PGC-1 coactivators: inducible regulators of energy metabolism in health and disease

TLDR: This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.

Abstract: Members of the nuclear receptor (NR) superfamily relay physiologic and nutritional cues to critical gene regulatory responses. The molecular links between external stimuli, cellular signaling events, and NR-mediated transcriptional control are currently being unraveled. New information emerging over the past decade has demonstrated that NRs receive regulatory input through multiple mechanisms including levels of endogenous ligand, availability of heterodimeric NR partners, and posttranslational modifications. Activating signals trigger the recruitment of coactivator complexes onto the NR platform, leading to enzymatic modification of chromatin, increased access of the RNA polymerase II machinery to RNA, and activation of target gene transcription (Figure ​(Figure1).1). Availability of certain coactivator proteins also serves critical regulatory functions linking physiologic stimuli to NR activity. Perhaps the best example of this latter mechanism involves the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators. PGC-1 coactivators serve as inducible NR “boosters” to equip the organism to meet the energy demands of diverse physiologic and dietary conditions. This Review will focus on the role of this interesting coactivator family in the control of organ-specific biologic responses to the physiologic and pathophysiologic milieu. Emphasis will be given to tissue-specific regulatory features relevant to heart failure and diabetes. Figure 1 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 ...