What this is
- This review explores the relationship between circadian rhythms and during pregnancy.
- Circadian rhythms play a crucial role in regulating , impacting maternal and fetal health.
- Disruptions in these rhythms may lead to adverse pregnancy outcomes, such as gestational diabetes and preeclampsia.
- The review emphasizes the need for further research into the mechanisms linking circadian dysregulation to disorders.
Essence
- Circadian rhythms significantly influence during pregnancy, affecting both maternal and fetal health. Disruptions in these rhythms can lead to metabolic disorders and adverse pregnancy outcomes.
Key takeaways
- Circadian rhythms regulate , which is crucial for fetal development. Disruption of these rhythms can lead to metabolic disturbances.
- Pregnancy induces significant changes in , with levels of triglycerides and cholesterol increasing as gestation progresses. These changes are essential for supporting fetal growth.
- Dysregulated circadian rhythms are linked to adverse outcomes such as gestational diabetes and preeclampsia, highlighting the importance of maintaining circadian health during pregnancy.
Caveats
- The mechanisms by which circadian rhythms affect during pregnancy are not fully understood, necessitating further research.
- Variability in individual responses to circadian disruptions may complicate the interpretation of findings related to and pregnancy outcomes.
Definitions
- circadian rhythm: An endogenous oscillation that aligns physiological processes with the 24-hour day-night cycle.
- lipid metabolism: The biochemical processes involved in the synthesis and degradation of lipids in the body.
- gestational diabetes mellitus (GDM): A form of diabetes that develops during pregnancy and typically resolves after childbirth.
Simplified
1. Introduction
Complicated maternal–fetal crosstalks contribute to a successful pregnancy, during which the uterus gradually transforms into a specialized niche, fulfilling the needs of a growing semi-allogeneic fetus and maintaining maternal–fetal tolerance [1,2]. An optimum supply of lipids, as one of the most essential nutrients in pregnancy, has important implications for the future health of gravidas and fetuses [3,4]. Intricate changes in lipid metabolism were observed in pregnant women, characterized by fat accumulation, maternal physiological hyperlipidemia, and increased tissue lipolysis [3,5]. Approximately 45% of reproductive-age women could be affected by lipid abnormalities [6]. It has been demonstrated that disturbances in maternal lipid profile could cause gestational diabetes mellitus (GDM), preeclampsia (PE), preterm birth, and fetal growth disorders [7,8]. Moreover, various adverse effects of dyslipidemia in reproductive-age women could continue beyond the termination of pregnancy [9,10]. Therefore, it is essential to explore the factors of susceptibility and the underlying mechanisms of lipid metabolism disorders, which may supply novel ideas for the therapy of metabolic disorders and adverse pregnancy outcomes.
A circadian rhythm, a term first noticed by Halberg in 1959 to explain an internal physiological regularity, represents an endogenous oscillation approximated to the Earth’s daily rotation period [11], and it exists in the brain and peripheral organs, such as the liver, skeletal muscle, esophagus, and reproductive organs [11,12,13]. Circadian rhythms have been demonstrated to exert a pivotal influence on implantation, decidualization, and pregnancy maintenance [14,15]. In humans and rodents, disruption of the circadian rhythm throughout pregnancy increased the risk of implantation failure, spontaneous abortion, preterm birth, and intrauterine growth restriction [16,17,18,19]. Research has indicated that the deficiency of circadian rhythm-related transcription factors in mice brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), circadian locomotor output cycles protein kaput (Clock), and period 1 (Per1) resulted in detrimental outcomes including implantation failure, miscarriage, and infertility [20,21].
The circadian rhythm precisely regulates important physiological activities, such as metabolic rhythm, sleep/wake cycles, and endocrine rhythm. Peroxisome proliferator-activated receptors (PPARs), as key transcriptional regulators of lipid metabolism, are regulated by circadian rhythm in the liver, muscle, and white and brown adipose tissue, hereby linking the circadian rhythm to the lipid metabolism [22,23,24]. However, the mechanism by which circadian rhythm affects lipid metabolism during pregnancy remains largely exclusive.
Based on the evidence presented above, the first half of the article provides an overview of the functional aspects of the circadian machinery and discusses current research connections between circadian clock genes and lipoproteins. In the second half, we focus on whether the circadian rhythm clock regulates lipid metabolism during pregnancy and the impact of their abnormalities on pregnancy outcomes.
2. The Molecular Components of the Circadian Clock
Circadian rhythm in the wild, entrained to 24 h through changing ambient cues, especially light, enables the human body to switch its behavior and physiology to anticipate and respond to associated changes in the external environment [25,26]. The changes in behavior and physiology, such as sleep deprivation, disrupted eating-time, and shift work, could markedly contribute to the disturbance of circadian rhythm in organisms [27,28,29,30,31], leading to the development and progression of several diseases, including pregnancy-related disorders [32,33]. A meta-analysis illustrated that pregnant women who worked rotating shifts, fixed night shifts, or longer hours could experience a miscarriage, preterm delivery, or give birth to low birth weight infants [16]. It is necessary to comprehend the formation mechanism of the circadian clock system before discussing the circadian regulation of lipid metabolism during pregnancy.
In mammals, the central clock that generates the circadian rhythm is located in the suprachiasmatic nucleus of the anterior hypothalamus, the prime pacemaker of the organism [34,35]. Neurons within the suprachiasmatic nucleus can directly or indirectly receive the retinal input of an electric pulse, which is the code of light information from the environment [36]. These neurons then synchronize the circadian rhythm in peripheral organs, such as adipose tissue, kidney, spleen, lung, liver, and leukocytes, via neural and humoral pathways [37], although peripheral clocks can also be entrained independently [38]. The master clock has also been shown to serve as the core regulator for diurnal rhythmic behavior, such as feeding and sleep [39,40,41]. Disturbances of circadian rhythms in pregnant individuals could be linked to alterations in the immune system as well as the endocrine system, such as the diurnal cortisol rhythm [42,43].
At the molecular level, the circadian rhythm is operated by auto-regulatory transcriptional–translational loops composed of a suite of molecular pacemakers, including Bmal1 (also called Mop3 or Arntl), Clock, Per, cryptochrome (Cry), Rev-erbα (encoded by nuclear receptor subfamily 1 group D member 1), and retinoic acid receptor-related orphan receptor (Ror) [44].
The transcriptional–translational loops consist of three loops, which constitute the basis of circadian rhythm regulation of the organism (Figure 1).
In the first loop, the proteins of two core genes Bmal1 and Clock combine to form a heterodimer in the cytoplasm, transfer to the nucleus, and integrate with canonical enhancer-box (E-box) sites on the promoters of clock-controlled genes, such as Per, Cry, Rev-erbs, Rors, and albumin D-site-binding protein (Dbp), forming a positive side of the loop [44,45,46,47]. Per and Cry heterodimers, as a negative side of the loop, translocate into the nucleus to suppress the transcriptional regulatory function of Bmal1/Clock heterodimers by interacting with them [48,49], thereby interfering with the transcription of other circadian rhythm-related genes as well as their own [50,51]. The repressive effect of these factors lessens, owing to the reduced expression of central genes. Then, the transcriptional regulation of Bmal1/Clock heterodimers starts anew with another 24 h period [52].
In the second loop, Rors (Rorα, Rorβ, and Rorγ) and Rev-erbs (Rev-erbα and Rev-erbβ), activated by the Bmal1/Clock heterodimers, compete for Ror-binding elements (RORE) on the promoter region of Bmal1, thereby bringing about negative (Rev-erbs) and positive (Rors) regulatory impacts on the Bmal1 transcription [53,54,55]. In addition, this loop plays a pivotal role in circadian oscillators of multiple metabolic pathways including lipid metabolism [54]. Research has revealed that nuclear receptor Rev-erbα could drive the rhythmic expression of cholesterol-7alpha-hydroxylase, the rate-limiting enzyme in the pathway converting cholesterol to bile acids [56].
In the third loop, Bmal1/Clock heterodimers regulate the Dbp transcription [57] and Cry1 binding to E-box could delay the phase of Dbp expression [58]. Rev-erbs and Rors regulate the Nfil3 transcription. Dbp and Nfil3 regulate the transcription of Pers and Rors positively and negatively via binding to D-box on the promoter region, respectively [59,60]. Therefore, the organism accomplishes the diurnal rhythmic regulation based on these three loops.
3. Connections Between Circadian Clock Genes and Lipid Metabolism
The circadian rhythm was proposed to be highly relevant for metabolic disorders and could take part in maintaining lipid homeostasis in mammals. Growing studies confirmed that resynchronizing the circadian rhythm might alleviate metabolic disturbance. Here, we focus on several circadian clock genes that directly regulate lipid metabolism.
3.1. Bmal1
Bmal1 is a core constituent of the circadian clock in mammals and dysregulation of Bmal1 results in aberrant lipid metabolism. In hepatocyte-specific Bmal1 knockout mice, perivascular adipose tissue exhibited increased levels of triglyceridess (TGs) and free fatty acids (FFAs), as well as elevated mRNA expression of some crucial metabolic genes, including PPARγ, adiponectin, and lipoprotein lipase [61]. These are in line with a previous study that reported that hepatic Bmal1-deficient mice could result in declined transcript levels of PPAR signaling, which is a kind of metabolic pathway related to lipid metabolism [62]. Furthermore, both fatty acid oxidation (FAO) and de novo lipogenesis could be simultaneously suppressed in ethanol diet-fed mice with liver-specific deletion of Bmal1, which could be restored by promoting the PPARα pathway [63]. Bmal1 has been proposed to be an upstream regulator of PPARα gene expression, and the latter could interact with the peroxisome proliferator-activated receptor γ coactivator 1α, thereby facilitating the FAO [64,65,66]. It might be intriguing to explore the mechanisms by which PPARs connect circadian clock genes to lipid metabolism.
Interestingly, there are also other mediators by which the circadian gene Bmal1 plays roles in lipid metabolism. By interacting with the enhancer of the zeste homolog, Bmal1 could result in reduced expression of glycerol-3-phosphate acyltransferase mitochondrial, a crucial enzyme in lipid biosynthesis, thereby leading to decreased triacylglycerol and lysophosphatidic acid (LPA) [67]. It has been confirmed that Bmal1 regulates microsomal triglyceride transfer protein and ATP binding cassette family G protein 5 or protein 8 through the small heterodimer partner and Gata4, respectively, thereby affecting lipoprotein production and biliary cholesterol excretion [68]. Furthermore, hepatic-specific Bmal1 inactivation contributed to increased plasma low-density lipoprotein/very-low-density lipoprotein cholesterol (LDL-C/VLDL-C) levels as a result of the dysfunction in proprotein convertase subtilisin/kexin type 9 [69]. It has also been reported that the oxidation capacity of fatty acids increased following the deletion of Bmal1 in both untreated and chronic insulin treatment cells, suggesting that Bmal1 reduced the utilization of fatty acids [70].
3.2. Clock
Clock is another critical component of the circadian rhythm in modulating lipid metabolism, and disruption of Clock could lead to lipid metabolic disorders. Clock mutant mice fed with cholesterol/cholic acids could accumulate a higher amount of cholesterol in the liver due to the reduced expression of cholesterol-7alpha-hydroxylase [56]. Compared with wild-type mice, ClockΔ19/Δ19 double mutant mice have been found to augment the absorption of intestinal cholesterol, increase the uptake of macrophage-modified lipoproteins, and attenuate the efflux of cholesterol from macrophages, which eventually lead to atherosclerosis [71]. Moreover, it was reported that homozygous Clock mutant mice showed greatly declined circadian feeding rhythms and a metabolic syndrome of hyperglycemia, hyperlipidemia, and hyperleptinemia [72]. A mechanistic link has been found between the perturbation of the Clock gene and the progression of nonalcoholic fatty liver disease [73]. CLOCK knockout mice presented disruptions of proliferation and adipogenesis markers within white adipose tissue, while ClockΔ19/Δ19 double mutant mice exhibited elevated fatty acid uptake attributed to heightened hypoxia-inducible factor 1α protein levels [56,74]. Additionally, the genetic perturbation of molecular clocks in Clock-deficient mice could result in the elimination of diurnal oscillations of triglycerides [75]. Persistent hypertriglyceridemia, increased lipid absorption, and a higher level of microsomal triglyceride transfer protein expression were also reported in Clock mutant mice in comparison to wild-type mice [76,77].
3.3. Rev-Erbs
The nuclear receptor Rev-erbα and its close homolog Rev-erbβ are transcriptional repressors in the circadian rhythm of mammals. Abnormal expression of Rev-erbs could result in dysregulation of lipid and energy metabolism. Rev-erbα/β-agonist-treated mice exhibited a decrease in fat mass, a 12% decline in plasma TG, and a 47% reduction in plasma total cholesterol [78]. It has been shown that Rev-erbα took part in the circadian modulation of sterol regulatory element-binding protein activity via the circadian transcription of insulin-induced gene 2, thereby involving the regulation of cholesterol and lipid metabolism [79,80]. The Rev-erbα protein recruits the histone de-acetylases 3 to take part in lipid metabolism, and dysfunction of either could cause hepatic steatosis [81,82]. In addition, Rev-erbs effectively inhibited the expression of lipogenic enzymes, such as stearoyl-CoA desaturase 1 and fatty acid synthase, thereby influencing the synthesis of fatty acid [78]. It has also been reported that Rev-erbs could play a vital role in the regulation of lipid metabolism via interacting with other circadian clock genes. For example, the Bmal1–Rev-erb–choline kinase axis could regulate hepatic phosphatidylcholine, suggesting that an intact circadian system is of particular importance for phospholipid metabolism [83].
3.4. Per
The transcriptional factors Per1 and Per2 play important roles in a series of physiological processes, including the circadian regulation of lipid metabolism. Studies have proposed that the circadian cycle of phospholipid biosynthesis in cultured fibroblasts disappeared after the deletion of Per1 [84,85]. Deletion of Per1 decreased TG accumulation in the serum and liver, while overexpression of Per1 up-regulated the expression of lipogenesis-related genes, including PPARα and its target genes [86].
Lipidomic profiling also showed that the clock gene Per2 is essential for normal lipid metabolism in white adipocyte tissue [87]. It has been confirmed that saturated and mono-unsaturated very-long-chain fatty acids levels augmented, while TG and white adipose tissue decreased in Per2 knockout mice compared with those in controls [87]. Moreover, Per2 could interact directly with PPARα, modify its activity via competing with the activities of PPARγ, and alter lipid metabolism [87].
3.5. Other Circadian Clock Genes
In addition, other clock genes might be involved in the regulation of lipid metabolism, such as Dec, Rors, and Nfil3. Dec1 and Dec2, the fifth clock gene family to regulate metabolic functions genes, inhibit lipogenesis in the liver via binding to the promoter region of sterol regulatory element-binding protein 1c, thereby modulating fatty acid synthesis [88,89]. Ror family members, required for cell-autonomous clock function in the liver, could regulate the expression of circadian rhythm clock genes via interacting with the peroxisome proliferator-activated receptor γ coactivator 1α [90]. Nfil3, an important factor of the circadian clock system, acts as a positive regulator of adipogenesis. Upregulated Nfil3 in the aging thymus was associated with steroid and adipogenesis process of thymic epithelial cells via promoting epithelial–mesenchymal transition [91]. Moreover, Nfil3, as a key pro-adipogenic transcription factor, could trans-repress cyclooxygenase-2 in glucocorticoid-associated adipocyte differentiation [92].
Taken together, these results emerged that circadian clock proteins controlled lipid metabolic homeostasis, possibly through specific transcription factors containing PPARs, sterol regulatory element-binding protein, and peroxisome proliferator-activated receptor γ coactivator 1α.
4. Circadian Regulation of Lipid Metabolism During Pregnancy
A disturbed clock during pregnancy has been identified as a contributing factor in disorders of carbohydrate metabolism as well as abnormal glucose metabolism [93]. There is also a cluster of evidence that disruption of the circadian clock may be associated with lipid metabolism. It has been proposed that the dysfunction of the circadian rhythm leads to changes in circulating energy consumption and lipid metabolism, thereby promoting the occurrence of liver cancer [94]. However, the exact molecular mechanisms underlying this effect during pregnancy have yet to be elucidated. Herein, we provide a comprehensive analysis of the physiological variation in the circadian rhythm and characteristics of lipid profile during pregnancy. Furthermore, we also concentrate on the interaction between disrupted lipid metabolism, dysregulated circadian rhythm, and several adverse pregnancy results.
4.1. Physiological Changes in Circadian Rhythm During Pregnancy
Sleep pattern in reproductive-age women is frequently affected by dramatic changes in hormone secretion, cardiovascular function, fetal movement, and frequent awakenings to urinate caused by a growing uterus [95]. Thus, significant changes in sleep pattern were observed during pregnancy (Figure 2). A midline estimating statistic of rhythm in the middle and late trimester is higher than that in the early trimester, reaching a peak at approximately 32 weeks of gestation [96]. Changes in sleep pattern during pregnancy have a similar result with the midline estimating statistic of rhythm [97]. The feature of sleep pattern in the first trimester of gestation involves shorter sleep latency, and poorer sleep quality compared with those in pre-pregnancy [98,99]. Temporarily improved sleep quality was observed in the mid-trimester gestation [99], while sleep quality could worsen from the 2nd to the 3rd trimester [100]. Moreover, sleep quality during the third trimester is even worse than that in first trimester [99,101]. Sleep duration decreased from the first to second trimester [102], with a shorter sleep duration in the third trimester than in the first [101]. It has been reported that a shorter sleep duration was associated with advancing gestational age [99,103]. However, recent research differing from previous reports indicated that sleep duration was prolonged in all trimesters compared to pre-pregnancy, which could be attributed to the baseline measurement [99]. To date, as there are still no clear mechanisms by which pregnancy exerts impacts on sleep pattern, it is fascinating to explore mutual regulation between circadian clock proteins and sleep patterns during pregnancy. Such data on sleep changes in healthy gestation might also be used as a baseline to identify sleep-related risk factors for adverse pregnancy outcomes.
Research has demonstrated that the total energy intake of the 3rd trimester increased by 9% (185 kcal/day) compared to the 1st trimester [104]. An increased energy supply is necessary for pregnancy to support various activities, particularly in relation to lactation, placental and fetal development, and maternal physiological adaptations [105]. However, late sleep midpoint (after 5:00 am) and short sleep duration during the second-trimester gestation correlate with gestational diabetes [106,107]. Similarly, other reports showed that a short sleep duration during pregnancy reduced the risk of glucose tolerance and increased the risk of hyperglycemia [108,109]. Long sleep durations were also implicated in placental abruption, while a short sleep duration has been linked to increased risks of placental abruption and preterm birth [110,111]. However, the mechanisms of energy metabolism abnormalities caused by sleep pattern changes during pregnancy are still unclear.
4.2. Characteristics of Lipid Metabolism During Pregnancy
Pregnancy is a unique physiological period in a woman’s life, during which a cluster of metabolic changes occur to provide energy for fetal growth and development. Two states, anabolic and catabolic, could be observed in maternal lipid metabolism during pregnancy [5,112,113]. The anabolic state occurs during the early and middle trimesters, as the body prepares for the fetal energy needed in the later stage of pregnancy. A decline in fat accumulation appears during the last trimester, resulting in a transition from the anabolic phase into the catabolic phase [113]. During this period, the activity of lipoprotein lipase in the adipose tissue could surge or stabilize [114,115]. It could increase hydrolysis of circulating triacylglycerol and the production of lipid products such as 2-monoacylglycerol, non-esterified fatty acids, and glycerol, which are then taken up and used for TG re-synthesis [116].
Owing to the processes mentioned above, changes in lipid levels are presented in a trimester-dependent manner during pregnancy. In the early trimester of pregnancy, LDL-C, apolipoprotein B, total cholesterol, and TG levels decline moderately and increase from the second trimester until the end of term [117]. The TG level increases by approximately 50–100%, while total cholesterol and LDL-C levels rise by around 30–50% [118]. High-density lipoprotein cholesterol levels and apolipoprotein A1 augment by 20–40% from the early trimester onwards and reach a plateau at around 20–24 weeks [117]. Moreover, the maternal pancreatic beta-cell mass rises to enhance the secretion of insulin, which is considered as an important regulator of lipoprotein lipase and catalyzes the hydrolysis and uptake of circulating TG [119,120]. The progressive increase in insulin resistance during pregnancy is significantly driven by prolactin, estrogen, and progesterone [121]. Moreover, elevated maternal adiposity, particularly in the 1st trimester, could exacerbate insulin resistance and increase lipolysis by the 3rd trimester, and contribute to raised FFA concentrations [122]. In turn, the resultant increase in maternal FFA levels exacerbates insulin resistance via hindering glucose uptake and augmenting hepatic gluconeogenesis [121]. It is for this reason that de novo lipogenesis is enhanced during gestation, leading to lipid storage [123]. Recent research indicated that the pronounced unsaturation of phospholipids remained a stable attribute during the embryonic transition to the blastocyst stage, which could be indispensable for membrane structure and cell signaling [124]. Indeed, multiple other factors have impacts on maternal lipid levels and the magnitude of this variation in pregnancy, such as pre-pregnancy body mass index, diet, age, and race [125,126,127,128,129].
Undesirable pregnancy outcomes could occur when lipid levels in pregnancy go beyond the physiologic range and develop dyslipidemia [130,131,132]. A study with 5690 women has confirmed a positive association between maternal blood pressure and certain lipids, including TG, LDL-C, non-high-density lipoprotein cholesterol, and especially TG [133]. Moreover, the research revealed that lipid levels during the early trimester of pregnancy were strongly linked to an increased risk of cardiovascular burden for the mother, including preeclampsia (PE) and sustained hypertension [133]. In a retrospective study of 12,715 women, a strong connection between increased first-trimester TG and GDM and PE was also observed [134]. TG-rich lipoproteins and their remnants during pregnancy might be associated with arterial stiffness, endothelial dysfunction and inflammation, which ultimately lead to consequent placental vessel dysfunction [135]. Recently, a retrospective study of 881 women with a twin pregnancy showed a similar conclusion that TG in the early trimester of pregnancy was highly relevant for PE and GDM [136]. Furthermore, recent retrospective cohort research also demonstrated that pregnant women with hypertensive disorders in pregnancy (HDP) might have an increase in serum lipids during pregnancy, with the exception of a decrease in FFA levels [137]. It is crucial for researchers to continue studying the mechanisms behind these associations in order to develop effective interventions and treatments for pregnant women with dyslipidemia.
4.3. Circadian Dysregulation of Lipid Metabolism and Adverse Pregnancy Outcomes
Multiple organs of the human body are involved in lipid metabolism, and these organs are controlled by the circadian clock to regulate the body’s metabolic functions. Previous studies have shown the interlocking of dyslipidemia and circadian disorders with pregnancy-related diseases, respectively, which might contribute to the treatment of pregnancy complications. In the next section, we will discuss the link between circadian rhythm disorders and dysregulated lipid metabolism in several adverse pregnancy outcomes, including miscarriage, GDM, and HDP (Figure 3).
4.3.1. Miscarriage
Miscarriage, a term for the loss of an intrauterine pregnancy up to 20–24 weeks of gestation, is the most common complication of pregnancy [138]. A remarkable association has been illustrated between lipid metabolism and miscarriage. For example, a defective LPA–autophagy axis could increase miscarriage risk by restricting decidual macrophage residence. LPA could alleviate embryo resorption in the spontaneous abortion model [139,140]. Meanwhile, a reduction in carnitine palmitoyltransferase 1A (CPT1a), a rate-limiting enzyme in the FAO pathway, has been shown to correlate with insufficient decidualization, heightening the likelihood of miscarriage [141]. Studies also suggested that the integration of polyunsaturated fatty acids (PUFAs) into membrane phospholipids promoted the creation of peroxides, thereby inducing ferroptosis [142,143,144]. Of note, decidual stromal cell ferroptosis could be implicated in the pathogenesis of recurrent pregnancy loss (RPL) [145].
In addition, research demonstrated that both decidualization and implantation could be affected by circadian genes [14,20,21]. Bmal1 could activate the migration and invasion of trophoblasts in RPL through the specificity protein 1–DNA 5′-cytosine-methyltransferases 1/DAB2 interaction protein axis, revealing a link between Bmal1 and RPL [146]. Apoptosis in mouse embryonic stem cells could be induced via downregulation of Clock, leading to an increase in miscarriage [147]. Per2 dysfunction does not synchronize aperiodic decidual gene expression with the initiation of endometrial proliferation, thereby resulting in RPL [148]. A declined implantation number, deficient decidualization, and increased abortion rate were observed in the sleep disorder models compared with those in normal mice, as decidualization could be regulated by the circadian gene Rev-erbα via the interleukin 6–progesterone receptors–CCAAT/enhancer-binding protein β pathway [149]. Moreover, we previously found that melatonin could reverse inflammation and decidualization resistance, indicating that the melatonin–melatonin receptor 1 signal might take part in pregnancy via regulating decidualization [150]. Numerous studies have provided evidence of the connection between sleep disorders and RPL, but the underlying mechanisms remain largely unclear.
Notably, while both the disturbance of Bmal1 and deficiency of LPA affected miscarriage, a link between the circadian gene Bmal1 and the lipid mediator LPA has been found [67], suggesting that miscarriage might be the result of lipid disorders caused by circadian clock perturbations. Per2 knockout in mice could affect lipid metabolism through altering the expression of CPT1 [151], while CPT1 has been shown to correlate with insufficient decidualization, heightening the likelihood of miscarriage and lipid disorders caused by circadian disruption. As a strong association has been observed among the circadian clock, lipid metabolism, and miscarriage, future studies should explore whether the miscarriage resulted from abnormal lipid metabolism induced by circadian disruption.
4.3.2. GDM
GDM, one of the most prevalent metabolic disorders in gestation, denotes the development of glucose intolerance during pregnancy [152]. The prevalence of GDM in China was reported to be 19.7%, and has shown an upward trend during the past few years [153]. It has been proposed that lipid metabolism is also an indispensable factor for the development of GDM, except for glycometabolism. In GDM women, proper supplementation of omega-3 PUFA could decrease insulin resistance and inflammation, thereby decreasing the risk of undesirable reproductive outcomes [154,155]. Both acute and chronic increases in FFA could induce insulin resistance, as a study has shown that β-cell compensatory responses might be impeded along with the chronic increase in FFA levels [32,156]. FFA levels in pregnant women with GDM varied dramatically during gestational periods, with the majority increasing from early to mid-pregnancy and gradually declining in late pregnancy [32]. In addition, studies have confirmed that α-β hydrolase domain-containing protein 5/CPT1b could regulate the accumulation of lipid droplets in trophoblast cells, which is the feature of GDM [157].
Likewise, a growing body of research has proven the notion that impairment of the diurnal system, particularly concerning sleep disorders, plays a pathogenic role in GDM patients. A meta-analysis of seven studies revealed that extreme sleep durations (long or short sleep) in the early and mid-trimester could lead to a 1.35-fold increase in the risk of GDM [158]. Another meta-analysis of 16 studies, including 2,551,017 pregnant women and 142,103 GDM cases, to a great extent arrived at a similar result that an increased risk of GDM could be related to short or long sleep durations [159]. In addition, poor sleep quality, snoring, and even obstructive sleep apnea syndrome could be related to an increased prevalence rate of GDM [159]. Compared with controls, lower transcript levels of Bmal1, Per3, and Cry2 were observed in GDM women, indicating that the deranged expression of the circadian clock-related genes are strongly linked to the occurrence of GDM [160].
Additionally, Bmal1 depletion enhanced FFA levels, including saturated and mono-unsaturated very-long-chain fatty acids [61]. Sleep fragmentation or intermittent hypoxia could increase the risk of GDM via declining insulin sensitivity or elevating plasma glucose levels [161,162]. Thus, it is reasonable to speculate that circadian rhythm might participate in the development of GDM via regulating lipid metabolism as multiple studies have reported that both lipid metabolism and the circadian clock could affect GDM.
4.3.3. HDP
HDP is categorized into four subtypes based on disease severity: gestational hypertension, chronic hypertension, PE, and chronic hypertension with superimposed preeclampsia. It was revealed that 15.3% of pregnant women could be affected by HDP, with PE being the most common subtype accounting for 54.9% of cases [33,163]. In recent years, several studies have provided accumulating evidence about the impact of lipid metabolism on the risk of HDP. For instance, perfluoroalkyl substances interfered with trophoblast invasion, inflammation, and lipid homeostasis by interacting with PPARs, thereby raising the incidence of PE [164]. Previous research has illustrated that PPARγ/Nrf2 signaling impacted ferroptosis by regulating lipid oxidation, which alleviated PE development [165]. The increased expression of acyl-CoA dehydrogenase very long chain involved in the FAO pathway could contribute to the development of PE through gluconeogenesis [166]. In women with PE, lower expression of genes involved in placental FAO and transport was exhibited compared with healthy women [167]. On the contrary, early and late-onset PE were also thought to profoundly affect maternal lipid metabolism, potentially contributing to increased cardiovascular risk later in life [168]. Thus, figuring out the relationship between lipid metabolism and the development of HDP is possibly needed in future research.
Meanwhile, the impact of the circadian system on the HDP occurrence has also been emphasized. Recent cohort research showed that circadian rhythm disturbance caused by skipping breakfast during gestation was related to the development of HDP [169]. It has been shown that the circadian gene Clock modulated the biological behavior of trophoblasts via hypoxia, participating in the pathogenesis of PE [170]. While extreme sleep duration and poor sleep quality in pregnancy augmented the risk of PE, sleep disorders among pregnant women comprising restless leg syndrome, subjective sleep-disordered breathing, and sleep apnea syndrome were also markedly associated with gestational hypertension and PE [171]. In addition, shift work during pregnancy was exhibited to increase the risk of PE [172,173]. Such major studies suggested that overall sleep disturbances in the gestation increased the risk of HDP occurrence, though the mechanisms underlying were poorly explained.
Significantly, it was observed that Clock mutant mice caused increased lipid absorption and persistent hypertriglyceridemia [72]. Future studies should investigate whether the circadian rhythm might modulate HDP via the lipid metabolism pathway.
5. Conclusions
Insights into the circadian clock and lipid metabolism have made significant advances during the past several decades. Dysregulation of the circadian clock could affect lipid synthesis and FAO, while dysfunction of this process could cause adverse pregnancy outcomes. Indeed, an increasing number of circadian rhythm studies have provided important insights that inspired us to correlate the expression of the circadian clock gene with lipid metabolism during pregnancy within the holistic understanding of the involved molecular mechanisms. However, we are only beginning to understand the systems and mechanisms, and clearly require additional experimentation to further broaden our comprehension of circadian rhythm and lipid metabolism during pregnancy. Hence, new insights that target key circadian clock genes with the intention of treating adverse pregnancy outcomes may provide more effective strategies, pharmacological approaches, and improved guidance for optimizing pregnancy development.