Protein malnutrition during pregnancy in C57BL/6J mice results in offspring with altered circadian physiology before obesity

Endocrinology. 2010 Apr;151(4):1570-80. doi: 10.1210/en.2009-1133. Epub 2010 Feb 16.


The mechanisms linking intrauterine growth retardation (IUGR) with adulthood obesity and diabetes are unclear. These studies investigated energy homeostasis in 8- and 20-wk-old male and female mice subjected to protein deficiency in utero. Pregnant C57BL/6J female mice were fed a protein-deficient diet (6% protein). Undernourished offspring (UO) and controls (CO) were cross-fostered to lactating dams fed a 20% control diet. The 24-h profiles of energy expenditure, feeding behavior, physical activity, and whole-body substrate preference was assessed using 8-wk UO and CO weaned onto control diet. Blood chemistries, glucose tolerance, and expression of genes involved in hepatic lipid and glucose metabolism were analyzed in 8- and 20-wk-old CO and UO fed control or a high-fat diet. UO exhibited IUGR with catch-up growth at 8 wk of age and increased severity of diet-induced obesity and insulin resistance by 20 wk of age. Therefore, fetal malnutrition in the C57BL/6J mouse increases sensitivity to diet-induced obesity. Abnormal daily rhythms in food intake and metabolism, increased lipogenesis, and inflammation preceded obesity in the UO group. Arrhythmic expression of circadian oscillator genes was evident in brain, liver, and muscle of UO at 8 and 20 wk of age. Expression of the clock-associated nuclear receptor and transcription repressor Rev-erbalpha was reduced in liver and muscle of UO. Altered circadian physiology may be symptomatic of the metabolic dysregulation associated with IUGR, and altered feeding behavior and substrate metabolism may contribute to the obese phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Adipose Tissue, White / metabolism
  • Analysis of Variance
  • Animals
  • Blood Glucose / metabolism
  • Brain / metabolism
  • CLOCK Proteins / genetics
  • CLOCK Proteins / metabolism
  • Circadian Rhythm / physiology*
  • Eating / physiology
  • Energy Metabolism / physiology
  • Feeding Behavior / physiology
  • Female
  • Gene Expression
  • Glucose Tolerance Test
  • Insulin Resistance / physiology
  • Lipid Metabolism / physiology
  • Liver / metabolism
  • Male
  • Mice
  • Motor Activity / physiology
  • Muscle, Skeletal / metabolism
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Obesity / etiology*
  • Obesity / metabolism
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism*
  • Prenatal Nutritional Physiological Phenomena / physiology*
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • Protein Deficiency / metabolism*
  • Severity of Illness Index


  • ARNTL Transcription Factors
  • Bmal1 protein, mouse
  • Blood Glucose
  • Neuropeptide Y
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Pro-Opiomelanocortin
  • CLOCK Proteins