Final Report Summary - OBESITY AND LIGHT (Bringing Obesity to Light - Do obesogenic chemicals affect lipid metabolism through changes in circadian rhythm?)
The incidence of obesity and its associated metabolic abnormalities like diabetes and hypertension have grown to epidemic proportions worldwide (Finucane et al., 2011). Nevertheless there is still much uncertainty about underlying physiological mechanisms and the current incidence of obesity cannot be fully explained by genetic, socio-economic factors or nutrition. Increasing evidence indicates that also environmental factors contribute to the etiology of obesity, including disturbance of circadian rhythms (Gooley and Chua, 2014) and exposure to environmental chemicals (Janesick and Blumberg, 2011). Circadian rhythms, endogenously driven cycles of roughly 24 hours, time biological clocks and coordinate biochemical, physiological and behavioral processes according to the organisms’ active periods. Also genes which regulate lipid synthesis and fatty acid oxidation are clock controlled (Gooley and Chua, 2014). Though disturbing circadian clocks has profound implications for human health, little is known about chemically induced alterations in clock activity and how they affect metabolic aspects like lipid accumulation and adipogenesis. The zebrafish (Danio rerio) is an established model for analyzing obesogenic and circadian effects. We could show that under continuous light but not under shifted light dark cycles a 7 fold higher number of zebrafish larvae developed adipocytes, even more than zebrafish larvae which were fed with hypercaloric diet. This could be due to altered expression of light driven clock genes that are linked to genes involved in adipogeneis. Adipogenesis is mainly regulated by three isoforms of the peroxisomal proliferator activated receptors (Ppars) and pparβδ shows several binding sites for the clock gene Rev-erbα. Thus, the regulatory pathways of circadian clocks and adipogenesis might be linked via these genes. The newly observed co-localization in zebrafish adipocytes of Rev-erbα and Pparγ, which can be activated by Pparβδ, is emphasizing a direct interplay. Furthermore, we demonstrated that environmental chemicals with obesogenic potential disturb circadian clocks and vice versa: exposure of zebrafish larvae to endocrine disrupting chemicals not only increased lipid accumulation remarkably but also affected core clock activity while exposure to known clock modulating chemicals increased lipid accumulation. Our data clearly strengthened the bidirectional link between circadian clocks and lipid metabolism and moreover revealed a novel mechanism of action of environmental obesogens. This first described effect widens the potential health implications of exposure. As the circadian clock regulates a wide variety of physiological processes, information about environmental compounds that disturb the biological clock may provide also important insights on the environmentally induced development of cancer, metabolic diseases or sleeping disorders. Furthermore, it might provide possible explanations for the increasing number of people suffering from obesity and might even offer new treatment approaches.
