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Download fileInsulin Directly Regulates the Circadian Clock in Adipose Tissue
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posted on 2021-06-28, 23:05 authored 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 KramerAdipose 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.