Circadian clock mechanisms: different zeitgebers lead to intricate transcription-translation feedback loop. circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like protein-1 (BMAL1) heterodimerise and regulate the transcription of multiple clock-dependent genes (solid arrows). PER, CRY, REV-ERBα, RORα, PPARα, PPARγ, SIRT1 all lead to regulation of CLOCK and BMAL1 and contribute to their own regulation (dotted arrows). Amplitude, period, phase and MESOR of the oscillations produced determine the rhythmicity and robustness of the circadian clock. PER (Period), CRY (Cryptochrome), RORα (receptor-related orphan receptor α), REV-ERBα (NR1D1 gene producing a protein called REV-ERBα), PPARα (peroxisome proliferator-activated receptor α), PPARγ (peroxisome proliferator-activated receptor γ), NAMPT (nicotinamide phosphoribosyltransferase), NAD+ (nicotinamide adenine dinucleotide), AMPK (AMP-activated protein kinase), CCGs (clock-controlled genes), SIRT1 (sirtuin 1), PGC1α (PPARγ coactivator 1α), MESOR (midline estimating statistic of rhythm).