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Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model
Derek O'Neil1, Hector Mendez-Figueroa, Toni-Ann Mistretta
1Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
In our primate model of maternal high fat diet exposure, we have described that fetal epigenomic modifications to the peripheral circadian Npas2 are associated with persistent alterations in fetal hepatic metabolism and non-alcoholic fatty liver. As the interaction of circadian response with metabolism is not well understood, we employed a murine knockout model to characterize the molecular mechanisms with which Npas2 reprograms the fetal hepatic metabolic response. cDNA was generated from Npas2-/- and +/+ (wild type) livers at day 2 (newborn) and at 25 weeks (adult) of life. Newborn samples were analyzed by exon array (n = 3/cohort). Independent pathway analysis software determined that the primary dysregulated pathway(s) in the Npas2-/- animals uniformly converged on lipid metabolism. Of particular interest, Ppargc1a, which integrates circadian and metabolism pathways, was significantly (p < .01) over expressed in newborn (1.7 fold) and adult (1.8 fold) Npas2-/- animals. These findings are consistent with an essential role for Npas2 in programming the peripheral circadian response and hepatic metabolism, which has not been previously described.
Insights
The circadian gene Npas2 is crucial for programming fetal liver metabolism. Its absence leads to lipid metabolism disruptions and fatty liver disease, highlighting a novel role in metabolic health.
Area of Science:
- * Chronobiology
- * Metabolic Disease Research
- * Epigenetics
Background:
- * Maternal high-fat diet exposure in primates causes fetal epigenomic changes to the peripheral circadian Npas2.
- * These epigenetic modifications are linked to persistent alterations in fetal hepatic metabolism and non-alcoholic fatty liver disease.
- * The intricate interaction between circadian rhythms and metabolic regulation remains incompletely understood.
Purpose of the Study:
- * To elucidate the molecular mechanisms by which Npas2 influences fetal hepatic metabolic programming.
- * To characterize the role of Npas2 in regulating lipid metabolism and circadian pathways in the liver.
Main Methods:
- * Utilized a murine knockout model (Npas2-/-) and wild-type (+/+) littermates.
- * Generated complementary DNA (cDNA) from liver tissues of newborn (day 2) and adult (25 weeks) mice.
- * Performed exon array analysis on newborn samples (n=3/cohort) followed by pathway analysis.
Main Results:
- * Pathway analysis revealed that lipid metabolism pathways were uniformly dysregulated in Npas2-/- mice.
- * The gene Ppargc1a, a key integrator of circadian and metabolic pathways, was significantly overexpressed (p < .01) in both newborn (1.7-fold) and adult (1.8-fold) Npas2-/- animals.
- * These findings indicate a critical role for Npas2 in metabolic regulation.
Conclusions:
- * Npas2 plays an essential role in programming the peripheral circadian response and hepatic metabolism.
- * Disruption of Npas2 function leads to significant alterations in lipid metabolism, potentially contributing to non-alcoholic fatty liver disease.
- * This study reveals a previously undescribed function of Npas2 in metabolic health.