ESPEYB19 11. Obesity and Weight Regulation New findings in adipose tissue biology (5 abstracts)
11.5. Insulin directly regulates the circadian clock in adipose tissue
Tuvia N , Pivovarova-Ramich O , Murahovschi V , Lück S , Grudziecki A , Ost AC , Kruse M , Nikiforova VJ , Osterhoff M , Gottmann P , Gögebakan Ö , Sticht C , Gretz N , Schupp M , Schürmann A , Rudovich N , Pfeiffer AFH & Kramer A
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Laboratory of Chronobiology, Berlin, Germany
achim.kramer@charite.de Diabetes 2021;70:1985–1999http://www.ncbi.nlm.nih.gov/pubmed/34226282
Brief Summary: This study analyzed gene expression in subcutaneous adipose tissue samples of adults with obesity collected before and after the hyperinsulinemic–euglycemic clamp or control saline infusion. They demonstrate that insulin regulates clock genes in both murine and human adipocytes and adipose-derived stem cells (ASCs).
Circadian clocks are a system of self-sustained oscillators that regulate various physiological processes through the generation of approximately 24h circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. Clock genes are set by external cues (so-called “zeitgeber”) to synchronize endogenous rhythms with environmental cycles. An important “zeitgeber” of peripheral tissues is food intake [1], and previous publications suggest that this might be mediated by insulin action [2,3].
Using reporter assays, the authors could show that insulin directly shifts the time-dependent expression of period circadian regulator 2 PER2. They further identified a region in the PER2 gene harboring potential binding sites for the transcriptional regulators NFY and SP1, which are downstream of the insulin signaling cascade. This suggests that insulin directly influences the circadian clock in adipose tissue by transcriptional regulation of clock genes.
The paper contributes to the long debate on the existence of a food-driven oscillator [4], which links feeding with peripheral circadian clock setting. This implicates that every time we eat, we reset our internal clock to synchronize with adipose tissue metabolism. This might also explain why rapid changes in eating behavior (e.g. due to jet lag, shift work or nighttime feeding) disturbs metabolic homeostasis. It would be interesting to further identify the downstream signals that mediate the effect of insulin on clock genes in the adipose tissue.
References: 1. Zvonic, S. et al. Characterization of peripheral circadian clocks in adipose tissues. Diabetes 55, 962–70 (2006). 2. Yamajuku, D. et al. Real-time monitoring in three-dimensional hepatocytes reveals that insulin acts as a synchronizer for liver clock. Sci. Rep. 2, 439 (2012). 3. Crosby, P. et al. Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time. Cell 177, 896–909.e20 (2019). 4. Mistlberger, R. E. Food-anticipatory circadian rhythms: concepts and methods. Eur. J. Neurosci. 30, 1718–29 (2009).
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