Hepatology (Baltimore, Md.)Jan 21, 2014

How internal body clocks control daily changes in mouse liver insulin sensitivity through SIRT1

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Knockdown of CLOCK or BMAL1 induces hepatic insulin resistance in mice.

CLOCK and BMAL1, core circadian transcription factors, correlate with hepatic insulin sensitivity.
Ectopic expression of CLOCK or BMAL1 reduces hepatic insulin resistance.
Circadian changes in insulin sensitivity are impaired in mice with mutations in Clock or liver-specific knockouts of Bmal1 or Sirt1.
CLOCK and BMAL1 are necessary for the circadian expression of the protein deacetylase SIRT1.
Circadian misalignment in mice, induced by constant darkness, decreases levels of hepatic BMAL1 and SIRT1, leading to insulin resistance.
Resveratrol treatment can reverse insulin resistance caused by circadian misalignment.

Simplified

UNLABELLED: The protein deacetylase, sirtuin 1 (SIRT1), involved in regulating hepatic insulin sensitivity, shows circadian oscillation and regulates the circadian clock. Recent studies show that circadian misalignment leads to insulin resistance (IR); however, the underlying mechanisms are largely unknown. Here, we show that CLOCK and brain and muscle ARNT-like protein 1 (BMAL1), two core circadian transcription factors, are correlated with hepatic insulin sensitivity. Knockdown of CLOCK or BMAL1 induces hepatic IR, whereas their ectopic expression attenuates hepatic IR. Moreover, circadian change of insulin sensitivity is impaired in Clock mutant, liver-specific Bmal1 knockout (KO) or Sirt1 KO mice, and CLOCK and BMAL1 are required for hepatic circadian expression of SIRT1. Further studies show that CLOCK/BMAL1 binds to the SIRT1 promoter to enhance its expression and regulates hepatic insulin sensitivity by SIRT1. In addition, constant darkness-induced circadian misalignment in mice decreases hepatic BMAL1 and SIRT1 levels and induces IR, which can be dramatically reversed by resveratrol.

CONCLUSION: These findings offer new insights for coordination of the circadian clock and metabolism in hepatocytes by circadian regulation of hepatic insulin sensitivity via CLOCK/BMAL1-dependent SIRT1 expression and provide a potential application of resveratrol for combating circadian misalignment-induced metabolic disorders.

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How internal body clocks control daily changes in mouse liver insulin sensitivity through SIRT1

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