Circulating leptin and NF‐κB activation in peripheral blood mononuclear cells across the menstrual cycle

Abstract

Using the menstrual cycle as a model, this study focused on longitudinal changes and associations within a physiological network known to play a role in female fertility, including, as biologically active nodes, NF-jB, leptin and adiponectin, bcarotene, adipose tissue, and progesterone. In 28 women, leptin, adiponectin, b-carotene, and progesterone concentrations, NF-jB p65 and p50 activation in peripheral blood mononuclear cells (known to possess estrogen, progesterone and leptin receptors), total body fat (TBF) and subcutaneous adipose tissue (SAT) mass were determined at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. Leptin and adiponectin concentrations were higher, while NF-jB p65 activation was lower at T3 compared with T1. NF-jB p65 activation was inversely related to leptin concentrations at T1, T3, and T4. b-Carotene was inversely related to leptin (T1,T2,T4) and SAT (T1,T3,T4). NF-jB p50 activation was inversely related to TBF (T4) and SAT (T3,T4), and leptin was positively related to TBF and SAT (T1-T4). Progesterone was inversely related to leptin (T2,T3), adiponectin (T3), TBF (T3,T4), and SAT (T2,T3,T4). By providing evidence of luteal phase-specific reduced NF-jB p65 activation in women under physiological conditions, this study bridges the gap between existing evidence of a Th1-Th2 immune response shift induced by reduced NF-jB p65 activation and a Th1-Th2 shift previously observed at luteal phase. For the first time, inverse regressions suggest inhibitory effects of leptin on NF-jB p65 activation at luteal phase, along with inhibitory effects of

Physiological predictors of leptin vary during menses and ovulation in healthy women

“…Previous studies have determined that there are higher leptin levels during the luteal phase than the follicular phase, and that leptin levels rise steadily throughout the menstrual cycle [8,27]. We found that leptin levels were higher (albeit not significantly so) during ovulation than during menses [8], but we further found that estradiol was a stronger predictor during menses than at ovulation.…”

Progesterone-associated arginine decline at luteal phase of menstrual cycle and associations with related amino acids and nuclear factor kB activation

“…As the second important finding for the proposed role of arginine in modulating immune functions for successful pregnancy, plasma arginine concentrations for the first time were identified, by using regression analysis, as predictors of the activation of the NF-κB p65 subunit in PBMC at late follicular phase, linking arginine to the role of NF-κB p65 in the immune response shift required for materno-fetal immune tolerance. So far, NF-κB p65 activation in PBMC was shown to be decreased in pregnancy [ 20 ], as well as to decline from follicular to luteal phase of the menstrual cycle, while associations with arginine or progesterone concentrations have not been reported [ 29 ].…”

“…For determination of the activation of the NF- κ B p65 subunit, blood was collected in BD Vacutainer® CPT TM tubes (Becton, Dickinson and Company, Franklin Lakes, NJ, USA), and PBMC were isolated. Whole cell extracts were prepared using Active Motif TM nuclear extract kit (Active Motif, Carlsbad, CA, USA), and activation of NF-κB p65 containing dimers was determined based on selective binding of activated dimers to their consensus binding sites in immobilized oligonucleotides, using the TransAM® NF-κB family kit (Active Motif, Carlsbad, CA, USA), as recently described in detail [ 29 ].…”

“…Arginine exerts immune modulatory functions [ 22 , 23 ] by specifically up-regulating the expression of the T cell antigen receptor zeta chain (CD3ζ) [ 24 , 25 ], which in turn induces the TCR-to-nuclear factor kappa B (NF-κB) pathway [ 26 ], resulting in nuclear translocation of NF-κB [ 27 ], known as a central regulator of immune responses [ 28 ]. The activation of the NF-κB p65 subunit in peripheral blood mononuclear cells (PBMC) was reduced not only during pregnancy, but also already at luteal phase [ 20 , 29 ], along with a shift from T H 1- to T H 2-type cytokines [ 19 – 21 ], which has been implicated in the preparation of the endometrium for implantation [ 30 , 31 ].…”

Variation of Leptin During Menstrual Cycle and Its Relation to the Hypothalamic–Pituitary–Gonadal (HPG) Axis: A Systematic Review

“…Of the included studies, 18 have shown significant changes in leptin level across different phases of the menstrual cycle [16][17][18][19][20]23,24,[31][32][33][34][35][36][37][38][39]41,43 (Table 1), while four studies reported no changes in leptin throughout the menstrual cycle 27,28,42,44 (Table 2). Most of the studies reported significant changes in leptin and showed a steady increment from the lowest level at the early follicular phase to its peak at late luteal phase-except two studies, where leptin peak was detected at the mid-cycle phase near the time of LH surge.…”