Cerebrospinal fluid levels of leptin, proopiomelanocortin, and agouti-related protein in human pregnancy: evidence for leptin resistance

Abstract

Context: Leptin suppresses appetite by modulating the expression of hypothalamic neuropeptides including proopiomelanocortin (POMC) and agouti-related peptide (AgRP). Yet during pregnancy, caloric consumption increases despite elevated plasma leptin levels.

Design and participants: To investigate this paradox, we measured leptin and soluble leptin receptor in plasma and leptin, POMC, and AgRP in cerebrospinal fluid (CSF) from 21 fasting pregnant women before delivery by cesarean section at a university hospital and from 14 fasting nonpregnant women.

Results: Prepregnancy body mass index was 24.6 ± 1.1 (SE) vs. 31.3 ± 1.3 at term vs. 26.5 ± 1.6 kg/m(2) in controls. Plasma leptin (32.9 ± 4.6 vs. 16.7 ± 3.0 ng/ml) and soluble leptin receptor (30.9 ± 2.3 vs. 22.1 ± 1.4 ng/ml) levels were significantly higher in pregnant women. However, mean CSF leptin did not differ between the two groups (283 ± 34 vs. 311 ± 32 pg/ml), consistent with a relative decrease in leptin transport into CSF during pregnancy. Accordingly, the CSF/plasma leptin percentage was 1.0 ± 0.01% in pregnant subjects vs. 2.1 ± 0.2% in controls (P < 0.0001). Mean CSF AgRP was significantly higher in pregnant subjects (32.3 ± 2.7 vs. 23.5 ± 2.5 pg/ml; P = 0.03). Mean CSF POMC was not significantly different in pregnant subjects (200 ± 13.6 vs. 229 ± 17.3 fmol/ml; P = 0.190). However, the mean AgRP/POMC ratio was significantly higher among pregnant women (P = 0.003), consistent with an overall decrease in melanocortin tone favoring increased food intake during pregnancy.

Conclusions: These data demonstrate that despite peripheral hyperleptinemia, positive energy balance is achieved during pregnancy by a relative decrease in central leptin concentrations and resistance to leptin's effects on target neuropeptides that regulate energy balance.

Figures

Fig. 1.

Plasma leptin concentration (A), CSF leptin concentration (B), and CSF/Plasma leptin percentage (C) in pregnant and nonpregnant subjects at term. *, P < 0.0001.

Fig. 2.

A, Soluble leptin receptor (OB-Re) concentrations in nonpregnant and pregnant subjects. B, Simple linear regression of the OB-Re concentration as a function of the plasma leptin concentration in nonpregnant and pregnant subjects.

Fig. 3.

CSF AgRP (A), CSF POMC (B), and the CSF AgRP/POMC Ratio (C) in nonpregnant and pregnant subjects. *, P < 0.003.

Fig. 4.

A, HPLC of a CSF pool from nonpregnant subjects with fractions assayed for AgRP by ELISA. Two peaks of immunoactivity were seen corresponding to AgRP (83–132) and full-length AgRP standards (arrows). The solid line represents the actual AgRP ELISA values. The dashed line represents a correction for values eluting in the position of AgRP (83–132) for the 17% crossreactivity of AgRP (83–132) in the AgRP ELISA. B, G-75 Sephadex chromatography of CSF from a nonpregnant subject with fractions assayed for POMC by ELISA. Arrows indicate the void volume and the elution positions of POMC and ACTH standards.