Transcriptional Control of Energy Homeostasis by the Estrogen-Related Receptors

Abstract

Transcriptional control of cellular energy metabolic pathways is achieved by the coordinated action of numerous transcription factors and associated coregulators. Several members of the nuclear receptor superfamily have been shown to play important roles in this process because they can translate hormonal, nutrient, and metabolite signals into specific gene expression networks to satisfy energy demands in response to distinct physiological cues. Estrogen-related receptor (ERR) alpha, ERRbeta, and ERRgamma are nuclear receptors that have yet to be associated with a natural ligand and are thus considered as orphan receptors. However, the transcriptional activity of the ERRs is exquisitely sensitive to the presence of coregulatory proteins known to be essential for the control of energy homeostasis, and for all intents and purposes, these coregulators function as protein ligands for the ERRs. In particular, functional genomics and biochemical studies have shown that ERRalpha and ERRgamma operate as the primary conduits for the activity of members of the family of PGC-1 coactivators. As transcription factors, the ERRs control vast gene networks involved in all aspects of energy homeostasis, including fat and glucose metabolism as well as mitochondrial biogenesis and function. Phenotypic analyses of knockout mouse models have shown that all three ERRs are indispensable for proper development and/or survival of the organism when subjected to a variety of physiological challenges. The focus of this review is on the recent and rapid advances in understanding the functions of the ERRs in regulating bioenergetic pathways, with an emphasis on their roles in the specification of energetic properties required for cell- and tissue-specific functions.

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

“…In immunity, ERRα −/− mice exhibit increased susceptibility to Listeria monocytogenes infection (23). Although not previously investigated in lymphocytes, these findings suggest ERRα may regulate genes that contribute to lymphocyte metabolism and activation (20,21).…”

“…The orphan nuclear hormone receptor, estrogen-related receptor-α (ERRα), is associated with poor prognosis (16,17) and tumor growth in breast cancer (18,19). ERRα is also known to regulate cell metabolism (20,21) and Drosophila ERR can promote gene expression to drive carbohydrate metabolism associated with proliferating cells in larval development (22). In immunity, ERRα −/− mice exhibit increased susceptibility to Listeria monocytogenes infection (23).…”

Neuropeptide Y mediates the short-term hypometabolic effect of estrogen deficiency in mice

“…37 We showed that NPY deficiency per se significantly increased brown adipose tissue weight, with no significant effect of OVX in mice of either genotype ( Figure 2a). There was no significant effect of OVX on UCP-1 or PGC1a (c) Dual-energy X-ray absorptiometry (DXA) scans at 18 and 54 days post surgery, referred to as 'short-term' and 'long-term' time-points, respectively, reveal that OVX-induced increases in whole-body fat mass in both genotypes occur only after long-term estrogen deficiency, with NPY À / À mice exhibiting a reduction in fat mass after short-term estrogen deficiency.…”

Glycolytic genes are targets of the nuclear receptor Ad4BP/SF-1

“…Therefore, the two nuclear receptors seem to regulate most glycolytic genes by binding to the same genetic loci. However, considering that Ad4BP/SF-1 is expressed only in endocrine tissues, for example, the adrenal cortex and gonads 3,10 , whereas ERRa is expressed in a broad range of tissues 48 , the contribution of these two nuclear receptors to glycolytic gene regulation likely varies among tissues.…”