163 - Sex Specific Hypothalamic Mediated Adiposity in an Animal Model of Maternal-Offspring Obesity

Poster Number: 163
Publication Number: 163.311

Debra Kulhanek, University of Minnesota Medical School, minneapolis, MN, United States; Lauren Buckley, University of Minnesota Medical School, Minneapolis, MN, United States; Megan E. Paulsen, University of Minnesota Medical School, Minneapolis, MN, United States

Background: There is an established relationship between maternal-offspring obesity. Female offspring demonstrate higher sensitivity to stress induced hypothalamic programming compared to males. Sex specific hypothalamic mechanisms contributing to programming of adiposity in offspring is poorly characterized.

Objective: Describe sex differences in hypothalamic mediated adiposity in adult C57Bl/6 offspring exposed maternal obesity.

Design/Methods: C57Bl/6 female (Nf16) mice were fed a control (CON) and high-fat-high-sugar (OB) diet.  Offspring (Nf31, 48% Female) were challenged with an OB diet. In vivo body composition, energy intake/expenditure, and activity were assessed using metabolic chambers.  Plasma lipid/hormone concentrations were measured by ELISA. Hypothalamic transcriptome was measured by RNA-sequencing in Galaxy. Differentially expressed genes (DEGs) were analyzed in Ingenuity Pathway Analysis. The effect of sex was determined by Two-way ANOVA.  Differences between groups was measured by unpaired students t-test and relationships between variables by Pearson’s correlation coefficient; p< 0.05 was significant.

Results: OB offspring had higher fat mass (+31%, p< 0.001), lower fat free mass (-4%, p< 0.002), higher plasma leptin (+40%, p=0.03), and higher plasma insulin (+40%, p=0.07) levels vs CON. There were no differences in energy intake or basal metabolic rate between groups or sex. OB-F had 32% lower activity (vs CON-F, p=0.04). There were no differences in activity between male offspring.  10% of genes (38/417) associated with quantity of adipose tissue were differentially expressed in OB offspring (vs. CON) hypothalamus. 22 genes were expressed in OB-F but not OB-M vs. CON. 67% of DEGs in OB-F were upregulated vs. CON-F.  Apob (+215.2-Fold), Fabp2 (+131.1-Fold), Apoa4 (+28.3-Fold), and Tnf (+18.9-Fold) were genes with >10-Fold differential expression in OB-F (vs CON-F, p< 0.0001).  14 genes were expressed in OB-M but not OB-F vs.CON. 19% of DEGs were upregulated in OB-M vs CON-M. There were no genes in OB-M with >10-fold differential expression compared to CON-M. Hypothalamic Igfbp2 was lower in OB-F (-2.95-Fold) and OB-M (-1.81-Fold) compared to CON. There was an interaction between maternal diet and offspring sex in the expression of Lcn2 (M: -3.45-Fold, F: +2.95-Fold, p< 0.001). Maternal weight at conception (r=+0.45, p=0.01) and cholesterol level (r=+0.54, p=0.02) were directly correlated to adult offspring fat mass.Conclusion(s): While adult offspring exposed to maternal obesity share a common metabolic phenotype, hypothalamic mechanisms which may explain this relationship are sex specific.