title: Macrophage migration inhibitory factor inhibition is deleterious for high-fat diet-induced cardiac dysfunction.
abstract: OBJECTIVE
  Development of metabolic syndrome is associated with impaired cardiac performance, mitochondrial dysfunction and pro-inflammatory cytokine increase, such as the macrophage migration inhibitory factor MIF. Depending on conditions, MIF may exert both beneficial and deleterious effects on the myocardium. Therefore, we tested whether pharmacological inhibition of MIF prevented or worsened metabolic syndrome-induced myocardial dysfunction.
  
  
  RESULTS
  C57BL/6J mice were fed for ten weeks with 60% fat-enriched diet (HFD) or normal diet (ND). MIF inhibition was obtained by injecting mice twice a week with ISO-1, for three consecutive weeks. Then, triglycerides, cholesterol, fat mass, glucose intolerance, insulin resistance, ex vivo cardiac contractility, animal energetic substrate utilization assessed by indirect calorimetry and mitochondrial respiration and biogenesis were evaluated. HFD led to fat mass increase, dyslipidemia, glucose intolerance and insulin resistance. ISO-1 did not alter these parameters. However, MIF inhibition was responsible for HFD-induced cardiac dysfunction worsening. Mouse capacity to increase oxygen consumption in response to exercise was reduced in HFD compared to ND, and further diminished in ISO-1-treated HFD group. Mitochondrial respiration was reduced in HFD mice, treated or not with ISO-1. Compared to ND, mitochondrial biogenesis signaling was upregulated in the HFD as demonstrated by mitochondrial DNA amount and PGC-1α expression. However, this increase in biogenesis was blocked by ISO-1 treatment.
  
  
  CONCLUSIONS
  MIF inhibition achieved by ISO-1 was responsible for a reduction in HFD-induced mitochondrial biogenesis signaling that could explain majored cardiac dysfunction observed in HFD mice treated with MIF inhibitor.
authors.affiliation: EA4484, Physiology Department, Lille 2 University, Lille, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Palud
authors.forename: Camille
authors.initials: C
authors.lastname: Marciniak
authors.forename: David
authors.initials: D
authors.lastname: Montaigne
authors.forename: Xavier
authors.initials: X
authors.lastname: Marechal
authors.forename: Caroline
authors.initials: C
authors.lastname: Ballot
authors.forename: Sidi Mohamed
authors.initials: SM
authors.lastname: Hassoun
authors.forename: Brigitte
authors.initials: B
authors.lastname: Decoster
authors.forename: Remi
authors.initials: R
authors.lastname: Neviere
authors.forename: Steve
authors.initials: S
authors.lastname: Lancel
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D009202:Cardiomyopathies / Q000209:etiology* / Q000503:physiopathology*; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications* / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects
chemical_list: C462499:3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D007555:Isoxazoles; D008263:Macrophage Migration-Inhibitory Factors; D005947:Glucose
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