show that circadian regulation of lipolysis by the adipose clock is also important for body weight control. Indeed, Fabp4-Cre Bmal1 fl/fl mice became heavier than wild-type controls kept on standard diet and developed morbid obesity when fed with high-fat diet.In summary, we found that the adipose tissue clock is responsible for the regulation of lipid mobilization and their usage as energy source. We conclude that the adipocyte clock is an integral part of the circadian system, which normal functioning is required for metabolic homeostasis neurotransmitters glutamate (Glu) and pituitary adenylate cyclase-activating protein (PACAP) which signal to the SCN. In turn, this activates signaling cascades and the phosphorylation of CREB, which can activate the transcription of Pers leading to phase-shifts of the molecular clockwork (reviewed in (Golombek and Rosenstein, 2010)). The SCN also can acquire non-photic entrainment signals via neuropeptide Y (NPY) and gamma-aminobutyric acid (GABA) containing neurons from the thalamic intergeniculate leaflet (IGL) and serotonergic termini from raphe nuclei. This combination of photic and non-photic signals leads to a more differentiated response of the SCN to light (reviewed in (Dibner et al., 2010)).
Peripheral oscillatorsUbiquitous expression patterns of clock genes indicate that peripheral tissues also contain a circadian clock (Sun et al., 1997;Tei et al., 1997). Indeed many organs show circadian expression of clock genes in vivo (Yamamoto et al., 2004). Furthermore peripheral clocks seem to rely on a similar molecular oscillator mechanism as the SCN (Yagita et al., 2001). Experiments with cell lines gave the first It is important to note that other cues can take over this SCN function. For instance, timing of food intake can uncouple peripheral clocks from SCN control. Upon restricted feeding (RF), when food is provided only during the rest period, the phase relationship between the central clock and peripheral clocks is inversed (Damiola et al., 2000;Stokkan et al., 2001).
Circadian clock and metabolismDay-night variations in food consumption, activity and rest imply daily changes in the body's energy state. Indeed, accumulating evidence indicates that circadian rhythms and metabolism are tightly Table 1. Metabolic defects in mice harboring mutations in clock genes. Modified from (Sahar and Sassone-Corsi, 2012).
CryptochromesOther important members of the TTL's negative loop are the Cryptochrome genes. Mice lacking both Cry genes are arrhythmic in constant darkness and are frequently used as general clock-deficient model (van der Horst et al., 1999). Not surprisingly, Cry1 -/-Cry2 -/mutants also exhibit a large variety of metabolic disturbances. Cry-deficient animals exhibit a marked reduction in size and body weight compared with controls (Bur et al., 2009). Nevertheless, Cry1 -/-Cry2 -/mice show perturbed sugar metabolism with hyperglycemia and glucose intolerance, hallmarks of diabetes (Lamia et al., 2011).Although blood triglyceride levels of Cry-deficient mice are r...