Central circadian regulation of leptin signaling

Most species, from cyanobacteria to humans, have evolved endogenous circadian clocks that control 24-h rhythms of behavior and physiology to optimize the organismÄs adaptation to environmental changes brough about by the Earth's rotation around its axis. In mammals the circadian system is comprised of a central pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN) that entrains subordinate clocks throught the brain and periphery (reviewd in Reppert & Weaver, 2002). At the cellular level circadian clocks are based on a set of clock genes organized in an interlocked system of transcriptional-translational feedback loops (reviewd in Partch et al., 2013). Pertubation of circadian clocks by clock gene disruption of by external pertubation of ciecadian rhythms promotes hyperphagy, obesity and the development of obesity-associated disorders (Turek et al., 2005; Karlsson et al., 2001). The role of non-SCN clocks in the brain in this context remina unclear. However, hypothalamic areas involved in energy homeostasis and thalamocortical reward circuits involved in hedonic food intake also harbour their own molecular oscillators (Guilding et al., 2009; Angeles-Castellanos et al., 2007). An important regulator of food intake and energy homeostasis acting in these brain areas is the adipokine leptin. By binding the "long" isoform of its receptor, ObRb, in the brain, leptin leads to a decrease of the homeostatic food intake via activating anorexigenic neurons and inhibiting oresigenic neurons. This receptor is highly expressed in the mediobasal hypothalamus, especially in the arcuate nucleus, but also in the reward system, e.g. the ventral tegmenal area (Elmquist et al., 1998; Figlewicz et al., 2006). Thus leptin influences the hemeostatic and the hedonic food intake (reviewed in Cota et al., 2006). We hypothesize that the circadian clock in leptin-receptive neurons is important for the diurnal regulation of homeostatic and hedonic food intake in response to peripheral engergy state. Therefore out laboratory has developed a genetic mouse model with deletion of the circadian clock in leptin-receptive neurons (ObRb.Bmal). Furthermore a reporter gene for a fluorescent protein is expressed in leptin-receptive neurons of these mice (ObRb.Bmal.Green). Preliminary results show alterations in body weight gain, diurnal hmeostatic and hedonic food intake and indicate indicate altered leptin signaling in the ObRb.Bmal mice. This project aims at characterizing the influence of the circadian clock in leptin-responsive neurons on the central and peripheral leptin signling and on other circadian clocks in the brain. Furthermore the influence of central leptin gating in these neurons on the reward system will be analyzed.

Publications

Heyde, I., Kiehn, J., and Oster, H.: Mutual influence of sleep and circadian clocks on physiology and cognition. Free Radic Bio Med, vol. 119, pp. 8-16, 2017, doi: 10.1016/j.freeradbiomed.2017.11.003

Husse, J., Kiehn, J., Barclay, J. L., Naujokat, N., Meyer-Kovac, J., Lehnert, H., and Oster, H.: Tissue-Specific Dissociation of Diurnal Transcriptome Rhythms During Sleep Restriction in Mice. Sleep, vol. 40(6), 2017, doi: 10.1093/sleep/zsx068 

Kiehn, J., Tsang, A. H., Heyde, I., Leinweber, B., Kolbe, I., Leliavski, A., and Oster, H.: Circadian Rhythms in Adipose Tissue Physiology. Compr Physiol, vol. 7(2), pp. 383-427, 2017, doi: 10.1002/cphy.c160017 

Kiehn, J. T., Koch, C., Walter, M., Brod, A., and Oster, H.: Circadian rhythms and clocks in adipose tissues: current insights. Chronophysiol Ther, vol. 7, pp. 7-17, 2017, doi: doi.org/10.2147/CPT.S116242 

Koch, C. E., Bartlang, M. S., Kiehn, J. T., Lucke, L., Naujokat, N., Helfrich-Förster, C., Reber, S. O., and Oster, H.: Time-of-day-dependent adaptation of the HPA axis to predictable social defeat stress. J Endocrinol, vol. 231(3), pp. 209-221, 2016, doi: 10.1530/JOE-16-0163