ERRγ Directs and Maintains the Transition to Oxidative Metabolism in the Postnatal Heart

Abstract

At birth, the heart undergoes a critical metabolic switch from a predominant dependence on carbohydrates during fetal life to a greater dependence on postnatal oxidative metabolism. This remains the principle metabolic state throughout life, although pathologic conditions such as heart failure and cardiac hypertrophy reactivate components of the fetal genetic program to increase carbohydrate utilization. Disruption of the ERRgamma gene (Esrrg), which is expressed at high levels in the fetal and postnatal mouse heart, blocks this switch, resulting in lactatemia, electrocardiographic abnormalities, and death during the first week of life. Genomic ChIP-on-chip and expression analysis identifies ERRgamma as both a direct and an indirect regulator of a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition. These findings reveal an unexpected and essential molecular genetic component of the oxidative metabolic gene program in the heart and highlight ERRgamma in the study of cardiac hypertrophy and failure.

Nuclear receptors, mitochondria and lipid metabolism

“…(Puigserver et al 1998;Herzig et al 2001;Lin et al 2002;Puigserver et al 2003;Rhee et al 2003;Arany et al 2005;St-Pierre et al 2006;Handschin et al 2007). While named for its interaction with PPARγ, many of these PGC-1-dependent adaptations appear to be largely dependent on ERRs and other metabolic transcription factors that are independent of PPAR/RXR Rhee et al 2003;Schilling et al 2006;Alaynick et al 2007;Huss et al 2007;Villena et al 2007). …”

GADD45γ regulates the thermogenic capacity of brown adipose tissue

“…BAT also expresses the ERRα-related receptors ERRβ and ERRγ, which can activate similar genes as ERRα and have been implicated in the transcriptional control of oxidative genes and Ucp1 (13)(14)(15)(16). Interestingly, ERRβ and ERRγ can activate their target genes in the absence of PGC-1 regulators (15,17), suggesting that they may provide an alternate pathway to induce thermogenic capacity in response to cold.…”

Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

“…In the last few years, there has been progress in beginning to elucidate ERR functions, which include regulating bone formation [2,3, 15,16] and mitochondrial biogenesis [16][17][18].…”