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Insulin Directly Regulates the Circadian Clock in Adipose Tissue

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posted on 28.06.2021, 23:05 by Neta Tuvia, Olga Pivovarova-Ramich, Veronica Murahovschi, Sarah Lück, Astrid Grudziecki, Anne-Catrin Ost, Michael Kruse, Victoria J. Nikiforova, Martin Osterhoff, Pascal Gottmann, Özlem Gögebakan, Carsten Sticht, Norbert Gretz, Michael Schupp, Annette Schürmann, Natalia Rudovich, Andreas F.H. Pfeiffer, Achim Kramer
Adipose tissue (AT) is a key metabolic organ which functions are rhythmically regulated by an endogenous circadian clock. Feeding is a zeitgeber aligning the clock in AT with the external time but mechanisms of this regulation remain largely unclear. We tested the hypothesis that postprandial changes of the hormone insulin directly entrain circadian clocks in AT and investigated transcriptional-dependent mechanism of this regulation. We analysed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp (EC) or control saline infusion (SC). The expression of core clock gene PER2, PER3 and NR1D1 in SAT were differentially changed upon insulin and saline infusion suggesting insulin-dependent clock regulation. In human stem cell-derived adipocytes, mouse 3T3-L1 cells and AT explants from mPer2Luc knockin mice, insulin induced a transient increase of the Per2 mRNA and protein expression leading to the phase shift of circadian oscillations and showing similar effects for Per1. Insulin effects were dependent on the region between the -64 and -43 in the Per2 promoter, but not on CRE and E-box elements. Our results demonstrate that insulin directly regulates circadian clocks in AT and isolated adipocytes and thus represent a primary mechanism of feeding-induced AT clock entrainment.

Funding

Study was supported by a grant from the German Science Foundation (DFG grants Pf164/021002 NR, ÖG, AFHP and KFO218 PF164/16-1 OPR, AK, AFHP) and by the Morgagni Prize of the European Association for the Study of Diabetes 2020 (OPR). MS was supported by the German Research foundation (DFG, grant SCHU 2546/4-1).

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