Insulin-Resistant Heart Exhibits a Mitochondrial Biogenic Response Driven by the Peroxisome Proliferator-Activated Receptor-α/PGC-1α Gene Regulatory Pathway

Abstract

Background-Obesity and diabetes mellitus are complex metabolic problems of pandemic proportion, contributing to significant cardiovascular mortality. Recent studies have shown altered mitochondrial function in the hearts of diabetic animals. We hypothesized that regulatory events involved in the control of mitochondrial function are activated in the prediabetic, insulin-resistant stage. Methods and Results-Morphometric analyses demonstrated that cardiac myocyte mitochondrial volume density was increased in insulin-resistant uncoupling protein-diptheria toxin A (UCP-DTA) transgenic mice, a murine model of metabolic syndrome, compared with littermate controls. Mitochondrial DNA content and expression of genes involved in multiple mitochondrial pathways were also increased in insulin-resistant UCP-DTA hearts. The nuclear receptor, peroxisome proliferator-activated receptor-␣ (PPAR␣), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPAR␣ in the observed mitochondrial biogenesis response in the insulin-resistant heart. Insulin-resistant UCP-DTA mice crossed into a PPAR␣-null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPAR␣ exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPAR␣-driven mitochondrial biogenic response revealed that expression of PPAR␥ coactivator-1␣ (PGC-1␣), a known regulator of mitochondrial biogenesis, was activated in wild-type UCP-DTA mice but not in PPAR␣-deficient UCP-DTA mice. Conclusions-These

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…2005, 2015) and has been linked to the activation of PPAR α and its coactivator PGC1 α (Duncan et al. 2007; Finck et al. 2002; Wright et al.…”

“…The upregulation of PPAR α and PGC1 α seen in our study confirms observations by Duncan et al. (2007) and drives the transcription of genes involved in fatty acid metabolism (such as CD36, CPT1, MCAD) in order to cope with excess provision of lipids from the circulation, and of PDK4 (Wende et al. 2005), which further suppresses glucose oxidation by decreasing PDH activity (Wu et al.…”

Peroxisome Proliferator–Activated Receptor γ Coactivator-1 (PGC-1) Regulatory Cascade in Cardiac Physiology and Disease

“…50,51 For example, myocardial PGC-1␣ is induced in response to acute food deprivation 51 and diabetes mellitus, 70,87 when the myocardium switches to the preferential utilization of fatty acids. In addition, cardiac (A. Wende and D. Kelly, unpublished data, 2005) and skeletal muscle [57][58][59] PGC-1␣ expression is activated by exercise training, a physiological stimulus wherein both fatty acid and glucose utilization is increased to meet the heightened demand for ATP synthesis.…”

The Krebs Cycle and Mitochondrial Mass Are Early Victims of Endothelial Dysfunction

“…Mitochondrial DNA (mtDNA) content was quantified by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on isolated vessels according to the modified protocols of Duncan et al 14 Briefly, mtDNA was extracted from the kidney microvasculature and real-time RT-PCR was performed using the Stratagen MX 3000 as previously reported. 15 Three different mtDNA sequences were assayed.…”