Insulin signaling in the hearts of uncoupling protein three knockout mice on a high fat diet
INTRODUCTION: People with diabetes are at high risk for cardiovascular disease; which is the major cause of death in diabetics. Current research suggests that excessive mitochondrial uncoupling is a potential mechanism for cardiac dysfunction in diabetic patients. Uncoupling protein 3 (UCP3) is an inner mitochondrial membrane protein that reduces the amount of reactive oxygen species (ROS) produced in the mitochondrial matrix by uncoupling the mitochondria. Mice lacking UCP3 (UCP3KO) have been shown to accumulate ROS and diacylglycerol in cardiac muscle. These two molecules have been shown to induce insulin resistance in skeletal muscle. The goal of my project was to determine if the absence of UCP3 in the heart will exacerbate diet-induced insulin resistance in the murine heart. MATERIALS AND METHODS: Whole heart homogenates were extracted from four groups of mice: (1) wild type (WT) fed normal chow (NC); (2) WT fed a high fat diet for 10 weeks (HF); (3) UCP3KO NC and (4) UCP3KO HF. Insulin signaling was examined using western-blotting to assess the phosphorylation status of key components of the insulin signaling pathway under non insulin and insulin-stimulated conditions in each group. Values form each group were analyzed using an ANOVA followed by a t test to determine any statistical significant differences between the groups. RESULTS: Phosphorylation of protein kinase B (Akt) (at serine 473 or threonine 308) and the downstream target glycogen synthase kinase 3 p at serine 9 was the same between all the groups. CONCLUSIONS: two major conclusions arise from this work; ( 1 ) 1 0 weeks of high fat diet does not affect insulin signaling in the heart and (2) despite increased ROS and DAG levels in the hearts of UCP3KO mice, insulin sensitivity was maintained. We speculate that UCP3KO mice have developed compensatory mechanisms that prevented the development of insulin resistance despite accumulation of compounds known to induce insulin resistance. These mechanisms remain to be determined in future studies.
University of Utah;
University of Utah;
Relation-Is Version Of
Digital reproduction of “Insulin signaling in the hearts of uncoupling protein three knockout mice on a high fat diet” J. Willard Marriott Library Special Collections QP6.5 2009 .T53