title: Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin.
abstract: OBJECTIVE
  Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state.
  
  
  METHODS
  Adult male C57BL/6J, apelin knock-out (KO) or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure, mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses.
  
  
  RESULTS
  In HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P<0.05), accelerated glucose oxidation (P<0.05) and mitochondrial damage. Treatment of HFD-fed mice with apelin for 4 weeks prevented pressure overload-induced decline in FA metabolism (P<0.05) and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose (P<0.01), improved glucose tolerance (P<0.05) and preserved cardiac function (P<0.05) in HFD-fed mice subjected to pressure overload. In apelin KO HFD-fed mice, spontaneous cardiac dysfunction is associated with reduced FA oxidation (P<0.001) and increased glucose oxidation (P<0.05). In isolated cardiomyocytes, apelin stimulated FA oxidation in a dose-dependent manner and this effect was prevented by small interfering RNA sirtuin 3 knockdown.
  
  
  CONCLUSIONS
  These data suggest that obesity-related decline in cardiac function is associated with defective myocardial energy metabolism and mitochondrial abnormalities. Furthermore, our work points for therapeutic potential of apelin to prevent myocardial metabolic abnormalities in heart failure paired with obesity.
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Alfarano
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Foussal
authors.affiliation: National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France.
authors.forename: O
authors.initials: O
authors.lastname: Lairez
authors.affiliation: 1] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France [2] US006, Microsurgery Services, Toulouse, France.
authors.forename: D
authors.initials: D
authors.lastname: Calise
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Attané
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: R
authors.initials: R
authors.lastname: Anesia
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: D
authors.initials: D
authors.lastname: Daviaud
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: E
authors.initials: E
authors.lastname: Wanecq
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: A
authors.initials: A
authors.lastname: Parini
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: P
authors.initials: P
authors.lastname: Valet
authors.affiliation: 1] National Institute of Health and Medical Research (INSERM) U1048, Toulouse, France [2] University of Toulouse, UPS, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
authors.forename: O
authors.initials: O
authors.lastname: Kunduzova
mesh_terms: D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D000073861:Apelin; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009765:Obesity / Q000473:pathology*; D010084:Oxidation-Reduction
chemical_list: D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D036341:Intercellular Signaling Peptides and Proteins