162 - Obesity and Metabolic Disease in C57Bl/6 Dams is Associated with Abnormal Hypothalamic Energy Metabolism in Adult Offspring

Poster Number: 162
Publication Number: 162.311

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

Background: Maternal obesity and metabolic disease (OMD) is linked to the development of chronic disease in offspring. Iron (Fe) is essential to cellular metabolism and associated with brain development. The hypothalamus, the master regulator of energy homeostasis, is the major communicator between body and brain. Whether the link between maternal OMD and chronic disease in offspring is caused by programmed alterations in hypothalamic energy metabolism in unknown.

Objective: Describe maternal OMD induced changes to hypothalamic energy metabolism in adult offspring.

Design/Methods: C57Bl/6 female (Nf16) mice were fed a control (CON) and obesogenic (OB) diet. Offspring (Nf31, 48% Female) were challenged with an OB diet and studied at 4 months of age. Hypothalamic neurochemical profile was determined using in vivo 1H MR spectroscopy (MRS) at 9.4T. Hematocrit (Hct), plasma lipid/hormone concentrations, and tissue Fe concentration in the hypothalamus, hippocampus, cortex, and cerebellum were determined. Hypothalamic transcriptome was measured by RNA-sequencing in Galaxy. Differentially expressed genes (DEGs) were analyzed in Ingenuity Pathway Analysis. 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 dams were heavier (+10%, p=0.01), had normal glucose tolerance, and higher plasma cholesterol (+40%, p=0.008) and leptin (+2.2-Fold, p=0.02). Hct did not differ between groups. Fe was increased in cerebellum (+44%, p< 0.01), cortex (+28%, p=0.06), and hypothalamus (+45%, p=0.09) in the OB group. MRS showed OB offspring had lower hypothalamic lactate (-11%, p=0.05) and higher phosphocreatine/creatine (PCr/Cr) ratio (+23%, p=0.04) suggesting reduced hypothalamic neuronal activity. Other metabolites were not altered. Oxidative phosphorylation (52% DEGs, p< 0.0001) was the canonical pathway most altered in the hypothalamus of OB offspring (vs CON). Genes involved in mitochondrial dysfunction (39% DEGs) were differentially expressed in OB offspring (vs CON, p< 0.001). 133 genes involved in nervous system development and function were differentially expressed in OB offspring (vs CON). Maternal fat (r=-0.48, p=0.02) and sucrose (r=-0.49, p=0.02) consumption, cholesterol (r=-0.57, p=0.04), and leptin (r=-0.49, p=0.02) were associated with offspring hypothalamic lactate concentration.Conclusion(s): Maternal OMD during pregnancy alters hypothalamic cellular metabolism in offspring. Neuroprotective interventions may reverse adverse programming effects in offspring exposed to maternal OMD.