Endocrine Abstracts

We have previously shown that the PGC-1 transcriptional coactivators are major regulators of several crucial aspects of energy metabolism. PGC-1alpha controls many aspects of oxidative metabolism, including mitochondrial biogenesis and respiration through the coactivation of many nuclear receptors, and factors outside the nuclear receptor family. ERRalpha NRF-1 and NRF-2 are key targets of the PGC-1s in mitochodrial biogenesis. We have recently addressed the question of the role of PGC-1 coactivators in the metabolism of reactive oxygen species (ROS). Since these factors are very powerful inducers of mitochondrial biogenesis and respiration, it might have been expected that they could increase ROS formation. We now show that PGC-1alpha and beta are induced when cells are given an oxidative stressor, H2O2. In fact, experiments with RNAi for the PGC-1s show that the ability of ROS to induce and ROS scavenging program depends entirely on the PGC-1s. This includes genes encoding mitochondrial proteins like SOD2, but also includes cytoplasmic proteins like catalase and GPX1. Cells lacking PGC1alpha are hypersensitive to death from oxidative stress caused by H2O2 or paraquat. Using mice deficient in PGC-1alpha, we have studied their resistance to oxidative challenges. The mice get excessive neurodegeneration when given kainic-acid induced seizures or MPTP, which causes Parkinsonism. These data show that the PGC-1s are important protective molecules against ROS generation and damage. The implications of this for diabetes and neurodegenerative diseases will be discussed.

PGC-1alpha controls the thermogenic gene program in brown fat, but we have now re-investigated factors that may control the determination of cell fate in the brown adipose lineage. We will discuss data showing that PRDM16 is a crucial factor controlling brown fat cell fate, including the ability to induce PGC-1alpha and UCP1. The implications of this for metabolic disease will be discussed.