Abstract
BackgroundCardiomyopathy is a devastating complication of obesity and type 2 diabetes mellitus (T2DM). It arises even in patients with normoglycemia (glycosylated hemoglobin, A1C ≤7 %). As obesity and T2DM are approaching epidemic levels worldwide, the cardiomyopathy associated with these diseases must be therapeutically addressed. We have recently analyzed the systemic effects of a 12-week high fat diet (HFD) on wild type mice from the C57Bl/6 (B6) strain and the wild type super-healing Murphy Roths Large (MRL) mouse strain. The MRL HFD mice gained significantly more weight than their control diet counterparts, but did not present any of the other usual systemic T2DM phenotypes.MethodsCardiac pathology and adaptation to HFD-induced obesity in the MRL mouse strain compared to the HFD C57Bl/6 mice were thoroughly analyzed with echocardiography, histology, qPCR, electron microscopy and immunoblots.ResultsThe obese HFD C57Bl/6 mice develop cardiac hypertrophy, cardiomyocyte lipid droplets, and initiate an ineffective metabolic adaptation of an overall increase in electron transport chain complexes. In contrast, the obese HFD MRL hearts do not display hypertrophy nor lipid droplets and their metabolism adapts quite robustly by decreasing pAMPK levels, decreasing proteins in the carbohydrate metabolism pathway and increasing proteins utilized in the β-oxidation pathway. The result of these metabolic shifts is the reduction of toxic lipid deposits and reactive oxygen species in the hearts of the obese HFD fed MRL hearts.ConclusionsWe have identified changes in metabolic signaling in obese HFD fed MRL mice that confer resistance to diabetic cardiomyopathy. The changes include a reduction of cardiac pAMPK, Glut4 and hexokinase2 in the MRL HFD hearts. Overall the MRL hearts down regulate glucose metabolism and favor lipid metabolism. These adaptations are essential to pursue for the identification of novel therapeutic targets to combat obesity related cardiomyopathy.
Highlights
Cardiomyopathy is a devastating complication of obesity and type 2 diabetes mellitus (T2DM)
We subjected the Murphy Roths Large (MRL) and control C57Bl/6 mouse strain (B6) mouse strains to 12 weeks of high fat diet (HFD) or control diet (CD) to investigate the abilities of the MRL mouse hearts to metabolically adapt to HFD
Because the HFD mouse model mirrors human T2DM, identifying and investigating these beneficial metabolic changes will be essential for future diabetic cardiomyopathy (DCM) therapies
Summary
Cardiomyopathy is a devastating complication of obesity and type 2 diabetes mellitus (T2DM). It arises even in patients with normoglycemia (glycosylated hemoglobin, A1C ≤7 %). We have recently analyzed the systemic effects of a 12-week high fat diet (HFD) on wild type mice from the C57Bl/6 (B6) strain and the wild type super-healing Murphy Roths Large (MRL) mouse strain. The MRL HFD mice gained sig‐ nificantly more weight than their control diet counterparts, but did not present any of the other usual systemic T2DM phenotypes. High fat diet (HFD)-fed mice recapitulate the etiology, pathology, and response to treatments to those of T2DM patients. HFD-fed C57Bl/6 (B6) mice gain weight, develop insulin resistance, hyperglycemia, and DCM just like patients do. Because MRL mice are globally resistant to HFD pathologies [9], we wanted to determine whether MRL mice develop cardiomyopathy from HFD-induced obesity and possible compensatory protective mechanisms if they did not
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