Hypothalamic Ceramides and the Ovarian Sympathetic System: At the Crossroads of Obesity and Puberty

Abstract

Childhood obesity has been linked to early puberty in girls but the mechanism(s) by which overnutrition triggers pubertal onset remain unclear. In a recent issue of Cell Metabolism, Heras et al., 2020 implicate a non-canonical central ceramide to ovarian sympathetic innervation pathway as a novel mediator of obesity-induced pubertal acceleration in female rats.

Figure 1.. Regulatory Pathways Governing Metabolic Control of Puberty Discerned from Rodent, Nonhuman Primate, and Human Studies

The hypothalamo-pituitary-gonadal axis: pulsatile hypothalamic secretion of GnRH into the hypophyseal-portal circulation drives pituitary gonadotropin (LH and FSH) secretion. Circulating LH and FSH in turn regulate ovarian sex steroid production and trigger ovulation. Upstream of GnRH, the kisspeptin-neurokinin B-dynorphin (KNDy) neurons from the ARC nucleus project to the GnRH terminals to coordinately regulate the pulsatile release of GnRH while kisspeptin neurons from the AVPV project to GnRH somas and orchestrate the pre-ovulatory LH surge in females (Navarro, 2020). The metabolic/energy sensors including mTOR, AMPK, SIRT, and leptin act either directly or indirectly on the ARC KNDy neurons, regulating GnRH neurosecretory activity based on the energy/nutrition status (Vazquez et al., 2019). Heras et al. implicate a novel central/ceramide pathway from the PVN that causes PP via ovarian sympathetic activation. In the periphery, excess adiposity increases production of aromatase from adipose tissue, induces insulin resistance, and lowers SHBG levels, leading to increased bioavailability of E2 to initiate premature thelarche (breast development) (Huang et al., 2020). Other unknown factors that may affect the pubertal timing via any of the pathways described above include ED chemicals and social-economic status. AMPK, AMP-activated protein kinase; ARC, arcuate; AVPV, anteroventral periventricular; CG, celiac ganglion; EED, embryonic ectoderm development; E2, estradiol; ED, endocrine disruptor; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; HPG, hypothalamic pituitary gonadal; KNDy, Kiss1, neurokinin B, and dynorphin; LH, luteinizing hormone; mTOR, mammalian target of rapamycin; POL2, DNA polymerase epsilon catalytic subunit A; PVN, periventricular nucleus; SIRT, sirtuin; SHBG, sex hormone binding globulin. Created with https://biorender.com/.