179 - Maternal diet-induced obesity in mice is associated with altered hypothalamic TNF-α expression in female, but not male, offspring

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 179
Publication Number: 179.403

Lauren A. Buckley, University of Minnesota Medical School, Minneapolis, MN, United States; Debra Kulhanek, University of Minnesota Medical School, Minneapolis, MN, United States; Juan E. Abrahante Llorens, University of Minnesota Medical School, Minneapolis, MN, United States; Theresa L. Powell, University of Colorado, Aurora, CO, United States; Thomas Jansson, University of Colorado School of Medicine, Aurora, CO, United States; Raghavendra Rao, University of Minnesota Medical School, Minneapolis, MN, United States; Tate Gisslen, University of Minnesota, Edina, MN, United States; Megan Paulsen, University of Minnesota Medical School, Minneapolis, MN, United States

Presenting Author(s)

Megan Paulsen, MD (she/her/hers)

Assistant Professor
University of Minnesota Medical School
Minneapolis, Minnesota, United States

First Author(s)

LB

Lauren A. Buckley, MD (she/her/hers)

Assistant Professor - Pediatrics
University of Minnesota Medical School
University of Minnesota
Minneapolis, Minnesota, United States

Background:

The obesity epidemic is a major public health crisis affecting more than 25% of American children. Maternal obesity is a significant risk factor for offspring obesity, mediated in part by in utero developmental programming of energy metabolism. Our group has previously shown that rat pups exposed to maternal obesity have higher adiposity and altered hypothalamic energy metabolism. Obesity-derived inflammatory stress occurring during key periods of development is a potential mechanism of hypothalamic-mediated programming of obesity.

Objective:

Describe the longitudinal effect of maternal diet-induced obesity on markers of hypothalamic inflammation using an established mouse model.

Design/Methods: C57Bl/6J female (n=36) mice were fed a control (CON) or high-fat-high-sugar, obesity-inducing (OB) diet. Once OB females gained 25% of their body weight, they were age matched with CON females and mated with CON males. Dams were maintained on their respective diets during pregnancy and lactation. Male and female offspring were studied in the neonatal period on postnatal day 9 (PN9, n=33) and in adulthood at 6 months (6M, n=30). Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) were measured in plasma by ELISA (dams, PN9) and in hypothalalmus by RT-qPCR (PN9, 6M). A separate group of offspring were challenged with OB diet and studied at 4 months (4M, n=31) with hypothalamic RNA-sequencing. Differentially expressed genes were analyzed via edgeR and Ingenuity Pathway Analysis. Group differences were measured by unpaired t-tests and relationships between variables were measured by Pearson’s correlation coefficient (r); p< 0.05 was considered significant.

Results: Plasma cytokines did not differ between CON and OB groups in dams or offspring at PN9. Hypothalamic TNF-α expression was downregulated by 31% in neonatal (PN9) female OB offspring and 37% in adult (6M) female offspring of OB dams. In diet-challenged adult (4M) female offspring of OB dams, RNA-sequencing detected 18.9-fold higher TNF-α expression compared to diet-challenged offspring of CON dams. TNF-α expression did not differ between any of the male offspring groups. IL-6 and IL-1β expression did not differ between diet groups in males or females. Maternal caloric intake (r = -0.70) and fat intake (r = -0.70) were strongly, inversely correlated with neonatal hypothalamic TNF-α expression in females but not in males.

Conclusion(s):

Maternal diet-induced obesity is associated with dysregulated TNF-α mRNA expression in female hypothalamus longitudinally. Substantial alteration in TNF-α expression pattern is observed in diet-challenged female offspring.