Crosstalk of central and peripheral circadian clocks in the regulation of adipose metabolic inflammation

Obesity and its secondary disorders like type-2 diabetes and the metabolic syndrome are a leading medical problem in modern society. The metabolic syndrome is characterized by altered glucose homeostasis and chronic low grade inflammation ("metaflammation"). A major risk factor for the development of overweight is the disruption of circadian rhythms. Circadian rhythm perturbations can occur due to trans-meridian travel, shift work or sleep impairments. A molecular circadian timing network coordinates daily physiological rhythms and is realigned or entrained to the daily 24-hour cycle by external cues such as the light-dark cycle. With the help of these inner clocks and their transcriptional output organisms anticipate recurring daily events by adapting physiological functions.

In mammals, the circadian network follows a hierarchical structure with a master clock located in the suprachiasmatic nuclei (SCN) of the ventral hypothalamus. The SCN clock is reset by the outer light-dark cycle and synchronizes central and peripheral clocks with external time.

Adipose tissue (AT) is both a metabolic and an endocrine organ and plays a major role in bodyweight regulation and energy metabolism. Besides adipocytes, AT also contains different immune cells – neutrophils and macrophages – which migrate through the tissue and play a role in the initiation of metaflammation. The migratory behavior of these cells is controlled by different chemoattractants, some of which are secreted in a circadian fashion from adipocytes themselves.

In this project I will elucidate the interplay between central and peripheral white adipose tissue clocks in the development of metabolic inflammation. I will further test the therapeutic potential of reinforcing peripheral adipose circadian rhythms for the prevention of metaflammation in an obesogenic environment.

Publications

Friedrichs, M., Kolbe, I., Seemann, J., Tsang, A. H., Cherradi, L., Klein, J., and Oster, H.: Circadian clock rhythms in different adipose tissue model systems. Chronobiol Int, vol. [Epub ahead of print], , 2018, doi: 10.1080/07420528.2018.1494603 

Kolbe, I., Carrasco-Benso, M. P., López-Mínguez, J., Luján, J., Scheer, F. A. J. L., Oster, a. H., and Garaulet, M.: Circadian period of luciferase expression shortens with age in human mature adipocytes from obese patients. FASEB J, vol. [Epub ahead of print], , 2018, doi: 10.1096/fj.201800441R 

Meyer-Kova, J., Kolbe, I., Ehrhardt, L., Leliavski, A., Husse, J., Salinas, G., Lingner, T., Tsang, A. H., Barclay, J. L., and Oster, H.: Hepatic gene therapy rescues high-fat diet responses in circadian Clock mutant mice. Mol Metab, vol. 6, pp. 512-523, 2017, doi: 10.1016/j.molmet.2017.03.008

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 

Kolbe, I., Husse, J., Salinas, G., Lingner, T., Astiz, M., and Oster, H.: The SCN Clock Governs Circadian Transcription Rhythms in Murine Epididymal White Adipose Tissue. J Biol Rhythms, vol. 31(6), pp. 577-587, 2016, doi: 10.1177/0748730416666170 

Kolbe, I., Dumbell, R., and Oster, H.: Circadian clocks and the interaction between stress axix and adipose function. Int J Endocrinol, vol. 2015, , 2015, doi: 10.1155/2015/693204 

Anthony, T., Kolbe, I., Seemann, J., and Oster, H.: Interaction of circadian and stress systems in the regulation of adipose physiology. Horm Mol Biol Clin Investig, vol. 19(2), pp. 103-15, 2014, doi: 10.1515/hmbci-2014-0020