Maternal Lipid Metabolism Directs Fetal Liver Programming following Nutrient Stress

Abstract

SUMMARY The extreme metabolic demands of pregnancy require coordinated metabolic adaptations between mother and fetus to balance fetal growth and maternal health with nutrient availability. To determine maternal and fetal contributions to metabolic flexibility during gestation, pregnant mice with genetic impairments in mitochondrial carbohydrate and/or lipid metabolism were subjected to nutrient deprivation. The maternal fasting response initiates a fetal liver transcriptional program marked by upregulation of lipid- and peroxisome proliferator-activated receptor alpha (Pparα)-regulated genes. Impaired maternal lipid metabolism alters circulating lipid metabolite concentrations and enhances the fetal response to fasting, which is largely dependent on fetal Pparα. Maternal fasting also improves metabolic deficits in fetal carbohydrate metabolism by increasing the availability of alternative substrates. Impairment of both carbohydrate and lipid metabolism in pregnant dams further exacerbates the fetal liver transcriptional response to nutrient deprivation. Together, these data demonstrate a regulatory role for mitochondrial macronutrient metabolism in mediating maternal-fetal metabolic communication, particularly when nutrients are limited.

mTORC1 activation is not sufficient to suppress hepatic PPARα signaling or ketogenesis

“…NADH) the redirection of carbon skeletons towards gluconeogenesis (16). Given the important roles of hepatic fatty acid ßoxidation, we were surprised that mice with a loss of hepatic Cpt2 could maintain normal blood glucose but a loss of ketone body production following a 24hr fast (5,11,12). This is possible due to both cell autonomous and non-cell autonomous compensatory processes to remarkably maintain systemic homeostasis such as the up-regulation of gluconeogenesis in the kidney (5,17).…”

“…The loss of hepatic fatty acid oxidation genes results in an increased expression of hepatic fatty acid catabolic gene expression as the mice attempt to compensate for a defect in the pathway (9,10). The liver-specific deletion of Carnitine Palmitoyltransferase 2 (Cpt2 L-/mice), an obligate enzyme in mitochondrial long chain fatty acid ß-oxidation, results in a robust increase in a procatabolic fasting-induced Pparα transcriptional program (5,11,12). This is likely mediated by the increased availability of lipids that can ligand and induce Pparα-dependent transcription.…”

“…J o u r n a l P r e -p r o o f RESULTS Generation of mice with a combined liver-specific loss of fatty acid oxidation and activation of mTorc1. Previously, we showed that the loss of hepatic fatty acid oxidation by the liverspecific deletion of Carnitine Palmitoyltransferase 2 (Cpt2 L-/mice) resulted in a robust increase in a pro-catabolic fasting-induced Pparα dependent transcriptional program (5,11,12). Alternatively, it has been previously reported that activating mTorc1 signaling in the liver by removing its negative regulator Tsc1 (Tsc1 L-/mice) was required for fasting-induced Pparα signaling and ketogenesis (3).…”

Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease

“… 2 ; Wako Diagnostics), and TG (TR0100, MilliporeSigma). Tissue TG levels were measured as previously reported ( 32 ). Lipid peroxidation in liver tissue was measured with thiobarbituric acid reactive substances (TBARS) assay (Cayman Chemical) as directed by the manufacturer.…”

Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan

“…Notably, mouse studies indicate that alterations in maternal diet may be able to partially compensate for offspring MPC deficiencies in utero. For example, a ketogenic diet [ 12 ] or maternal fasting [ 15 ], which shifts metabolic substrate use from glucose and thus pyruvate to greater use of either fatty acids or ketones, attenuates some defects in pyruvate metabolism, such as lactic acidosis, in mice with Mpc1 -mutated fetuses. A ketogenic diet also rescues many of the developmental defects observed in utero.…”