Birth is a highly stressful and critical event. In the womb, babies rely on the supply of oxygen and nutrients provided by the placenta. However, once they are born they need to breathe for themselves and gain all their nutrients from suckling milk. The placenta provides a sugar-rich diet, while milk is richer in fat. Failing to cope with this change in diet leads to serious complications and sometimes death. Therefore, a better understanding of how the body adapts to these changes may shed light on pathways that are important for good health in later life.

The liver plays a central role in processing the nutrients absorbed by the gut. It uses fats to produce molecules called ketone bodies, such as β-hydroxybutyrate, which are then used as fuel by other tissues and organs including the heart, muscle and the brain. A protein called PPARα controls the production of ketone bodies primarily by regulating genes that are involved in the uptake and breakdown of fat in the liver. However, little is known about how this protein affects the development of the liver.

Here, Rando, Tan et al. report that mice start to produce more PPARα in the liver shortly before birth. This ultimately activates several genes that encode enzymes that break down fats. The experiments show that during labor, stress hormones called glucocorticoids directly stimulate the production of PPARα in the liver of the fetus to prepare newborn mice for harnessing energy from fat-rich milk.

In the absence of PPARα, mouse liver cells are less able to break down fats after birth and so start to accumulate fat, resulting in fewer ketone bodies being produced. Rando, Tan et al. show that β-hydroxybutyrate regulates some PPARα target genes, including one called Fgf21. The activity of this gene increases only after milk suckling starts and it encodes a protein that enhances the breakdown of fats in the liver. Without PPARα, the expression levels of its target genes, including Fgf21, do not increase after birth, which promotes the build up of fats in liver cells, a condition known as liver steatosis.

Overall, the results reported by Rando, Tan et al. highlight how stress during labor plays an important role in priming the body to cope with a fat-rich diet after birth. Future studies will need to determine if stress hormones and ketone bodies could be used as therapies for babies born by caesarean section with liver steatosis.

In mammals, embryonic and postnatal development depends on nutrition from placentation and lactation, respectively (Brawand et al., 2008).Before birth, hepatic energy metabolism relies mainly on glucose catabolism. Metabolic fluxes change abruptly at birth when milk, which has a higher lipid but relatively lower glucose content, becomes the exclusive nutrient (Girard et al., 1992). At the first few hours after birth, liver expresses the rate-limiting enzymes responsible for extracting energy from milk (Krahling et al., 1979; Huyghe et al., 2001). However, whether lipid catabolism at birth is developmentally programmed or an adaptive response requiring an external stimulus remains unknown. Failure to adapt to this catabolic switch results in life-threatening errors of metabolism, with serious energy imbalances that are recapitulated in mouse models of neonatal liver steatosis (Ibdah et al., 2001; Cherkaoui-Malki et al., 2012).

Peroxisome proliferator-activated receptor α (PPARα) is a key transcriptional regulator of lipid metabolism owing to its activation by a lipid surge to induce lipid catabolism (Desvergne et al., 2006; Montagner et al., 2011, 2016). However,the role of PPARα in the perinatal liver is not fully understood. Certain PPARα target genes (e.g., acyl-CoA oxidase 1 [Acox1]) are highly expressed in fetal liver at the end of gestation, whereas the expression of others (e.g., fibroblast growth factor 21 [Fgf21]) strictly depends on postnatal milk uptake (Hondares et al., 2010; Yubero et al., 2004). Based on these contrasting observations, we hypothesized the presence of a PPARα-triggering program before birth that does not require milk suckling for activation. Given that fetal liver metabolism mostly relies on glycolysis rather than lipid oxidation, we postulated that the liver phenotype of PPARα-deficient fetuses may not be obvious due to the absence of a lipid-rich diet challenge.

By measuring gene expression in prenatal and postnatal livers, we show that PPARα activation has already occurred a few days before birth, and that glucocorticoid receptor (GR)-mediated control of PPARα in late gestation prepares its physiological role in the pups for harnessing milk lipids immediately after birth. However, before birth we could barely detect the expression of certain PPARα target genes such as Fgf21, which is exclusively involved in adaptive metabolism. Therefore, we explored the mechanistic basis for the temporal regulation of PPARα target genes. We found that certain PPARα target genes, including Fgf21 and Angptl4 (Angiopoietin-like 4), are epigenetically controlled by histone deacetylase 3 (HDAC3) and de-repressed in response to β-hydroxybutyrate, a by-product of fatty acid oxidation (FAO). Taken together, our data provide the evidence of a major role of glucocorticoid signaling in direct hepatic regulation of PPARα and indirect HDAC3-mediated regulation of FGF21, which controls important metabolic and thermogenic events in the early days of life (Hondares et al., 2010).

In mammals, the transition to extra-uterine life represents a sudden shift in the source of energy (i.e., from a carbohydrate-laden fetal diet to a high-fat, low-carbohydrate diet). The neonatal liver must coordinate hepatic FAO, gluconeogenesis, and ketogenesis in order to maintain bioenergetic homeostasis and to meet the metabolic demands associated with extra-uterine life which depends exclusively on milk (Cotter et al., 2013). In contrast to the carbohydrate-replete nutrient state experienced in utero, neonatal energy is dominated by PPARα-dependent transcriptional regulation of lipid catabolism. We found that this anticipatory regulation of PPARα activity and lipid metabolism is directly controlled by GR before birth.

Glucocorticoid hormones are crucial in the functional maturation of many key tissues, notably in preparation for birth (Cottrell and Seckl, 2009). The initiation of parturition is marked by short bursts of stress hormones (Barlow et al., 1974). We demonstrate that this short burst of glucocorticoids at the initiation of birth directly stimulate the GR-dependent transcription of PPARα and its lipid catabolic target genes, which in turn prepare neonates for the sudden shift to fat-rich milk diet as the primary source of energy (Figure 8A,B). Indeed, we previously demonstrated the GR-mediated hormonal induction of PPARα in adult hepatocytes (Lemberger et al., 1994), while others showed that ligand-activated PPARα interferes with the recruitment of GR and Pol2 to the promoter of classical GRE-driven genes, inhibiting their transcription (Bougarne et al., 2009). This is also consistent with our observation of a reduced expression of Nr3c1 in Ppara^-/- livers, implicating a reciprocal regulatory relationship between GR and PPARα.

Figure 8

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We indicate that lipid catabolic target genes of PPARα, particularly those involved in mitochondrial, peroxisomal, and microsomal oxidation, are switched on just before birth in anticipation of a postpartum lipid-rich meal. In the neonatal liver, however, we show that mitochondrial β-oxidation prevails as the major contributor to the neonatal oxidative capacity and protects against hepatic steatosis when faced with a sudden surge in dietary fat. Our findings are consistent with the notion that mitochondrial FAO represents the dominant metabolic pathway whereas peroxisomal FAO assumes a relatively minor role (Hashimoto et al., 1999). Accordingly, long-chain FAs constitute more than 60% of the total FAs in animals and milk (Smith et al., 1968), and their abundance makes them the only significant source of metabolic fuel for the mitochondrial, but not peroxisomal, β-oxidation system (Reddy and Mannaerts, 1994). Moreover, decreased mitochondrial FAO has been considered one of the major contributing factors leading to liver steatosis (Ockner et al., 1993). Thus, we conclude that the concomitant presence of lipid content of milk, a lower number of mitochondria and overt mitochondrial dysfunctions jointly contributes to the development of liver steatosis in Ppara^-/-neonates. Notably, mitochondrial dysfunctions were evident in Ppara^-/- hepatocytes due to reduced ∆_ΨM and increased intracellular ROS levels. We postulate that an increased intracellular ROS level likely precedes the loss of ∆_ΨM and mitochondria dysfunction. As this oxidative stress condition continues to worsen after birth, perhaps induced by nutritional lipid as previously indicated (Tirosh et al., 2009), reduced ∆_ΨM and ATP production ultimately ensue. This is in agreement with a previous report of a similar mitochondrial disorder associated with the dysfunctional respiratory chain components (Lebiedzinska et al., 2010). Particularly, the increased intracellular ROS levels observed in Ppara^-/- hepatocytes may be due to the reduced clearance of ROS as evidenced by the down-regulation of genes coding for mitochondrial superoxide dismutase 2 (SOD2) and copper chaperone for SOD1 (a metalloprotein responsible for delivering copper as a co-factor to SOD1) before and/or after birth (Figure 2—source data 1). This observation is consistent with the report that PPARα activation by agonist clofibrate stimulates SOD1 and catalase activities as part of the defense mechanisms against oxidative stress in the heart (Ibarra-Lara et al., 2016).

Many of the PPARα-regulated genes involved in FAO have previously been shown to contain a PPRE in their promoter region and hence, recognized as direct PPARα target genes (Rakhshandehroo et al., 2010). This implicates that the reduced oxidative capacity observed in Ppara^-/- mice was due to the lack of direct PPARα-mediated stimulatory effects rather than a cellular-autonomous metabolic adaptation in response to lower mitochondria numbers. As discovered by Semenkovich andRakhshandehroo et al., 2010 co-workers (Chakravarthy et al., 2005, 2009), newly synthesized FA by fatty acid synthase may also regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of a distinct physiological pool of PPARα ligands in adult liver. However, we doubt that de novo synthesis of FA plays a predominant role in the regulation of PPARα activity during early postnatal period since insulin/glucagon ratio is low, which promotes FAO rather than de novo synthesis of FA (Girard et al., 1977). Our recent work indicates that PPARα has little impact on the expression of lipogenic genes in normal conditions (Montagner et al., 2016). Moreover, an effective hepatic FAO is essential for the provision of acetyl-CoA and NADH to support hepatic de novo ketogenesis and gluconeogenesis (Girard, 1986). This notion is consistent with the hypoketonemia and hypoglycemia in Ppara^-/-neonates reported in this work and by Crawford and co-workers (Cotter et al., 2014). Notably, the hypoglycemic phenotype previously reported in Ppara^-/-neonates by Cotter et al. happened at P1 due to a decreased hepatic gluconeogenesis from glycerol. However, we did not detect any sign of hypoglycemia in these mice starting from P2. This apparent discrepancy is likely attributable to the rapid (~1 day) and dynamic adaptive functions of Ppara^-/- neonatal liver in providing glucose as the primary source of energy required for postnatal growth and in maintaining glucose homeostasis. Our finding also supports the work of others indicating a preserved gluconeogenesis from glycerol in adult Ppara^-/- mice (Xu et al., 2002). We elucidated that this cell-autonomous metabolic adaptation was enhanced in the absence of PPARα and mediated through the up-regulation of hepatic ALT and anaplerotic amino acid oxidation. Thus far, the mechanism behind the increased production and secretion of ALT in Ppara^-/- neonatal liver still remains unclear. It is notable that ALT2 expression is up-regulated under metabolic stress and that plasma and tissue ALT levels are elevated in response to endoplasmic reticulum (ER) stress (Salgado et al., 2014; Josekutty et al., 2013). Interestingly, defective PPARα signaling has been reported to cause hepatic mitochondrial and ER stress in the pathogenesis of hepatic steatosis through reduced mRNA expression of the sarco/endoplasmic reticulum calcium ATPase (SERCA) (Su et al., 2014). In addition, our transcriptome analysis revealed a consistent reduction by ~1.2-fold in the expression of Atp2a2, which encodes SERCA, in Ppara^-/- liver at E19.5 and P2 (Figure 2—source data 1). Moreover, we also delineated that most of the rate-limiting enzymes involved in amino acid oxidation were concomitantly up-regulated in Ppara^-/- neonatal liver to provide essential intermediate substrates in TCA/Krebs cycle required for gluconeogenesis. Hence, we speculate that de novo synthesis of glucose becomes the primary energy source in sustaining normal postnatal growth in Ppara^-/- neonates as evidenced by the observed growth retardation upon decoupling of amino acid oxidation from gluconeogenesis. This is in conjunction with the failure of Ppara^-/- neonatal liver in harnessing energy from ketone bodies and lipids due to defective mitochondrial functions. In parallel, the compensatory up-regulation of pyruvate carboxylase (Pcx) and other gluconeogenic genes in Ppara^-/-neonates at P2 probably corresponds with a lower hepatic acetyl-CoA level, as supported by a recent report that hepatic acetyl-CoA acts as an allosteric regulator of Pcx (Perry et al., 2015). Importantly, these findings in Ppara^-/-mice illustrate the tremendous flexibility of the neonatal liver in coordinating ketogenesis, FAO, and gluconeogenesis so as to meet the energy demand required for normal growth especially when faced with an energy crisis caused by defective oxidative metabolism and hypoketonemia.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) is one of the rate-liming enzymes involved in ketogenesis. Hmgcs2 contains a PPRE in its promoter region and is under the direct transcriptional control of PPARα (Rodríguez et al., 1994). HMGCS2 has been shown to induce mitochondrial FAO and FGF21 expression, possibly via a SIRT1-dependent mechanism (Vilà-Brau et al., 2011). Furthermore, Hmgcs2 mRNA expression peaks 16 hr after birth and coincides with a decline in Acox1 mRNA expression thereafter (Yubero et al., 2004; Serra et al., 1993, 1996). These reports substantiate our findings of preferential activation of mitochondrial FAO at birth. Our results also support the in vivo finding that β-hydroxybutyrate is a potent physiological inhibitor of HDAC3 (Shimazu et al., 2013), suggesting that PPARα-mediated activation of HMGCS2 and β-hydroxybutyrate production precedes the PPARα-regulated production of FGF21. Similar to other PPARα target genes, we detected PPARα occupancy in the Fgf21 promoter before birth, but its transcription is ultimately determined by the alleviation of HDAC3-mediated inhibition (Figure 8B). Thus, fatty acid catabolism provides β-hydroxybutyrate, which acts as a secondary signal to initiate the de-repression of the Fgf21 promoter by HDAC3, allowing it to become PPARα responsive. It was previously indicated that HDAC-mediated histone deacetylation may inhibit transcription at the initiation and/or elongation step (Wang et al., 2009). If the genes are loaded by Pol2 at the TSS, similar to what we observed at the Fgf21 TSS upon PPARα agonistic activation, HDAC-mediated inhibition of transcription most likely happens at the elongation step although abortive initiation of the TSS bound Pol2 cannot be excluded. Our results suggest that PPARα activation induces the recruitment and assembly of a transcription initiation complex at the Fgf21 TSS. However, the elongation of Fgf21 mRNA transcript only ensues after alleviation of HDAC3 inhibition by β-hydroxybutyrate. Therefore, it is consistent with our findings that PPARα agonist has no effect on Fgf21 mRNA or transcriptional activation in the absence of β-hydroxybutyrate.

Both human and mouse neonates exhibit mild ketogenic conditions during early postpartum period (0–1 day, 0.2–0.5 mmol/L), which further exacerbates after 5–10 days (0.5–1.1 mmol/L) (Hamosh, 2004). We believe that it could be due to the use of lipids as preferred fuel for growth while the carbohydrate parts of milk (e.g., lactose and oligosaccharide−two main carbohydrates in milk) mainly contribute to brain growth (i.e., myelin synthesis) and gut microbiota nourishment (Edmond, 1992; Chichlowski et al., 2011). Further, the observed ketogenic condition may also be explained by the low insulin/glucagon ratio in early postpartum life (Girard et al., 1977; Ferré et al., 1979; Girard et al., 1992). We found that ketone bodies act as a hit that is important to prime PPARα-dependent expressions of Fgf21 and Angptl4 by modulating HDAC3 activity on their promoter. Both FGF21 and ANGPTL4 function as secreted systemic effectors of PPARα (Badman et al., 2007; Dijk and Kersten, 2014). However, unlike Fgf21, the expression of Angptl4 has already begun in the fetal liver. This finding is congruent with the report that ANGPTL4 functions as a glucocorticoid-dependent gatekeeper of FA flux by inhibiting the activity of adipose tissue lipoprotein lipase during fasting (Koliwad et al., 2012; Dijk and Kersten, 2014). In fact, significant overlap exists between the bioenergetic challenges experienced during fasting and at birth. Liver-derived FGF21 acts as an endocrine regulator of ketogenesis, which links the phenotypes observed during fasting and in newborns (Badman et al., 2007; Hondares et al., 2010). This concept is evident in Ppara^-/- mice, which have reduced plasma FGF21 levels. During fasting, the switch to a lipid-dominated nutrient supply provokes hypoketonemia, hypoglycemia, and hepatic steatosis in adult Ppara^-/- mice (Kersten et al., 1999; Montagner et al., 2016). In concordance with a recent report (Cotter et al., 2014), the shift to a high-fat, low-carbohydrate ketogenic diet in Ppara^-/- neonates results in steatosis similar to that observed in fasted adult Ppara^-/- mice. Notably, FGF21 has previously been shown to stimulate hepatic FAO and to prevent hepatic steatosis following ingestion of lipid-laden milk (Xu et al., 2009). Hence, we believe that the physiological relevance of FGF21 induction in neonates after milk suckling relates to its role in metabolic regulation by stimulating lipid catabolism rather than a response to starvation or a low calorie condition which no longer exists upon milk ingestion. It is also important to note that the early human breast milk is not initially ketogenic due to the relatively high lactose content, which gradually decreases while the fat content increases as the milk matures over time (Jenness, 1979). In contrast, mouse milk is likely a ketogenic diet as evidenced by a previous report that early mouse milk comprises ~17% of fat and ~1.7% of lactose at P3 (Görs et al., 2004). Therefore, direct translation of our findings to human situations needs to be cautioned for such differences in milk composition.

In summary, we provide evidence that prenatal expression of PPARα is under the direct control of GR. The GR-dependent PPARα activity is pivotal for the induction of hepatic FA catabolic genes, pointing to a novel anticipatory role of PPARα in the fetal liver in preparation for the efficient use of milk fat as an energy source. In addition, hepatic FA catabolism provides essential co-factors for the synthesis of ketone bodies such as β-hydroxybutyrate. Interestingly, ketone bodies act as a secondary signal that further activates PPARα-dependent regulation of the hepatokine FGF21. Therefore GR-PPARα axis may represent a critical signaling pathway in late gestation for the ability of mammalian newborns to use nutrients and maintain whole-body homeostasis. We conclude that in the absence of PPARα, a vicious cycle pertaining to the (i) lower mitochondria numbers, (ii) mitochondrial dysfunctions, (iii) impaired mitochondrial FA β-oxidation, (iii) hypoketonemia either due to a lack of direct PPARα stimulation of Hmgcs2 or a lack of essential co-factors provided by functional FAO, (iv) lack of epigenetic activation of FGF21 by ketone bodies (e.g., β-hydroxybutyrate), and (v) a surge in nutritional lipids upon milk suckling, exists to concomitantly contribute to the development of hepatic steatosis in neonates (Figure 8C).

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Author details

1. Gianpaolo Rando

   Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

   Contribution

   GR, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Chek Kun Tan

   Competing interests

   The authors declare that no competing interests exist.

2. Chek Kun Tan

   Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

   Contribution

   CKT, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Gianpaolo Rando

   Competing interests

   The authors declare that no competing interests exist.

3. Nourhène Khaled

   Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

   Contribution

   NK, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

4. Alexandra Montagner

   UMR 1331 ToxAlim Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France

   Contribution

   AM, Contributed to the experiments, Data acquisition, Revised the manuscript, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

5. Nicolas Leuenberger

   Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

   Contribution

   NL, Contributed to the experiments, Data acquisition, Revised the manuscript, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

6. Justine Bertrand-Michel

   IFR 150 Plateforme Metatoul, Institut Fédératif de Recherche Bio-Médicale de Toulouse INSERM U563, Toulouse, France

   Contribution

   JB-M, Contributed to the experiments, Data acquisition, Revised the manuscript, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Eeswari Paramalingam

   Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore

   Contribution

   EP, Contributed to the experiments, Data acquisition, Revised the manuscript, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

8. Hervé Guillou

   UMR 1331 ToxAlim Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France

   Contribution

   HG, Contributed to the experiments, Data acquisition, Revised the manuscript, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

9. Walter Wahli

   1. Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
   2. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
   3. UMR 1331 ToxAlim Research Centre in Food Toxicology, INRA, Université de Toulouse, Toulouse, France

   Contribution

   WW, Designed the study and was involved in all aspects of the experiments, Wrote the manuscript, Supervised this study, Analysis and interpretation of data

   For correspondence

   walter.wahli@ntu.edu.sg

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-5966-9089

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