Neonatal-Perinatal Medicine Fellow University of Minnesota University of Minnesota Minneapolis, Minnesota, United States
Background: Perinatal inflammation, such as maternal obesity or early onset sepsis, is associated with adult obesity. Sex-specific developmental programming mechanisms that explain the association between perinatal inflammation and offspring obesity are poorly characterized. The hypothalamus, the master regulator of energy homeostasis, is sensitive to inflammation induced changes during development.
Objective: Investigate sex differences in hypothalamic appetite signaling following perinatal inflammation in neonatal C57Bl/6J mice.
Design/Methods: Female C57Bl/6J mice (n=14) were fed high-fat-high-sugar (HFHS) or control (CON) diet. Up to two male and female pups per litter (M: n= 18; F: n=13) received an intraperitoneal injection of lipopolysaccharide (LPS, 1 µg/g) or saline (SAL) on postnatal (PN) day 7. At PN9, key targets of inflammation (Il1β, Il6, Tlr4, Tnfα, Ιkkα, Crp)were measured in liver and hypothalamus and key targets of appetite signaling (Pomc, Npy, Nr3c1, Insr, Lepr) were measured in hypothalamus by RT-qPCR. Group differences between dams (CON, HFHS) were analyzed by unpaired t-test and neonatal pups by two-way ANOVA (CON-SAL, CON-LPS, HFHS-SAL, HFHS-LPS). Pearson correlation coefficient (r) was used to measure linear correlation. A p</i>-value <0.05 was considered significant. Males and females were analyzed separately.
Results: HFHS dams were 12% heavier and had 2.1-fold increased caloric intake compared to CON dams. PN9 pup weight did not differ between groups. At PN9, dam HFHS diet was associated with downregulation of hypothalamic leptin receptor (-67%, Lepr), glucocorticoid receptor (-53%, Nr3c1), and hunger neuropeptide (-90%, Npy) in males. Dam HFHS diet caused 65% lower hypothalamic Il1βin males. Females exposed to maternal HFHS diet trended towards lower hepatic Il6 (-47%, p=0.09). LPS caused downregulation of hepatic Il6 in both sexes (M: -86%, F: -48%). Males treated with LPS trended towards increased hepatic Tlr4 (+58%, p=0.08); females trended towards decreased Il1b (-66%, p=0.09) and Ikka (-66%, p=0.07). There was no correlation between hypothalamic and hepatic inflammatory targets. PN9 hepatic Crp was correlated with both hypothalamic inflammation and appetite signaling: Il6 (r=+0.60), Npy (r=+0.66), Pomc (r=-0.43), InsR,(r=+0.72), LepR (r=+0.60) and Nr3c1 (r=+0.70). Conclusion(s): Maternal overnutrition and postnatal LPS caused sex- and tissue-specific inflammatory changes in offspring hypothalamus and liver.
Authors/Institutions: Lauren Buckley, University of Minnesota, Falcon Heights, Minnesota, United States; Debra Kulhanek, University of Minnesota, St. Paul, Minnesota, United States; Garima Singh, University Of Minnesota, Minneapolis, Minnesota, United States; Tate Gisslen, University of Minnesota, Minneapolis, Minnesota, United States; Megan Paulsen, University of Minnesota, Minneapolis, Minnesota, United States
