Circadian Rhythms: Adaptations to Pregnancy and Disruption by Obesity

I've already spoken about circadian rhythms here, but time to go into more detail I guess...

Control of circadian rhythms

The main "clock" involved in circadian rhythms is in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. This SCN clock is entrained by "zeitgebers," which I'm pretty sure is German for "timers" or literally "time-givers." These zeitgebers are mainly environmental cues, such as light, food and temperature. Zeitgebers induce changes in molecular clock genes, such as Bmal1 and Clock.

Just like all other genes, Bmal1 and Clock are transcribed in the nucleus and translated in the cytoplasm. In the cytoplasm, they dimerise and then return to the nucleus, where they induce transcription of Per and Cry genes. After translation in the cytoplasm, Per and Cry also dimerise, and return to the nucleus where they downregulate Bmal1 and Clock. As such, Bmal1/Clock genes tend to peak when Per/Cry is at a minimum, and vice versa. Bmal1/Clock heterodimers can also activate accessory clock genes, such as Rev-erbα and Rorα. Rev-erbα can inhibit Bmal1, whereas Rorα can stimulate Bmal1 and Clock. All of these clock genes have further effects on clock-controlled genes that are found all over the body.

Clock genes are important in metabolic homeostasis. If Clock is deleted, hyperphagia and metabolic syndrome results. Deletion of Bmal1 results in altered carbohydrate metabolism and, as mentioned here, extreme weight loss. Deletion of Cry1 and Cry2 can result in an inflammatory phenotype. Food intake can also affect clock gene expression: for example, Bmal1, Clock and Per2 have all been shown to decrease with a high-fat diet.

Maternal adaptations to pregnancy

There are many changes that occur during pregnancy, mostly due to the endocrine placenta. In the first phase of pregnancy, a lot of anabolism occurs in order to store nutrients for later use. In the second phase, a lot of catabolism occurs in order to supply the fetus with nutrients. Since we know that clock genes are important in metabolism, the next step is to see whether or not circadian rhythms are important in the metabolic changes during pregnancy. Most experiments have been done in rats, using cosinor analysis (kind of like a linear regression but with the cosine function rather than a straight line). The attributes that experimenters look for are the mesor (average over the cycle) and amplitude (distance from the mesor to the base or peak of the curve).

Studies in rats have shown that body temperature circadian rhythm appears to be somewhat disrupted during pregnancy (though our lecturer didn't really explain how...) and decreases over the course of pregnancy. On the other hand, circadian rhythms of glucocorticoids are maintained, but absolute levels are increased (as mentioned here, glucocorticoids are important for fetal organ maturation). Gene expression in maternal livers and adipose tissue are also altered: in early pregnancy, maternal liver Bmal1 and Per1 increase in both mesor and amplitude. At the same time, adipose Bmal1, Per1, Per2 and Rev-erbα decrease in mesor, and Bmal1 and Rev-erbα also decrease in amplitude.

Since shift workers have been found to have an increased risk of preterm birth, low birthweight and spontaneous abortion, rat studies have also looked at how disruptions to the circadian rhythm can affect pregnancy. Sure enough, corticosterone, glucose, insulin, leptin, free fatty acids, triglycerides and cholesterol have all been found to be disrupted by disrupting the circadian rhythms of rats. The maternal liver has been found to have disrupted Bmal1 and Per1 expression, while the fetal liver has been shown to have disrupted Per2 and Rev-erbα expression. The offspring were also found to have an increase in weight gain and possible insulin resistance.

Obesity

Roughly 50% of women in the USA enter pregnancy either overweight or obese, which is a real problem as obesity is associated with gestational diabetes, preeclampsia (hypertension and proteinuria), miscarriage and abnormal birth weight. Studies in rats have shown that inducing obesity with a poor diet can alter clock gene expression, which in turn can alter metabolism. Altering metabolism may in turn affect fetal growth, as detailed here. In rats fed a poor diet, the mesor and amplitude of clock genes decreased. There was also a phase advance (left shift in the graph) in hepatic clock gene expression.