The multiple universes of estrogen-related receptor α and γ in metabolic control and related diseases

Abstract

The identification of the estrogen-related receptors (ERRs) as the first orphan nuclear receptors ignited a new era in molecular endocrinology, which led to the discovery of new ligand-dependent response systems. Although ERR subfamily members have yet to be associated with a natural ligand, the characterization of these orphan receptors has demonstrated that they occupy a strategic node in the transcriptional control of cellular energy metabolism. In particular, ERRs are required for the response to various environmental challenges that require high energy levels by the organism. As central regulators of energy homeostasis, ERRs may also be implicated in the etiology of metabolic disorders, such as type 2 diabetes and metabolic syndrome. Here, we review the recent evidence that further highlights the role of ERRs in metabolic control, particularly in liver and skeletal muscle, and their likely involvement in metabolic diseases. Consequently, we also explore the promises and pitfalls of ERRs as potential therapeutic targets.

Figure 1

ERRs are key transcriptional factors that regulate cellular energy metabolism. Through the control of vast transcriptional networks, the ERRs are master regulators of energy metabolism in the cell. Their target genes include several glucose transporters (SLC2A1, SLC2A2, SLC2A4, and SLC2A12, also known as GLUT1, GLUT2, GLUT4, and GLUT12, respectively), most genes in the glycolysis pathway, and several genes that encode different LDH isoforms, which indicate the ERRs are key components in cellular glucose metabolism. By regulating the levels of key gatekeepers (such as PDK4), they also control the switch between glucose and fatty acid oxidation (FAO) by the mitochondria. ERRs are also essential for mitochondrial activity by targeting most genes in the TCA cycle and the electron transport chain (ETC). Recent results indicate that they also play a role in other metabolic functions of the cell, including amino acid and nucleotide synthesis and metabolism, which remain to be fully elucidated. Several examples of the regulated genes are provided for each function, which are based on microarray and ChIP-sequencing analysis in human cell lines and mouse models.

Figure 2

ERRs as pharmacological targets to manage type 2 diabetes. In the skeletal muscles of patients with type 2 diabetes, mitochondrial activity is deficient and cells are less responsive to insulin regarding glucose uptake and usage. Increasing ERR activity using a compound with agonist-like activity would result in increased glucose uptake and usage, as well as increased mitochondrial activity, which would therefore ameliorate insulin signaling in skeletal muscle. In the livers of patients with type 2 diabetes, elevated energy production sustains an increased gluconeogenesis that results in higher blood glucose levels, which leads to hyperglycemia. ERR inhibition would have the benefit of blocking mitochondrial activity, which would therefore reduce the ATP production that feeds gluconeogenesis and restore normal blood glucose levels. This mechanism is similar to metformin, the most prescribed drug for the treatment of type 2 diabetes, which inhibits hepatic mitochondrial activity and gluconeogenesis. In addition, the inhibition of ERRγ activity would also have the advantage of directly blocking gluconeogenesis.