Inflammation as a Sex-Specific Mediator in the Relationship between Maternal and Offspring Obesity in C57Bl/6J Mice

Abstract

Maternal obesity is a well-established risk factor for offspring obesity development. The relationship between maternal and offspring obesity is mediated in part by developmental programming of offspring metabolic circuitry, including hypothalamic signaling. Dysregulated hypothalamic inflammation has also been linked to development of obesity. We utilized an established C57Bl/6J mouse model of high-fat, high-sugar diet induced maternal obesity to evaluate the effect of maternal obesity on systemic and hypothalamic TNF-α, IL-6, and IL-1β levels in neonatal and adult offspring. The offspring of dams with obesity demonstrated increased adiposity and decreased activity compared to control offspring. Maternal obesity was associated with decreased plasma TNF-α, IL-6 and IL-1β in adult female offspring and decreased plasma IL-6 in neonatal male offspring. Neonatal female offspring of obese dams had decreased TNF-α gene expression in the hypothalamus compared to control females, while neonatal and adult male offspring of obese dams had decreased IL-6 gene expression in the hypothalamus compared to control males. In summary, our results highlight important sex differences in the inflammatory phenotype of offspring exposed to maternal obesity. Sex-specific immunomodulatory mechanisms should be considered in future efforts to develop therapeutic interventions for obesity prevention and treatment.

Keywords: energy metabolism; fetal development; hypothalamus; inflammation; obesity; sex differences.

Figure 1

Characteristics of dams fed CON or OB diets. (a) Body weights at mating and weaning were significantly higher in OB versus CON dams. (b–d) Plasma cytokines measured on postnatal day 21 (TNF-α, IL-6, IL-1β) did not significantly differ between CON and OB dams. Results expressed as mean ± SEM; significance determined by unpaired t-test, * p < 0.05, ** p < 0.01. Gray bars: CON. Red bars: OB. N = 9–10/group.

Figure 2

Maternal obesity alters offspring energy balance. (a) OB males are heavier than CON males, and (b) OB females have increased adiposity compared to CON females. (c,d) Energy intake and BMR are similar between groups. (e) OB female offspring have decreased activity compared to CON females. Results expressed as mean ± SEM; significance determined by unpaired t-test with males and females analyzed separately. * p < 0.05. Open triangles: female offspring. Open squares: male offspring. Gray bars: CON offspring. Red bars: OB offspring. N = 8/group/sex.

Figure 3

Maternal obesity is associated with decreased plasma cytokine levels in adult female offspring and decreased plasma IL-6 in neonatal male offspring. Plasma concentrations of (a) IL-1β, (b) TNF-α, and (c) IL-6 measured in neonatal and adult offspring of CON and OB dams. Results expressed as mean ± SEM; significance determined by unpaired t-test, * p < 0.05. Open triangles: female offspring. Open squares: male offspring. Gray bars: CON offspring. Red bars: OB offspring. N = 6–8/group.

Figure 4

Maternal OB diet downregulates hypothalamic cytokine expression in neonatal and adult offspring in a sex-specific manner. Hypothalamic gene expression of (a) TNF-α, (b) IL-6, and (c) IL-1β measured in neonatal and adult offspring of CON and OB dams. Results expressed as mean ± SEM; significance determined by unpaired t-test, * p < 0.05. Open triangles: female offspring. Open squares: male offspring. Gray bars: CON offspring. Red bars: OB offspring. N = 6–10/group.