Maternal hypothalamic response to LPS is inhibited by pregnancy and remains unchanged in multiparity-associated obesity.

Multiparity increases the risk of obesity in both humans and animal models. We have previously discovered an increase in proinflammatory cytokine mRNA levels in adipose tissues, placentas, and livers of females in their fourth vs first pregnancy, regardless of age or adiposity, suggesting an increased inflammatory state with subsequent pregnancies. The goal of the current study was to determine whether similar changes in inflammatory markers would be evident in the maternal brain in a fourth pregnancy compared to a first pregnancy, either at baseline or in response to an immune challenge. Females were studied at pregnancy 18.5 days post-conception (dpc; P), at 25 days postpartum (dpp; PP), and in age-matched never pregnant (NP) mice. Pregnant multiparous females had increased fat masses compared to females in their first pregnancy, and increased mRNA levels of Il6, Il1β, and Tnfα in the retroperitoneal and ovarian adipose tissue depots. While mRNA levels of hypothalamic proinflammatory genes were mostly similar in females at baseline, regardless of first vs fourth pregnancy or pregnancy status, LPS markedly induced inflammation in NP and PP females compared to P females; genes affected included Cxcl10, Ccl2, Il1β, Il6, Tnfα, Socs3, Nfkb, Tlr2, and Tgfβ. The response of Cxcl10, Socs3, and Tlr2 to LPS was greater in NP than PP females. Unlike the proinflammatory genes, a few noninflammatory genes had an age effect (mainly decreased with age), but not a pregnancy effect, including Dlg4, Dnmt1/3, Esr1, and Ki67. Overall, pregnant females were protected from a proinflammatory insult compared to NP and PP females.