Dr. Karen Plaut Lab
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Homeorhesis and lactation
The transition from pregnancy to lactation is the most stressful period of an adult female's life. During this transition, homeorhetic adaptations are coordinated across almost every organ and are marked by changes in hormones and metabolism to accommodate the increased energetic demands of lactation. Recent data from our laboratory showed that changes in circadian clocks occur in multiple tissues during the transition period in rats and indicates that the circadian system coordinates changes in the dam's physiology needed to support lactation. Circadian rhythms coordinate the timing of physiological processes and synchronize these processes with the animal's environment. Circadian rhythms are generated by molecular circadian clocks located in the hypothalamus (the master clock) and peripherally in every organ of the body. The master clock receives environmental and physiological cues and, in turn, synchronizes internal physiology by coordinating endocrine rhythms and metabolism through peripheral clocks. The effect of the circadian clock on lactation may be inferred by the photoperiod effect on milk production, which is accompanied by coordinated changes in the dam's endocrine system and metabolic capacity to respond to changes in day length. We hypothesize the circadian system coordinates the metabolic and hormonal changes needed to initiate and sustain lactation, and we believe that the dam's capacity to produce milk and cope with metabolic stresses in early lactation is related to her ability to set circadian rhythms during the transition period.
For a recently completed NIH Grant 1R03HD062692-01A1 we captured circadian oscillation of core clock genes in mammary and liver collected from late pregnant (pregnancy day 17) and early lactation (lactation day 3) mouse dams every 4 hrs over a 24 hr period (data not shown). Comparison of BMAL1 and CLOCK protein expression levels between late pregnant and lactating mammary glands showed that the molecular clock in the mammary gland increased in amplitude during the transition from pregnancy to lactation. This was an important finding because the amplitude of a particular rhythm is believed to be indicative of the relative strength of the circadian clock. We hypothesized that the circadian clock that resides in the mammary gland is regulated by lactogenic hormones and functions to control the expression of genes important to milk synthesis. Thus this increase in amplitude was expected and we envision that it was due to the increase in mammary metabolic output. Our hypothesis was further supported by an increase in circadian rhythm amplitude of alpha- lactatalbumin (Lalba, a milk protein that functions as a regulatory subunit of lactose synthase; Figure 2a). Changes in circadian amplitude of liver Acaca (a rate limiting enzyme in fatty acid synthesis; Figure 2b) mRNA expression and plasma levels of corticosterone (Figure 2c) in these same mice show and provide additional support of our original finding that coordinated changes in the circadian system occurred across multiple tissues during the transition from pregnancy to lactation.
Figure 2. To capture temporal changes within a day and between physiological stages, tissue and blood were collected from WT mice on pregnancy day 17 (orange) and lactation day 3 (blue) every 4 hr over a 24 hr period. Changes in a) mammary Lalba and b) liver Acaca relative gene expression (RQ) measured using RT-q-PCR and c) plasma corticosterone levels measured using a commercially available ELISA kit (ALPCO) suggested that outputs of peripheral clocks change during the transition from pregnancy to lactation. ZT = Zeitgeber time; Values are mean ± SE.