In this manner, a systemic integration of time and food signals is achieved, balancing energy homeostasis. This concept is also illustrated by the finding that the regulation of dopaminergic transmission and reward is altered

in mice mutant for the gene Clock and associated with increased expression and phosphorylation of tyrosine hydroxylase (TH) ( McClung et al., 2005), INCB018424 molecular weight the rate-limiting enzyme for dopamine synthesis. Additionally, these mutants show elevated leptin levels ( Turek et al., 2005), which may be responsible for the elevated TH activity, because leptin increases the synthesis and activity of TH ( Fulton et al., 2006). As a consequence, these animals probably have elevated dopamine levels contributing to the mania-like behavior ( Roybal et al., 2007) and the increased firing rate of VTA dopaminergic neurons observed in these animals ( Mukherjee et al., 2010). The circadian system is strongly entwined with metabolism Imatinib (see above, Dallmann et al., 2012), organizing it in a temporal fashion that optimizes the organism’s performance over the day’s 24 hr. Concurrently, this organization ensures tissue homeostasis by keeping various physiological processes in balance. Perturbations of the circadian system caused by rotating shift work, frequent transmeridian

flights and stress lead to de-synchronization of the various body clocks. This is likely to be a confounding factor that favors the development of diseases such as metabolic syndrome (obesity, diabetes, cardiovascular problems) and neurological disorders. In these disorders, energy uptake and expenditure, and neuronal activation and inhibition become imbalanced. Studies in humans suggest that disruption of daily metabolic rhythms is an exacerbating factor in the metabolic syndrome (Gallou-Kabani et al., 2007). Shift-work and sleep deprivation are known to dampen rhythms in growth hormone

and Dichloromethane dehalogenase melatonin, reduce insulin sensitivity, and elevate circulating cortisol levels (Spiegel et al., 2009). These changes favor weight gain, obesity, and development of metabolic syndrome. Recently, forced circadian desynchronization (a simulation of shift work) in humans was shown to impact on neuroendocrine control of glucose metabolism and energetics (Scheer et al., 2009). Participants subjected to the shift-work protocol showed increased blood pressure, inverted cortisol rhythms accompanied by hypoleptinemia and insulin resistance (Scheer et al., 2009). Interestingly, patients with diabetes display dampened rhythms of glucose tolerance and insulin secretion (Boden et al., 1999), indicating that the relationship between circadian disruption and metabolic pathologies is bidirectional (Figure 1B, pink arrows). This suggests that circadian disruption may lead to a vicious cycle contributing to the augmentation and progression of metabolic syndrome.