title: A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart.
abstract: Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, UK. mark.cole@dpag.ox.ac.uk
authors.forename: Mark A
authors.initials: MA
authors.lastname: Cole
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murray
authors.forename: Lowri E
authors.initials: LE
authors.lastname: Cochlin
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Heather
authors.forename: Sara
authors.initials: S
authors.lastname: McAleese
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Knight
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sutton
authors.forename: Amira Abd
authors.initials: AA
authors.lastname: Jamil
authors.forename: Nadege
authors.initials: N
authors.lastname: Parassol
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
mesh_terms: D000818:Animals; D004032:Diet / Q000009:adverse effects*; D005227:Fatty Acids / Q000009:adverse effects; D015151:Immunoblotting; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction / Q000187:drug effects; D010101:Oxygen Consumption / Q000502:physiology; D010170:Palmitoyl-CoA Hydrolase; D051381:Rats; D017208:Rats, Wistar; D013869:Thiolester Hydrolases / Q000378:metabolism; D000071247:Uncoupling Protein 3
chemical_list: D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604393:Ucp3 protein, mouse; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D013869:Thiolester Hydrolases; C546434:Acot2 protein, rat; D010170:Palmitoyl-CoA Hydrolase