title: Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling.
abstract: BACKGROUND
  Cardiomyopathy 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.
  
  
  METHODS
  Cardiac 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  We 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.
authors.affiliation: The University of Illinois at Chicago, COMRB 2035, MC 901, 835 South Wolcott Ave., Chicago, IL, 60612-7352, USA. nrober2@uic.edu.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Roberts
authors.affiliation: The University of Illinois at Chicago, COMRB 2035, MC 901, 835 South Wolcott Ave., Chicago, IL, 60612-7352, USA. mgonza92@uic.edu.
authors.forename: Magdalis
authors.initials: M
authors.lastname: González-Vega
authors.affiliation: The University of Illinois at Chicago, COMRB 2035, MC 901, 835 South Wolcott Ave., Chicago, IL, 60612-7352, USA. tirsitb@gmail.com.
authors.forename: Tirsit K
authors.initials: TK
authors.lastname: Berhanu
authors.affiliation: The University of Illinois at Chicago, COMRB 2035, MC 901, 835 South Wolcott Ave., Chicago, IL, 60612-7352, USA. assembler10@yahoo.com.
authors.forename: Aaron
authors.initials: A
authors.lastname: Mull
authors.affiliation: The University of Illinois at Chicago, COMRB 2035, MC 901, 835 South Wolcott Ave., Chicago, IL, 60612-7352, USA. garmar@uic.edu.|The Center for Cardiovascular Research, Chicago, IL, 60612, USA. garmar@uic.edu.
authors.forename: Jesús
authors.initials: J
authors.lastname: García
authors.affiliation: The University of Illinois at Chicago, COMRB 2035, MC 901, 835 South Wolcott Ave., Chicago, IL, 60612-7352, USA. ahlkeh@uic.edu.|The Center for Cardiovascular Research, Chicago, IL, 60612, USA. ahlkeh@uic.edu.
authors.forename: Ahlke
authors.initials: A
authors.lastname: Heydemann
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000222:Adaptation, Physiological; D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004272:DNA, Mitochondrial / Q000378:metabolism; D059305:Diet, High-Fat; D004040:Dietary Carbohydrates / Q000378:metabolism; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D020257:Ventricular Remodeling; D015430:Weight Gain
chemical_list: D004272:DNA, Mitochondrial; D004040:Dietary Carbohydrates; D045222:Electron Transport Chain Complex Proteins; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D006593:Hexokinase; C000598049:hexokinase 2, mouse; D055372:AMP-Activated Protein Kinases