High-fat diet disrupts diurnal expression of circadian genes in mammary glands of prepubertal mice

Authors: SUNDARAM, SNEHA - Former ARS Employee; JOHNSON, LUANN - University Of North Dakota; Yan, Lin

Submitted to: Frontiers in Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/4/2020
Publication Date: 6/18/2020
Citation: Sundaram, S., Johnson, L., Yan, L. 2020. High-fat diet disrupts diurnal expression of circadian genes in mammary glands of prepubertal mice. Frontiers in Endocrinology. https://doi.org/10.3389/fendo.2020.00349.
DOI: https://doi.org/10.3389/fendo.2020.00349

Interpretive Summary: Childhood obesity is prevalent worldwide. In girls, it is associated with early breast development and growth, a risk factor for breast cancer in adulthood. The biological clocks exist in all organs in our bodies, including breast. The clock cycles for approximately every 24 hours and controls the daily rhythms of physiological functions and metabolism. Our dietary practice, as an environmental cue, can alter the rhythms of the clock and affect physiological development and growth. We studied whether obesity, as a change in dietary practice, altered the biological clock in mammary glands in a mouse model of prepubertal breast development. We found that obesity induced by a high-fat diet, compared to a normal control diet, altered the expression of key clock genes in prepubertal mammary glands. Furthermore, the high-fat diet resulted in changes in concentrations of the female sex hormone estrogen and its receptors in mammary glands. The homeostasis of estrogen and its receptors is important to mammary development and growth at the prepubertal stage. Our findings indicate that obesity disrupts the biological clock in prepubertal mammary glands may lead to abnormal breast development and growth.

Technical Abstract: Childhood obesity in girls is associated with early breast development; it increases the risk of breast cancer in adulthood. Breast tissue exhibits circadian rhythms; however, the circadian gene expression in prepubertal mammary glands and its alteration by obesity on breast homeostasis remain uninvestigated. We hypothesized that an obesogenic, high-fat diet (HFD) disrupts the circadian rhythms in prepubertal mammary glands. Weanling female C57BL/6 mice were fed an AIN93G diet or an HFD (16% or 45% of energy from soybean oil) for three weeks. Mammary glands were harvested from prepubertal, six-week-old mice every four hours on Zeitgeber time over a 48-hour period; rhythmic expression of circadian genes and genes of estrogen receptor and progesterone receptor was analyzed by using the Cosinor model. Compared to the AIN93G diet, the HFD reduced the amplitude of diurnal expression of Per2 and Cry1 and elevated that of Clock, Rev-erba, and Per1 in prepubertal mammary glands. The HFD delayed the acrophase (the hour at which the rhythm peaks) of Bmal1, reduced Mesor (the mean of the rhythm from peak to trough) of Bmal1, Per2, and Cry1, and elevated Mesor of Rev-reb and Per1. Furthermore, the HFD altered diurnal expression of estrogen receptor and progesterone receptor at both mRNA and protein levels. Mammary concentrations of estrogen, estrogen receptor 1, and progesterone receptor were higher and that of estrogen receptor 2 were lower in HFD-fed mice than in AIN93G controls. In conclusion, the HFD disrupted the diurnal circadian rhythms in prepubertal mammary glands. This alteration may lead to aberrant mammary development and growth in prepubertal mice.