Circadian regulation of metabolism

Abstract

In association with sleep-wake and fasting-feeding cycles, organisms experience dramatic oscillations in energetic demands and nutrient supply. It is therefore not surprising that various metabolic parameters, ranging from the activity status of molecular energy sensors to circulating nutrient levels, oscillate in time-of-day-dependent manners. It has become increasingly clear that rhythms in metabolic processes are not simply in response to daily environmental/behavioral influences, but are driven in part by cell autonomous circadian clocks. By synchronizing the cell with its environment, clocks modulate a host of metabolic processes in a temporally appropriate manner. The purpose of this article is to review current understanding of the interplay between circadian clocks and metabolism, in addition to the pathophysiologic consequences of disruption of this molecular mechanism, in terms of cardiometabolic disease development.

Keywords: circadian rhythms; glucose metabolism; lipid; metabolism.

Figure 1. The mammalian circadian clock mechanism

The core circadian clock mechanism relies on a transcriptional-translational feedback loop comprised of the transcription factors BMAL1 and CLOCK. On the positive side of loop, BMAL1 and CLOCK heterodimerize and bind E-box elements in PER and CRY genes that encode negative members of the feedback loop PER1-3 and CRY1-2. The PER and CRY proteins repress their own transcription by interfering with CLOCK-BMAL1 activity. A second feedback loop involving opposing actions of REV-ERBα and RORα nuclear receptors controls the rhythmic expression of BMAL1, which is essential for the generation of circadian clock rhythms. CLOCK-BMAL1 also promotes transcription of many non-core clock and metabolic genes; a.k.a., clock-controlled genes. BMAL1, brain and muscle ARNT-like 1; CLOCK, circadian locomotor output cycles kaput; CCG, clock controlled gene; CRY1-2, cryptochrome 1–2; PER1-3, period 1–3; REV-ERBA or α, nuclear receptor subfamily 1, group D; RORA or α, RAR-related orphan receptor alpha; and RRE, retinoid response element.

Figure 2. Hypothetical role for the circadian clock in anticipation of fasted (A) versus fed (B) states

As outlined in the text, we hypothesize that the circadian clock within skeletal and/or cardiac myocytes anticipate increased energetic demand during the active period, through mechanisms such as AMPK activation (possibly through the NAMPT/SIRT1/LKB1/AMPK axis), which promotes substrate uptake and utilization. Similarly, clock-mediated augmentation of β-adrenergic sensitivity during the active period would facilitate efficient energy store breakdown, for continued contraction. Should the animal be successful in its forage for food (B), increased clock-mediated augmentation of insulin sensitivity during the active phase would promote efficient uptake and storage of nutrients. Clock symbol represents a clock-controlled process; dashed lines indicate positive regulation on a process; thickness of solid lines represents relative flux through a pathway. Acetyl CoA, acetyl coenzyme A; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; LKB1, liver kinase B1; NAMPT, nicotinamide phosphoribosyltransferase; SIRT1, sirtuin 1.

Figure 3

Metabolic feedback loops of the mammalian circadian clock. Clock-mediated induction of ALAS1, LDHa, OGT, and NAMPT, likely form feedback loops through regulation of heme biosynthesis, redox status, protein O-GlcNAcylation, and protein deacetylation, respectively (for additional details, please see relevant text within the METABOLIC REGULATION OF THE MOLECULAR CIRCADIAN CLOCK subsection. ALAS1, δ-aminolevulinate synthase; BMAL1, brain and muscle ARNT-like 1; CLOCK, circadian locomotor output cycles kaput; CCC, circadian clock components; CCG, clock controlled genes; LDHA, lactate dehydrogenase A; NAMPT, nicotinamide phosphoribosyltransferase; OGT, O-GlcNAc transferase; REV-ERBα, nuclear receptor subfamily 1, group D; and SIRT1, sirtuin 1.