Adopting new orphans into the family of metabolic regulators

Abstract

The importance of the adopted metabolite receptors, such as peroxisome proliferator-activated receptor, liver X receptor, and farnesoid X receptor, in transcriptional control of metabolic pathways has been appreciated for many years. However, it is becoming increasingly clear that the number of nuclear receptors with roles in metabolism is much larger than initially suspected. Recent years have brought an intense effort to define the biological functions of the most enigmatic group of the nuclear receptor superfamily, the true orphan receptors, including nuclear receptor 4As, estrogen-related receptors, retinoid-related orphan receptors, and Rev-erbs. Unexpectedly, several of these receptors also turn out to have important functions in various aspects of metabolic control.

Figure 1

Differential Cofactor Recruitment by ERRs %Members of the estrogen receptor-related family of nuclear receptors regulate metabolism in a tissue-specific manner, likely due to specific cofactor interactions. A, ERRα and ERRγ recruit PGC-1α to target gene promoters in slow-twitch skeletal muscle to induce genes involved in fatty acid oxidation and mitochondrial function. B, ERRα and ERRγ interact with RIP140, a corepressor that reduces expression of factors with negative affects on triglyceride storage. This interaction potentially explains the reduced body fat and decreased lipogenesis seen in ERRα −/− mice.

Figure 2

Extracellular Signals Regulate NR4 Receptor Levels and Activity %Expression of members of the NR4 family of nuclear receptors is induced by a variety of stimuli that activate sympathetic signaling to regulate glucose metabolism in liver and fast-twitch skeletal muscle. β-AR, β-Andrenergic receptor.

Figure 3

Rev-erbs and RORs Link Circadean Rhythms and Metabolisms %The Ror and Rev-erb families of nuclear receptors regulate clock genes and metabolic targets in a reciprocal manner.