Untersuchung regulatorischer Mechanismen zur Kontrolle der Rate differenzierender Fettzellen in vitro und in vivo
Zusammenfassung der Projektergebnisse
Chronic stressors flatten circadian glucocorticoid oscillations, which has been correlated with negative health outcomes including obesity. How flatter circadian glucocorticoid oscillations affect metabolism and fat storage remains unknown. Here we aimed to investigate consequences of flattened glucocorticoid oscillations in mice. We found that flattening circadian glucocorticoid oscillations results in body weight gain mainly due to an increase in white fat depot mass. In detail, subcutaneous and visceral fat depots expanded due to an increase in cell volume caused by increased fat accumulation in adipocytes. In the visceral fat depot an increase in the cell number of adipocytes could be demonstrated as well. Higher adipocyte numbers are likely explained by higher rates of adipogenesis upon flattening of glucocorticoids. We demonstrated that preadipocytes failed to differentiate in vitro in response to short or pulsatile glucocorticoid stimuli of 12-hour peak duration whereas more persistent GC signals triggered fat cell differentiation. Furthermore we showed that this differentiation decision is controlled by a filtering mechanism requiring a slow and fast positive feedback circuit that controls PPARγ, the main regulator of adipogenesis. In addition to expansion of the white fat depots, flattened glucocorticoid oscillations lead to hyperinsulinemia and fat accumulation in brown adipose tissue, which precedes fat accumulation in the white adipose tissue. A transcriptomic analysis of white and brown adipose tissues revealed that flattened glucocorticoid oscillations resulted in a dysregulated lipid metabolism. Flattening glucocorticoid oscillations promoted lipogenesis and lipolysis at the same time resulting in a futile cycle of TG synthesis and breakdown. This futile cycle has been described for application of glucocorticoids in higher concentrations to cause lipid accumulation in the white fat depots, and is likely contributing to the increase in cell volume due to lipid accumulation in the white and brown fat depots upon flattening of glucocorticoid oscillations. In addition, the fatty acid transporter Cd36 was upregulated in the white and brown fat depots. The importance of Cd36 for lipid accumulation was highlighted by using Cd36 knockout mice, which were partially protected against body weight gain, and lipid accumulation in visceral white adipose tissue and brown adipose tissue induced by flattening of glucocorticoid oscillations. Summarized, these findings demonstrate that flattened glucocorticoid oscillations cause lipid accumulation in white and brown adipose tissue by increasing lipid uptake as well as promoting triglyceride synthesis and breakdown at the same time. Furthermore, these results provide insights how conditions associated with flattened or disrupted circadian glucocorticoid oscillations, as observed during depression, jet lag, irregular eating and sleeping cycles, aging, or prolonged glucocorticoid, cause obesity.
Projektbezogene Publikationen (Auswahl)
- ‘A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation.’ Cell Metabolism, Apr 3;27(4):854-868 (2018)
Bahrami-Nejad Z., Zhao M., Tholen S., […], and Teruel M.
(Siehe online unter https://doi.org/10.1016/j.cmet.2018.03.012) - Circadian glucocorticoid oscillations are required to maintain functional brown adipose tissue. FASEB Science Research Conference on "The Regulation of Glucose Metabolism”, Palm Springs, USA (2019)
Tholen S., […], and Teruel M.
- Flattened circadian glucocorticoid oscillations cause obesity due to increased lipid turnover and lipid uptake
Tholen S., […], and Teruel M.
(Siehe online unter https://doi.org/10.1101/2020.01.02.893081) - The highly expressed lipid buffer FABP4 enforces adipocyte cell identity by driving the initial cell differentiation process
Bahrami-Nejad Z., Chen T., Tholen S., […], and Teruel M.
(Siehe online unter https://doi.org/10.1101/2020.01.03.894493)
