Impairment of peripheral circadian clocks precedes metabolic abnormalities in ob/ob mice

Endocrinology. 2011 Apr;152(4):1347-54. doi: 10.1210/en.2010-1068. Epub 2011 Feb 1.

Abstract

Recent studies have demonstrated relationships between the dysfunction of circadian clocks and the development of metabolic abnormalities, but the chicken-and-egg question remains unresolved. To address this issue, we investigated the cause-effect relationship in obese, diabetic ob/ob mice. Compared with control C57BL/6J mice, the daily mRNA expression profiles of the clock and clock-controlled genes Clock, Bmal1, Cry1, Per1, Per2, and Dbp were substantially dampened in the liver and adipose tissue, but not the hypothalamic suprachiasmatic nucleus, of 10-wk-old ob/ob mice. Four-week feeding of a low-calorie diet and administration of leptin over a 7-d period attenuated, to a significant and comparable extent, the observed metabolic abnormalities (obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia) in the ob/ob mice. However, only leptin treatment improved the impaired peripheral clocks. In addition, clock function, assessed by measuring levels of Per1, Per2, and Dbp mRNA at around peak times, was also reduced in the peripheral tissues of 3-wk-old ob/ob mice without any overt metabolic abnormalities. Collectively these results indicate that the impairment of peripheral clocks in ob/ob mice does not result from metabolic abnormalities but may instead be at least partially caused by leptin deficiency itself. Further studies are needed to clarify how leptin deficiency affects peripheral clocks.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Caloric Restriction
  • Circadian Clocks / drug effects
  • Circadian Clocks / genetics*
  • Cryptochromes / genetics
  • Cryptochromes / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Genotype
  • Leptin / pharmacology
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / genetics*
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Polymerase Chain Reaction
  • Radioimmunoassay
  • Suprachiasmatic Nucleus / drug effects
  • Suprachiasmatic Nucleus / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cryptochromes
  • DNA-Binding Proteins
  • Dbp protein, mouse
  • Leptin
  • Per1 protein, mouse
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Transcription Factors
  • CLOCK Proteins