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.

Metabolic imaging of acute and chronic infarction in the perfused rat heart using hyperpolarised [1‐13C]pyruvate

“…The time-course data produced were subsequently fitted to a sigmoidal function to allow the calculation of the signal increase observed on addition of gadolinium. 31 P spectra were processed and quantified using jMRUI (45).…”

“…The isolated perfused rat heart (28) is ideal for the assessment of both physiological and pathological metabolism (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). It can be studied independent of hormonal and neuronal influences present in vivo, making causal changes in disease easier to determine.…”

“…In all infarcted hearts, DNP-CSI data were used to generate crosssectional maps of pyruvate, lactate and bicarbonate, which were compared with those from control perfused hearts. In addition, MR images acquired during the first pass of a gadolinium contrast agent were used to assess myocardial perfusion (44), and 31 P MRS was used to examine myocardial energetics (45). Histological assessment was performed following imaging in the chronically infarcted hearts to confirm the presence of scar in the region of infarction (46,47).…”

The Partial Replacement of Lard by Caryocar brasiliense Oil in a Western Diet improves Cardiovascular Risk Factors in Rats

“…This could be explained because western diets suppress cardiac function overall and, in this situation, maybe there is a depression of the sinus node pacemaker activity [53].…”

Myocardial substrate metabolism in obesity

“…This decreases the potential difference between matrix and inter-mitochondrial membrane space, and therefore DG 0 ATP . Raised FFAs also increase the expression of uncoupling proteins, 54 which decrease mitochondrial efficiency 43 by allowing the passage of protons into the matrix via non-ATPgenerating pathways. Indeed, when the heart is perfused with increasing concentrations of FFAs, this results in an additional oxygen cost of between 25 and 48% for the same work output when compared with glucose and insulin infusion.…”