Pregnancy-specific Adaptations in Leptin and Melanocortin Neuropeptides in Early Human Gestation

Introduction: Pregnancy is characterized by increased appetitive drive beginning early in gestation, yet the central mechanisms underlying this adaptation are poorly understood in humans. To elucidate central mechanisms underlying appetite regulation in early pregnancy, we examine plasma and cerebrospinal fluid (CSF) leptin and Agouti-related peptide (AgRP) as well as CSF proopiomelanocortin (POMC) as surrogates for brain melanocortin activity. Methods: Plasma leptin, soluble leptin receptor, AgRP, and CSF leptin, POMC, and AgRP were collected from pregnant women before cerclage placement (16.6 +/- 1.1 weeks; N = 24), scheduled cesarean section (39.2 +/- 0.2 weeks; N = 24), and from nonpregnant controls (N = 24), matched for age and body mass index. Results: Plasma leptin was 1.5 times higher in pregnancy vs controls (P = 0.01), but CSF leptin did not differ. CSF/plasma leptin percentage was lower in early pregnancy vs controls (0.8 +/- 0.1 vs 1.7 +/- 0.2; P < 0.0001) and remained unchanged at term (0.9 +/- 0.1), supporting a decrease in leptin transport into CSF in pregnancy. Plasma AgRP, a peripheral biomarker of the orexigenic hypothalamic neuropeptide, was higher in early pregnancy vs controls (95.0 +/- 7.8 vs 67.5 +/- 5.3; P = 0.005). In early gestation, CSF AgRP did not differ from controls, but CSF POMC was 25% lower (P = 0.006). In contrast, at term, CSF AgRP was 42% higher vs controls (P = 0.0001), but CSF POMC no longer differed. Overall, the CSF AgRP/POMC ratio was 1.5-fold higher in early pregnancy vs controls, reflecting a decrease in melanocortin tone favoring appetitive drive. Conclusions: Pregnancy-specific adaptions in the central regulation of energy balance occur early in human gestation and are consistent with decreased leptin transport into brain and resistance to the effects of leptin on target melanocortin neuropeptides.