Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling

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.

An Overview of Murine High Fat Diet as a Model for Type 2 Diabetes Mellitus

“…However, after chronic HFD mice and individuals become metabolically inflexible [ 79 ]. For example, cardiac tissue often responds to HFD by increasing its carbohydrate utilizing proteins to extract as much energy from glucose as possible [ 16 , 18 ]. However when the diet then switches to a normal diet the heart draws too many calories from glucose causing a pathologic excessive caloric intake [ 41 ].…”

“…The gold standard is perhaps by electron microscopy so that lipid droplet location can also be determined. Lipid droplets in the mitochondria [ 12 , 16 ] versus cytoplasmically located [ 102 ] would reveal specific pathologic mechanisms. Inflammation and specific cells of the invading immune system can be measured by histology or flow cytometry.…”

“…Alternatively, other investigators have identified pathologies within shorter HFD protocols. For example, in a 12-week HFD study we identified cardiomyocyte hypertrophy, unsuccessful metabolic adaptations, and lipid droplet accumulation [ 16 ]. These results indicate that caution must be used when designing HFD experiments, especially for diabetic cardiomyopathy assessments.…”

Enhanced cartilage repair in ‘healer’ mice—New leads in the search for better clinical options for cartilage repair

“…Collectively, these studies suggest that MRL/MpJ mice have an intrinsic ability to bypass the normal fibrotic ‘repair’ response and instead implement a more ‘regenerative’ program of tissue restoration. Enhanced healing has been extended beyond directed tissue damage with the recent finding that MRL/MpJ mice are also resistant to high fat diet-induced metabolic changes, including type-2 diabetes [45] and cardiac remodeling [46]. However, it is important to note that not all injuries heal better in the MRL/MpJ strain.…”

Paeoniflorin protects diabetic mice against myocardial ischemic injury via the transient receptor potential vanilloid 1/calcitonin gene-related peptide pathway

“…Diabetes mellitus (DM) has become a global problem that threatens human health [ 1 , 2 ]. DM is characterized by increased plasma glucose levels and is often accompanied by several complications including microangiopathy, neuropathy and mobilopathy, which lead to high morbidity and mortality [ 3 – 5 ].…”