Nuclear Receptor Expression Links the Circadian Clock to Metabolism

Abstract

As sensors for fat-soluble hormones and dietary lipids, oscillations in nuclear receptor (NR) expression in key metabolic tissues may contribute to circadian entrainment of nutrient and energy metabolism. Surveying the diurnal expression profiles of all 49 mouse nuclear receptors in white and brown adipose tissue, liver, and skeletal muscle revealed that of the 45 NRs expressed, 25 are in a rhythmic cycle and 3 exhibit a single transient pulse of expression 4 hr into the light cycle. While thyroid hormones are generally constant, we find that TRalpha and beta dramatically cycle, suggesting that fundamental concepts such as "basal metabolism" may require reexamination. The dynamic but coordinated changes in nuclear receptor expression, along with their key target genes, offers a logical explanation for known cyclic behavior of lipid and glucose metabolism and suggests novel roles for endocrine and orphan receptors in coupling the peripheral circadian clock to divergent metabolic outputs.

Orphan nuclear receptor estrogen-related receptor-β suppresses in vitro and in vivo growth of prostate cancer cells via p21WAF1/CIP1 induction and as a potential therapeutic target in prostate cancer

“…Moreover, ectopic ERRa expression can promote lipid accumulation in primary cardiac myocytes (Huss et al, 2004), whereas its loss of function reduces body fat in ERRa-knockout mouse (Luo et al, 2003). In a recent expression profiling study of all 49 NRs in mouse tissues, ERRb is shown to be widely and rhythmically expressed in many organ systems, suggesting that ERRb together with other NRs are important in maintaining global basal metabolism under circadian control Yang et al, 2006). Taken together, our present data provide indirect evidence that ERRb may be involved in energy metabolism and mitochondrial biogenesis, similar to its close relative ERRa.…”

PPARs Integrate the Mammalian Clock and Energy Metabolism

“…The expression of PPAR α has a diurnal rhythm in mouse liver, heart, kidney, and, to a lesser extent, in the SCN [25, 29]. This circadian pattern might be partially controlled by some hormonal factors, such as glucocorticoids and insulin, whose secretions display diurnal variations [29, 30].…”

“…Agonists of PPAR γ rosiglitazone and pioglitazone have been widely used for many years for treating type 2 diabetes, owing to their effectiveness in promoting insulin sensitivity. Recently, PPAR γ was shown to exhibit a remarkable circadian expression pattern in mouse liver, fat, and blood vessels [25, 28]. Global deletion of PPAR γ in mice abolished or dampened circadian rhythms at both behavioral and cellular levels [43].…”

“…Despite accumulating evidence supporting the role of PPAR β / δ in metabolic control and energy homeostasis [6, 50] and abundant data showing association between metabolism and circadian rhythm [51], little is known concerning the influence of PPAR β / δ in circadian rhythm unlike PPAR α and PPAR γ , even though mRNA level of PPAR β / δ is cyclic in mouse liver and brown adipose tissue [25]. REV-ERB α and miR-122 may serve as a possible link between PPAR β / δ and circadian clock.…”

“…These feedback loops also control numerous target genes (termed clock controlled genes, CCG) in a circadian manner. Recently, all PPAR isoforms in mouse tissues were found to be rhythmically expressed [25]. Furthermore, PPAR α and PPAR γ have direct interactions with the core clock genes [26–28], suggesting that they may act as molecular links between circadian rhythm and energy metabolism.…”