Instituto Maimónides de Investigation Biomédica de Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Córdoba and Hospital Universitario Reina Sofia, 14004 Córdoba, Spain.
Instituto Maimónides de Investigation Biomédica de Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Córdoba and Hospital Universitario Reina Sofia, 14004 Córdoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 14004 Córdoba, Spain.
Cell Metab. 2020 Dec 1;32(6):951-966.e8. doi: 10.1016/j.cmet.2020.10.001. Epub 2020 Oct 19.
Childhood obesity, especially in girls, is frequently bound to earlier puberty, which is linked to higher disease burden later in life. The mechanisms underlying this association remain elusive. Here we show that brain ceramides participate in the control of female puberty and contribute to its alteration in early-onset obesity in rats. Postnatal overweight caused earlier puberty and increased hypothalamic ceramide content, while pharmacological activation of ceramide synthesis mimicked the pubertal advancement caused by obesity, specifically in females. Conversely, central blockade of de novo ceramide synthesis delayed puberty and prevented the effects of the puberty-activating signal, kisspeptin. This phenomenon seemingly involves a circuit encompassing the paraventricular nucleus (PVN) and ovarian sympathetic innervation. Early-onset obesity enhanced PVN expression of SPTLC1, a key enzyme for ceramide synthesis, and advanced the maturation of the ovarian noradrenergic system. In turn, obesity-induced pubertal precocity was reversed by virogenetic suppression of SPTLC1 in the PVN. Our data unveil a pathway, linking kisspeptin, PVN ceramides, and sympathetic ovarian innervation, as key for obesity-induced pubertal precocity.
儿童肥胖症，尤其是女孩，通常与青春期提前有关，而青春期提前与日后更高的疾病负担有关。这种关联的机制仍不清楚。在这里，我们发现脑神经酰胺参与了女性青春期的调控，并导致了早期肥胖症大鼠青春期的改变。出生后超重导致青春期提前，并增加了下丘脑神经酰胺含量，而神经酰胺合成的药理学激活模拟了肥胖引起的青春期提前，特别是在女性中。相反，中枢阻断从头合成神经酰胺会延迟青春期，并防止促性腺激素释放激素 kisspeptin 的作用。这种现象似乎涉及一个包含室旁核 (PVN) 和卵巢交感神经支配的回路。早期肥胖症增强了 SPTLC1 的表达，这是神经酰胺合成的关键酶，并且加速了卵巢去甲肾上腺素能系统的成熟。反过来，通过在 PVN 中病毒遗传抑制 SPTLC1，肥胖引起的青春期早熟得到了逆转。我们的数据揭示了一条通路，将 kisspeptin、PVN 神经酰胺和卵巢交感神经支配联系起来，作为肥胖引起的青春期早熟的关键。
