Night-time restricted feeding normalises clock genes and Pai-1 gene expression in the db/db mouse liver

Diabetologia. 2004 Aug;47(8):1425-36. doi: 10.1007/s00125-004-1461-0. Epub 2004 Jul 29.


Aims/hypothesis: An increase in PAI-1 activity is thought to be a key factor underlying myocardial infarction. Mouse Pai-1 (mPai-1) activity shows a daily rhythm in vivo, and its transcription seems to be controlled not only by clock genes but also by humoral factors such as insulin and triglycerides. Thus, we investigated daily clock genes and mPai-1 mRNA expression in the liver of db/db mice exhibiting high levels of glucose, insulin and triglycerides.

Methods: Locomotor activity was measured using an infrared detection system. RT-PCR or in situ hybridisation methods were applied to measure gene expression. Humoral factors were measured using measurement kits.

Results: The db/ db mice showed attenuated locomotor activity rhythms. The rhythmic expression of mPer2 mRNA was severely diminished and the phase of mBmal1 oscillation was advanced in the db/db mouse liver, whereas mPai-1 mRNA was highly and constitutively expressed. Night-time restricted feeding led to a recovery not only from the diminished locomotor activity, but also from the diminished Per2 and advanced mBmal1 mRNA rhythms. Expression of mPai-1 mRNA in db/db mice was reduced to levels far below normal. Pioglitazone treatment slightly normalised glucose and insulin levels, with a slight reduction in mPai-1 gene expression.

Conclusions/interpretation: We demonstrated that Type 2 diabetes impairs the oscillation of the peripheral oscillator. Night-time restricted feeding rather than pioglitazone injection led to a recovery from the diminished locomotor activity, and altered oscillation of the peripheral clock and mPai-1 mRNA rhythm. Thus, we conclude that scheduled restricted food intake may be a useful form of treatment for diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • CLOCK Proteins
  • Circadian Rhythm / physiology*
  • Diabetes Mellitus, Experimental / blood*
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / prevention & control
  • Diet, Reducing*
  • Hypoglycemic Agents / therapeutic use
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Motor Activity
  • Pioglitazone
  • Thiazolidinediones / therapeutic use
  • Time Factors
  • Trans-Activators / genetics


  • Blood Glucose
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Trans-Activators
  • CLOCK Proteins
  • Clock protein, mouse
  • Pioglitazone