High-fat diet-induced juvenile obesity leads to cardiomyocyte dysfunction and upregulation of Foxo3a transcription factor independent of lipotoxicity and apoptosis.
BACKGROUND
Obesity is associated with dyslipidemia, which leads to elevated triglyceride and ceramide levels, apoptosis and compromised cardiac function.


METHODS
To determine the role of high-fat diet-induced obesity on cardiomyocyte function, weanling male Sprague-Dawley rats were fed diets incorporating 10% of kcal or 45% of kcal from fat. Mechanical function of ventricular myocytes was evaluated including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocity of shortening and relengthening (+/- dl/dt). Intracellular Ca properties were assessed using fluorescent microscopy.


RESULTS
High-fat diet induced hyperinsulinemic insulin-resistant obesity with depressed PS, +/- dl/dt, prolonged TPS/TR90 reduced intracellular Ca release and Ca clearing rate in the absence of hypertension, diabetes, lipotoxicity and apoptosis. Myocyte responsiveness to increased stimulus frequency and extracellular Ca was compromised. SERCA2a and phospholamban levels were increased, whereas phosphorylated phospholamban and potassium channel (Kv1,2) were reduced in high-fat diet group. High-fat diet upregulated the forkhead transcription factor Foxo3a, and suppressed mitochondrial aconitase activity without affecting expression of the caloric sensitive gene silent information regulator 2 (Sir2), protein nitrotyrosine formation, lipid peroxidation and apoptosis. Levels of endothelial nitric oxide synthase (NOS), inducible NOS, triglycerides and ceramide were similar between the two groups.


CONCLUSIONS
Collectively, our data show that high-fat diet-induced obesity resulted in impaired cardiomyocyte function, upregulated Foxo3a transcription factor and mitochondrial damage without overt lipotoxicity or apoptosis.
Relling
David P
DP
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North Dakota, USA.
Esberg
Lucy B
LB
Fang
Cindy X
CX
Johnson
W Thomas
WT
Murphy
Eric J
EJ
Carlson
Edward C
EC
Saari
Jack T
JT
Ren
Jun
J
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D032383:Myocytes, Cardiac / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D000099211:Phospholamban
D000154:Aconitate Hydratase; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002518:Ceramides; D004041:Dietary Fats; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D019001:Nitric Oxide Synthase; D024642:Potassium Channels, Voltage-Gated; D050796:STAT3 Transcription Factor; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D056564:Sirtuin 1; D037761:Sirtuins; D014280:Triglycerides; D014443:Tyrosine; D000099211:Phospholamban; C499517:FOXO3 protein, human; C002744:3-nitrotyrosine; C488368:Sirt1 protein, rat