Only time will tell: the interplay between circadian clock and metabolism

Figures & data

Figure 1. Circadian clock in Drosophila and mammals. (a) Primary and secondary feedback loops in the Drosophila circadian clock. The core clock machinery in Drosophila is composed of an interlocked TTFL with the positive limb CLK/CYC and a negative limb PER/TIM. Circadian photoreceptor CRY mediates the light entrainment of circadian clocks in Drosophila. The secondary feedback loop consists of VRI and PDP1 that inhibit and activate Clk transcription, respectively. (b) Primary and secondary feedback loops in the mammalian circadian clock. In mammals, the TTFL consists of the positive arm CLOCK/BMAL1 and a negative arm PER/CRY. REV-ERB and ROR, inhibit and activate Bmal1 transcription, respectively.

Figure 2. Central and peripheral circadian clocks in Drosophila and mammals.

(a) Schematic cross-section of Drosophila brain with the known circadian clock neurons and clock machinery. Clock neuron subsets are named based on their anatomical location in the brain. Small ventrolateral neurons (s-LNvs, blue), large ventrolateral neurons (l-LNvs, yellow), dorsolateral neurons (LNds, red), lateral posterior neuron (LPN- green), and dorsal neurons (DN1- orange, DN2-blue open circle, DN3-black). Core clock proteins, such as PER, TIM, and CLK, are expressed rhythmically in the clock neurons. Peripheral metabolic clocks present in the fat body, muscle, and gut regulate various physiological processes, including metabolism. SIFamide (SIFa) expressed in neuronal subsets of the pars intercerebralis (PI) drives the feeding rhythm. Drosophila insulin-like peptides (DILPs) produced by insulin-producing cells (IPC) in the PI regulates the rhythmic expression of metabolic transcripts in the fat body. While the central and peripheral circadian clocks regulate various metabolic pathways, food, and energy status send feedback signals into the clock. Square brackets collectively represent all the metabolic peripheral clocks. Solid and dashed arrows represent known and putative pathways involved in this cross-talk. (b) A schematic cross-section of an adult mammalian brain. In mammals, the central clock suprachiasmatic nucleus (SCN) is located at the base of the hypothalamus. Core clock proteins PER, CRY, and BMAL1 are rhythmically expressed in the SCN. Light input is conveyed to the SCN through intrinsic photosensitive retinal ganglion cells (ipRGCs). Neural and endocrine signaling from the central clock and the peripheral clocks in metabolic tissues, such as liver, pancreas, adipose tissue, stomach, and gut, regulate glucose, lipid metabolism, and nutrient absorption in a rhythmic manner. Stomach oxyntic cells produce the hunger hormone ghrelin that stimulates food intake. However, leptin hormone secreted by adipocytes and insulin from pancreas suppresses food intake. Nutrient status sends feedback signals to the central and peripheral clocks. A high-fat diet alters the phase of the adiponectin signaling pathway components in the liver, and the food intake pattern can alter the microbiota rhythmicity in the gut. SIRT1 transduces the signal back to the circadian clock, and AMPK phosphorylates the core clock components. Square brackets collectively represent all the metabolic peripheral clocks, and blunt end lines represent inhibitory effects. Solid and dashed arrows represent known and putative pathways, respectively, involved in the interaction between clock and metabolism.