Insulin Directly Regulates the Circadian Clock in Adipose Tissue

Diabetes. 2021 Sep;70(9):1985-1999. doi: 10.2337/db20-0910. Epub 2021 Jul 5.


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 a transcriptional-dependent mechanism of this regulation. We analyzed gene expression in subcutaneous AT (SAT) of obese subjects collected before and after the hyperinsulinemic-euglycemic clamp or control saline infusion (SC). The expressions of core clock genes 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, with similar effects for Per1 Insulin effects were dependent on the region between -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, thus representing a primary mechanism of feeding-induced AT clock entrainment.

Trial registration: NCT00774488.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue / drug effects*
  • Adipose Tissue / metabolism
  • Animals
  • Circadian Clocks / drug effects*
  • Circadian Rhythm / drug effects*
  • Humans
  • Insulin / pharmacology*
  • Mesenchymal Stem Cells / drug effects
  • Mice
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Promoter Regions, Genetic / drug effects


  • Insulin
  • NR1D1 protein, human
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • PER2 protein, human
  • PER3 protein, human
  • Period Circadian Proteins

Associated data

  • figshare/10.2337/figshare.14791830