Patients with insulin resistance and type 2 diabetes have poor cardiac outcomes following myocardial infarction (MI). The mitochondrial uncoupling protein 3 (UCP3) is down-regulated in the heart with insulin resistance. We hypothesized that decreased UCP3 levels contribute to poor cardiac recovery following ischemia/reperfusion (I/R). After confirming that myocardial UCP3 levels were systematically decreased by 20–49% in animal models of insulin resistance and type 2 diabetes, we genetically engineered Sprague–Dawley rats with partial loss of UCP3 (ucp3+/−). Wild-type littermates (ucp3+/+) were used as controls. Isolated working hearts from ucp3+/− rats were characterized by impaired recovery of cardiac power and decreased long-chain fatty acid (LCFA) oxidation following I/R. Mitochondria isolated from ucp3+/− hearts subjected to I/R in vivo displayed increased reactive oxygen species (ROS) generation and decreased respiratory complex I activity. Supplying ucp3+/− cardiac mitochondria with the medium-chain fatty acid (MCFA) octanoate slowed electron transport through the respiratory chain and reduced ROS generation. This was accompanied by improvement of cardiac LCFA oxidation and recovery of contractile function post ischemia. In conclusion, we demonstrated that normal cardiac UCP3 levels are essential to recovery of LCFA oxidation, mitochondrial respiratory capacity, and contractile function following I/R. These results reveal a potential mechanism for the poor prognosis of type 2 diabetic patients following MI and expose MCFA supplementation as a feasible metabolic intervention to improve recovery of these patients at reperfusion.Electronic supplementary materialThe online version of this article (10.1007/s00395-018-0707-9) contains supplementary material, which is available to authorized users.

Objective Uncoupling protein 3 (UCP3) is a mitochondrial carrier related to fatty acid metabolism. Although gene variants of UCP3 are associated with human obesity, their contribution to increased adiposity remains unclear. This study investigated the impact that loss of UCP3 has on diet‐induced obesity in rats. Methods Male UCP3 knockout rats (ucp3−/−) and wild‐type littermates (ucp3+/+) were fed a high‐fat, high‐carbohydrate Western diet for 21 weeks. Body composition was analyzed by EchoMRI. Whole‐body insulin sensitivity and rates of tissue glucose uptake were determined by using hyperinsulinemic‐euglycemic clamp. Changes in tissue physiology were interrogated by microscopy and RNA sequencing. Results Loss of UCP3 decreased fat mass gain, white adipocytes size, and systemic inflammation. The ucp3−/− rats also exhibited preserved insulin sensitivity and increased glucose uptake in interscapular brown adipose tissue (iBAT). Brown adipocytes from ucp3−/− rats were protected from cellular degeneration caused by lipid accumulation and from reactive oxygen species–induced protein sulfonation. Increased glutathione levels in iBAT from ucp3−/− rats were linked to upregulation of genes encoding enzymes from the transsulfuration pathway in that tissue. Conclusions Loss of UCP3 partially protects rats from diet‐induced obesity. This phenotype is related to induction of a compensatory antioxidant mechanism and prevention of iBAT whitening.

Insulin resistance and diabetes are associated with poor prognosis following myocardial infarction and reperfusion (MI/R). Uncoupling protein 3 is a mitochondrial anion carrier which is down‐regulated by up to 50% in humans and animal models with obesity, insulin resistance, and type 2 diabetes. We previously reported that isolated hearts from Sprague Dawley rats which have been genetically modified to mimic this UCP3 deficiency (ucp3+/−) have poorer recovery of contractile function linked to an impairment of long‐chain fatty acid oxidation when subjected to ischemia/reperfusion. The goal of the present study was to extend these findings by investigating whether UCP3 deficiency similarly affects cardiac recovery in response to MI/R in vivo. Male ucp3+/− rats (n=16) and their wild type ucp3+/+ littermates (n=7) were subjected to 45 min MI by ligation of the left anterior coronary artery. Cardiac structure and function were assessed by echocardiography before surgery and at 2, 14, and 28 days following MI/R. On the 28th day, left ventricular (LV) hemodynamic parameters were measured with a Millar pressure‐volume catheter. Masson's trichrome staining was then performed to measure the infarct size relative to LV area. The mortality rate at 24 hrs post MI/R was higher in ucp3+/− rats (44%) when compared to the ucp3+/+ controls (28%). At day 28 post MI/R, LV ejection fraction (22.6±1.5 vs. 36.6±2.9%), fractional shortening (10.9±0.7 vs. 19.8±1.2%). and LV end‐systolic anterior wall thickness (LVAWs; 1.3±0.1 vs. 2.0±0.1 mm) were all significantly decreased for the ucp3+/− rats. Analysis of LV pressure‐volume loops also revealed greater impairment for −dP/dt min (1898+167 vs. 2832+380 mm Hg s−1), dP/dt max (1956±213 vs. 2981±219 mm Hg s−1), and for the LV relaxation time constant (Tau; 12.6±1.0 vs. 18.7±2.1 ms). The infarct size was also bigger for ucp3+/− rats (52±4 vs. 26±4%). In summary, the results demonstrate that partial UCP3 deficiency is sufficient to impair functional recovery of the heart following MI/R in vivo. Future studies will determine whether the defect can be corrected by implementing therapeutic strategies aiming to improve fatty acid oxidation at reperfusion.Support or Funding InformationThis work was supported by NIH Grants R01HL136438, R00HL112952, P01HL051971, and P20GM104357.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.