The PGC-1 coactivator family: inducible boosters of gene transcription. (A) The schematic uses generic NRs as an example of how inducible PGC-1 coactivators dock to transcription factor targets and recruit protein complexes that activate transcription via either enzymatic modification of chromatin, such as histone acetylation (e.g., by steroid receptor coactivator-1 [SRC-1] or p300), or direct interaction with the transcription initiation machinery (e.g., the thyroid hormone receptor–associated protein/vitamin D receptor–interacting protein [TRAP/DRIP] coactivator complex). The NR binds cognate NR response elements (NRREs) within the promoter region of the target gene. Specific histone modifications, including acetylation (Ac) and methylation (Me), are shown, as is the RNA polymerase II (Pol II) complex. (B) The schematic depicts the relative length and shared domains of the 3 members of the PGC-1 coactivator family. The nature of the domains is indicated in the key. (C) A schematic of the PGC-1α molecule is shown to denote several key functional domains involved in the interaction with specific target transcription factors including NRs, nuclear respiratory factor-1 (NRF-1), MEF-2, and FOXO1. MAPK phosphorylation (P) sites are also shown.

Potential contributions of organ-specific dysregulation of PGC-1α to the development of insulin resistance and type 2 diabetes. (A) PGC-1α expression and activity have been shown to be increased in the liver and pancreatic β cell in several animal models of diabetes mellitus. Conversely, gene expression profiling indicates that PGC-1α expression is diminished in skeletal muscle of type 1 and 2 diabetic humans along with reduced expression of genes involved in oxidative phosphorylation (OXPHOS). This tissue-specific pattern of dysregulated PGC-1α activity is predicted to potentially contribute to systemic insulin resistance, glucose intolerance, and insulin deficiency. (B) The generalized PGC-1α–deficient mouse is relatively protected against diet-induced insulin resistance and glucose intolerance despite impairments in skeletal muscle OXPHOS capacity. Improved insulin sensitivity may stem from diminished hepatic glucose production, a principal constituent of whole-body glucose homeostasis. However, the relative contribution of individual organ systems to the systemic insulin-sensitive phenotype requires further investigation.

The PGC-1 gene regulatory cascade. The schematic indicates the upstream signaling events and downstream gene regulatory actions of the inducible PGC-1 coactivators, using PGC-1α as the representative factor. The interaction of PGC-1α with its cognate transcription factor targets is shown linked to specific organ systems. For example, PGC-1α coactivates members of the PPAR nuclear receptor transcription factor family, to activate the expression of genes involved in mitochondrial fatty acid oxidation. The signaling pathways shown at the top of each organ system transduce extracellular physiologic and nutritional stimuli to the expression and/or activity of PGC-1α. LXR, liver X receptor; TAG, triacylglycerol; RXR, retinoid X receptor; mtDNA, mitochondrial DNA; OXPHOS, oxidative phosphorylation.