaptive organ that demonstrates remarkable structural, functional, and metabolic remodeling in response to physiological and pathological stimuli. We hypothesize that the heart undergoes differential adaptations in high-fat and high-fructose diet, resulting in a distinct phenotype.


METHODS
High-fat and high-fructose diet-induced obese and non-obese insulin resistance (IR) rat models were used to understand how the heart adapts to long-term (12-week) overnutrition.


RESULTS
Rats fed the high-fat diet developed obese IR, whereas high-fructose diet developed non-obese IR. Obese IR rats developed fibrotic hypertrophy with impairment of preload-independent contractility. The sympathetic and renin-angiotensin-aldosterone (RAA) systems and myocardial adrenergic signaling were activated in obese IR rats. Non-obese IR rats developed apoptotic cardiomyopathy with severe systolic dysfunction. Myocardial calcium cycling regulatory proteins (CCRPs) were dysregulated in non-obese IR rats; specifically, troponin I protein expression was downregulated. Moreover, compared with the controls, lipidomics analysis revealed substantial differences in lipid metabolites in non-obese IR and obese IR rats. The overproduction of lysophosphatidylcholine (lysoPC) and fatty acids was observed in non-obese IR rat hearts. A strong correlation was observed between the myocardial lysoPC and plasma troponin I levels. Treatment of cardiomyocytes with lysoPC resulted in cell death in a dose- and time-dependent manner. The overproduction of myocardial lysoPCs was associated with circulating sPLA2 levels.


CONCLUSIONS
Obese IR rats developed severe fibrotic hypertrophy with the activation of adrenergic signaling and sympathetic and RAA systems. The sPLA2-lysoPC may play a crucial role in the induction of apoptotic cardiomyopathy in high fructose-induced non-obese IR rats.
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Jiung-Pang
JP
Huang
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Heart Failure Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Mei-Ling
ML
Cheng
Heart Failure Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
Chao-Hung
CH
Wang
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Ming-Shi
MS
Shiao
Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Jan-Kan
JK
Chen
Department of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Center for Healthy and Aging Research, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Heart Failure Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan. Electronic address: lisahung@mail.cgu.edu.tw.
Li-Man
LM
Hung
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage* / Q000009:adverse effects; D007333:Insulin Resistance; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects; D019210:Troponin I / Q000378:metabolism
D005227:Fatty Acids; D008244:Lysophosphatidylcholines; D019210:Troponin I; D005632:Fructose
Apoptotic cardiomyopathy; Fibrotic hypertrophy; Insulin resistance; Lipidomics; Metabolic syndrome